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In the center of the city, in the center of life, with passion for care Serge Rozenberg CHU St Pierre VUB-ULB Belgium [email protected] Clinical overview of conjugated estrogens/bazedoxifene (CE/BZA) BMS 14.11.2015

Serge Rozenberg CHU St Pierre VUB-ULB Belgium serge ...menopausesociety.be/upl_docs/en/clinical-overview-of-conjugated... · Serge Rozenberg CHU St Pierre VUB-ULB Belgium ... Research

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In the center of the city in the center of life with passion for care

Serge Rozenberg CHU St Pierre VUB-ULB Belgium

serge_rozenbergstpierre-brube

Clinical overview of conjugated

estrogensbazedoxifene (CEBZA)

BMS 14112015

Conflict of interest amp Disclosure

Conflicts of interest nil

Disclosure SR

Research funding IRIS- King Baudouin Fondation Vesale research Foundation Amgen MSD

Speakers bureau ampor Advisory Boards

Abbot Pfizer Will Gedeon Richter MSD Amgen

1 Kagan R J Womenrsquos Health (Larchmt) 2012

the OPTIMAL Menopausal Therapy

should demonstrate1

ndash Favorable safety and tolerability profile

ndash Relief of menopausal symptoms

ndash Prevention of osteoporosis CVD Cognitive function

ndash No stimulation of the endometrium breast and ovary

1 Kagan R J Womenrsquos Health (Larchmt) 2012

the OPTIMAL Menopausal Therapy

should demonstrate1

ndash Favorable safety and tolerability profile

ndash Relief of menopausal symptoms

ndash Prevention of osteoporosis CVD Cognitive function

ndash No stimulation of the endometrium breast and ovary

Variations in Associated Breast Cancer Risk Between CE alone and

CEMPA

Cumulative hazards

adjusted for age and

raceethnicity for

invasive breast cancer

by randomization

assignment in the WHI

CE-alone and CEMPA

trials

Anderson GL et al Lancet

Oncol 2012

0 0

1 2 3 4 5 6 7 8 9 10 11 12 13

001

002

003

004

005

Cu

mu

lati

ve

ha

za

rd

Time since randomization (years)

CEMPA

Placebo (in CEMPA arm)

HR 125 (95 CI 107ndash146)

CE alone

Placebo (in CE-alone arm)

HR 077 (95 CI 062ndash095)

CEMPA

CE alone

Placebo (CE-alone)

Placebo (CEMPA)

Estrogen only therapy

Endometrial cancer

Hysterectomy specimen showing cancer invading myometrium

following unopposed estrogen therapy for 15 years

Courtesy Dr David Sturdee

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone1-3

bull This means that progestins are not needed

From the Womenrsquos Health Initiative to the combination

of estrogen and selective estrogen receptor

modulators to avoid progestin addition

bull Marie-Ceacutecile Valera Pierre Gourdy Florence Treacutemolliegraveres Jean-Franccedilois Arnal

bull Maturitas Volume 82 Issue 3 November 2015 Pages 274ndash277

bull

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Conflict of interest amp Disclosure

Conflicts of interest nil

Disclosure SR

Research funding IRIS- King Baudouin Fondation Vesale research Foundation Amgen MSD

Speakers bureau ampor Advisory Boards

Abbot Pfizer Will Gedeon Richter MSD Amgen

1 Kagan R J Womenrsquos Health (Larchmt) 2012

the OPTIMAL Menopausal Therapy

should demonstrate1

ndash Favorable safety and tolerability profile

ndash Relief of menopausal symptoms

ndash Prevention of osteoporosis CVD Cognitive function

ndash No stimulation of the endometrium breast and ovary

1 Kagan R J Womenrsquos Health (Larchmt) 2012

the OPTIMAL Menopausal Therapy

should demonstrate1

ndash Favorable safety and tolerability profile

ndash Relief of menopausal symptoms

ndash Prevention of osteoporosis CVD Cognitive function

ndash No stimulation of the endometrium breast and ovary

Variations in Associated Breast Cancer Risk Between CE alone and

CEMPA

Cumulative hazards

adjusted for age and

raceethnicity for

invasive breast cancer

by randomization

assignment in the WHI

CE-alone and CEMPA

trials

Anderson GL et al Lancet

Oncol 2012

0 0

1 2 3 4 5 6 7 8 9 10 11 12 13

001

002

003

004

005

Cu

mu

lati

ve

ha

za

rd

Time since randomization (years)

CEMPA

Placebo (in CEMPA arm)

HR 125 (95 CI 107ndash146)

CE alone

Placebo (in CE-alone arm)

HR 077 (95 CI 062ndash095)

CEMPA

CE alone

Placebo (CE-alone)

Placebo (CEMPA)

Estrogen only therapy

Endometrial cancer

Hysterectomy specimen showing cancer invading myometrium

following unopposed estrogen therapy for 15 years

Courtesy Dr David Sturdee

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone1-3

bull This means that progestins are not needed

From the Womenrsquos Health Initiative to the combination

of estrogen and selective estrogen receptor

modulators to avoid progestin addition

bull Marie-Ceacutecile Valera Pierre Gourdy Florence Treacutemolliegraveres Jean-Franccedilois Arnal

bull Maturitas Volume 82 Issue 3 November 2015 Pages 274ndash277

bull

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

1 Kagan R J Womenrsquos Health (Larchmt) 2012

the OPTIMAL Menopausal Therapy

should demonstrate1

ndash Favorable safety and tolerability profile

ndash Relief of menopausal symptoms

ndash Prevention of osteoporosis CVD Cognitive function

ndash No stimulation of the endometrium breast and ovary

1 Kagan R J Womenrsquos Health (Larchmt) 2012

the OPTIMAL Menopausal Therapy

should demonstrate1

ndash Favorable safety and tolerability profile

ndash Relief of menopausal symptoms

ndash Prevention of osteoporosis CVD Cognitive function

ndash No stimulation of the endometrium breast and ovary

Variations in Associated Breast Cancer Risk Between CE alone and

CEMPA

Cumulative hazards

adjusted for age and

raceethnicity for

invasive breast cancer

by randomization

assignment in the WHI

CE-alone and CEMPA

trials

Anderson GL et al Lancet

Oncol 2012

0 0

1 2 3 4 5 6 7 8 9 10 11 12 13

001

002

003

004

005

Cu

mu

lati

ve

ha

za

rd

Time since randomization (years)

CEMPA

Placebo (in CEMPA arm)

HR 125 (95 CI 107ndash146)

CE alone

Placebo (in CE-alone arm)

HR 077 (95 CI 062ndash095)

CEMPA

CE alone

Placebo (CE-alone)

Placebo (CEMPA)

Estrogen only therapy

Endometrial cancer

Hysterectomy specimen showing cancer invading myometrium

following unopposed estrogen therapy for 15 years

Courtesy Dr David Sturdee

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone1-3

bull This means that progestins are not needed

From the Womenrsquos Health Initiative to the combination

of estrogen and selective estrogen receptor

modulators to avoid progestin addition

bull Marie-Ceacutecile Valera Pierre Gourdy Florence Treacutemolliegraveres Jean-Franccedilois Arnal

bull Maturitas Volume 82 Issue 3 November 2015 Pages 274ndash277

bull

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

1 Kagan R J Womenrsquos Health (Larchmt) 2012

the OPTIMAL Menopausal Therapy

should demonstrate1

ndash Favorable safety and tolerability profile

ndash Relief of menopausal symptoms

ndash Prevention of osteoporosis CVD Cognitive function

ndash No stimulation of the endometrium breast and ovary

Variations in Associated Breast Cancer Risk Between CE alone and

CEMPA

Cumulative hazards

adjusted for age and

raceethnicity for

invasive breast cancer

by randomization

assignment in the WHI

CE-alone and CEMPA

trials

Anderson GL et al Lancet

Oncol 2012

0 0

1 2 3 4 5 6 7 8 9 10 11 12 13

001

002

003

004

005

Cu

mu

lati

ve

ha

za

rd

Time since randomization (years)

CEMPA

Placebo (in CEMPA arm)

HR 125 (95 CI 107ndash146)

CE alone

Placebo (in CE-alone arm)

HR 077 (95 CI 062ndash095)

CEMPA

CE alone

Placebo (CE-alone)

Placebo (CEMPA)

Estrogen only therapy

Endometrial cancer

Hysterectomy specimen showing cancer invading myometrium

following unopposed estrogen therapy for 15 years

Courtesy Dr David Sturdee

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone1-3

bull This means that progestins are not needed

From the Womenrsquos Health Initiative to the combination

of estrogen and selective estrogen receptor

modulators to avoid progestin addition

bull Marie-Ceacutecile Valera Pierre Gourdy Florence Treacutemolliegraveres Jean-Franccedilois Arnal

bull Maturitas Volume 82 Issue 3 November 2015 Pages 274ndash277

bull

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Variations in Associated Breast Cancer Risk Between CE alone and

CEMPA

Cumulative hazards

adjusted for age and

raceethnicity for

invasive breast cancer

by randomization

assignment in the WHI

CE-alone and CEMPA

trials

Anderson GL et al Lancet

Oncol 2012

0 0

1 2 3 4 5 6 7 8 9 10 11 12 13

001

002

003

004

005

Cu

mu

lati

ve

ha

za

rd

Time since randomization (years)

CEMPA

Placebo (in CEMPA arm)

HR 125 (95 CI 107ndash146)

CE alone

Placebo (in CE-alone arm)

HR 077 (95 CI 062ndash095)

CEMPA

CE alone

Placebo (CE-alone)

Placebo (CEMPA)

Estrogen only therapy

Endometrial cancer

Hysterectomy specimen showing cancer invading myometrium

following unopposed estrogen therapy for 15 years

Courtesy Dr David Sturdee

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone1-3

bull This means that progestins are not needed

From the Womenrsquos Health Initiative to the combination

of estrogen and selective estrogen receptor

modulators to avoid progestin addition

bull Marie-Ceacutecile Valera Pierre Gourdy Florence Treacutemolliegraveres Jean-Franccedilois Arnal

bull Maturitas Volume 82 Issue 3 November 2015 Pages 274ndash277

bull

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Estrogen only therapy

Endometrial cancer

Hysterectomy specimen showing cancer invading myometrium

following unopposed estrogen therapy for 15 years

Courtesy Dr David Sturdee

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone1-3

bull This means that progestins are not needed

From the Womenrsquos Health Initiative to the combination

of estrogen and selective estrogen receptor

modulators to avoid progestin addition

bull Marie-Ceacutecile Valera Pierre Gourdy Florence Treacutemolliegraveres Jean-Franccedilois Arnal

bull Maturitas Volume 82 Issue 3 November 2015 Pages 274ndash277

bull

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Endometrial cancer

Hysterectomy specimen showing cancer invading myometrium

following unopposed estrogen therapy for 15 years

Courtesy Dr David Sturdee

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone1-3

bull This means that progestins are not needed

From the Womenrsquos Health Initiative to the combination

of estrogen and selective estrogen receptor

modulators to avoid progestin addition

bull Marie-Ceacutecile Valera Pierre Gourdy Florence Treacutemolliegraveres Jean-Franccedilois Arnal

bull Maturitas Volume 82 Issue 3 November 2015 Pages 274ndash277

bull

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone1-3

bull This means that progestins are not needed

From the Womenrsquos Health Initiative to the combination

of estrogen and selective estrogen receptor

modulators to avoid progestin addition

bull Marie-Ceacutecile Valera Pierre Gourdy Florence Treacutemolliegraveres Jean-Franccedilois Arnal

bull Maturitas Volume 82 Issue 3 November 2015 Pages 274ndash277

bull

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

From the Womenrsquos Health Initiative to the combination

of estrogen and selective estrogen receptor

modulators to avoid progestin addition

bull Marie-Ceacutecile Valera Pierre Gourdy Florence Treacutemolliegraveres Jean-Franccedilois Arnal

bull Maturitas Volume 82 Issue 3 November 2015 Pages 274ndash277

bull

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Other combinations of an estrogen (E2) + a SERM studied have

not produced favorable results

bull Objective To compare effects of 52 weeksrsquo treatment with either raloxifene 60 mgday alone (RLX) or in combination with 17B-estradiol 1 mgday (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy Endometrial effect Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase Two women (328) in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy No one in RLX alone did

bull 1 Stovall D et al Menopause The Journal of The North American Menopause Society 2007

bull For the safety analyses data from women randomized before and after the protocol amendment were pooled which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

EFFICACY

VASOMOTOR

SYMPTOMS

SMART-2

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

DUAVIVE Efficacy for the Treatment of Moderate to

Severe VMS Associated With Menopause

14

1 Pinkerton JV et al Menopause 2009

Postmenopausal women

with a uterus

Age 42-64 year

(avg 53 yr)

(N=318)

DUAVIVE (CE 045BZA 20)

(n=127)

Placebo

(n=63)

bull 12-week randomized double-blind placebo-controlled study1

bull Inclusion criteria

‒ Postmenopausal women with an intact uterus

‒ Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

Change from baseline to

Weeks 4 and 12 in

bull Average daily number of

moderate to severe hot

flushes

bull Average daily severity

score of hot flushes

Primary End Points

Safety population (took at least one dose)

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Significant Reduction vs Placebo in

Average Daily Number of Hot Flushes

DUAVEE [package insert] New York NY Pfizer Inc 2013

ANCOVA=analysis of covariance

Reduction in average daily number of

moderate to severe hot flushes ndash primary end point

Ad

jus

ted

mean

ch

an

ge

fro

m b

aselin

edagger

Week 4 Week 12

ndash31

ndash27

Treatment

differencedagger ndash59

ndash28

ndash76

ndash49

Treatment

differencedagger

22

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Reduction in the Observed Average Daily Number

of Moderate to Severe Hot Flushes

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

change from baseline to week 12

74 for DUAVIVE

51 for placebo

Observed Average Daily Number of Hot Flushes

Ob

serv

ed a

vera

ge d

aily

nu

mb

er o

f m

od

erat

e to

sev

ere

ho

t fl

ush

es

0 1 2 3 4 5 6 7 8 9 10 12 0 1

11

2

4 3

6 5

7 8 9

10

28

54

DUAVIVE (n=122) Placebo (n=62)

Weeks

Primary analysis showed statistically significant separation at weeks 4 and 12

Average daily number of hot flushes from baseline to week 12

103 to 28 for DUAVIVE

105 to 54 for placebo

Based on mathematical means

not statistically analyzed

105 103

Pinkerton JV et al Menopause 2009

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Significant Reduction vs Placebo in

Average Daily Severity Score of Hot Flushes

17

Week 4 Week 12

ndash05

ndash06

Treatment

differencedagger

Treatment

differencedagger

DUAVEE [package insert] New York NY Pfizer Inc 2013

Reduction in average daily severity score of hot flushes ndash primary end point

Ad

jus

ted

me

an

ch

an

ge

fro

m b

aselin

edagger

Plt001 vs placebo daggerBased on data analysis using ANCOVA model Change from baseline = Treatment + Baseline + Site

DUAVIV

E

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Reduction in the Observed Average

Daily Severity Score of Hot Flushes

Observed Average Daily Severity Score of Hot Flushes

19

DUAVIVE (n=122) Placebo (n=62)

Weeks

Ob

serv

ed a

vera

ge d

aily

sev

erit

y sc

ore

of

ho

t fl

ush

es

0

05

10

15

25

20

0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

14

Data on file CSR-67461 Protocol 3115A1-305 Table 1511 Pfizer Inc New York NY

Primary analysis at weeks 4 and 12 prespecified secondary end points at all other weeks

change from baseline to week 12

39 for DUAVIVE

14 for placebo

Average daily severity score of hot flashes from baseline to week 12

23 to 14 for DUAVIVE

23 to 19 for Placebo

Based on mathematical means

not statistically analyzed

23

23

Pinkerton JV et al Menopause 2009

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Effects on bone mineral density (BMD)

SMART 512

20

bull 12-month double-blind randomized placebo- and active-controlled study

bull Primary end point endometrial hyperplasia at 1 year

bull Secondary BMD changes at 1 year

1 DUAVEE [package insert] New York NY Pfizer Inc 2013 2 Pinkerton J Clin Endocrin Metab 2014

This study included a different dose of CEBZA and comparators The schematic shown here depicts only the patients who received the approved dose of DUAVIVE or placebo

Change from baseline in

bull Lumbar Spine BMD (Primary ndash BMD Substudy)

bull Total Hip BMD (Secondary ndash BMD Substudy)

BMD Analysis

DUAVIVE

(CE 045BZA 20)

(n=119)

Placebo

(n=139)

BMD Analysis

Postmenopausal women with a uterus

Less than 5 years since LMP

(N=590)

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

DUAVIVE Significantly Increased Lumbar Spine and Total

Hip BMD vs Placebo at 12 Months ndash Study 2

M

ean

ch

an

ge f

rom

baselin

e

Lumbar Spine Total Hip

121 151 Treatment

difference Treatment

difference

Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY Pinkerton J Clin Endocrin Metab 2014 30

Plt001 vs placebo

Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-US) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward

DUAVIV

E

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

TOLERABILITY

AND SAFETY

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Rates of BleedingSpotting and Amenorrhea

Similar to Rates with Placebo

bull High and similar cumulative rates of amenorrhea at year 1 among women treated with CE 045BZA 20 and placebo and was higher than seen in women treated with CE 045MPA 151

bull Noncumulative rates of spotting and bleedingspotting were similar among women treated with CEBZA or placebo and consistently higher in women treated with CE 045MPA 152

0

90

Cycle

100

Pe

rce

nta

ge

of

Su

bje

cts

80

70

60

50

40

30

20

10

88

54

Placebo

CE 045BZA 20 CE 045MPA 15

Percentage of subjects with cumulative amenorrhea during consecutive 4-week periods (cycles) in SMART-5

MPA medroxyprogesterone acetate Plt0001 vs all other treatment groups 1 Pinkerton JV et al J Clin Endocrinol Metab 2014 2 Data on file CSR-81040 Protocol 3115A1-3307 Pfizer Inc New York NY

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Adverse Reactions in Placebo-

Controlled Trials Safety analyses have been conducted in 6210 postmenopausal women aged 40 to 75 years (mean age 55 years) following up to 2 years of treatment in SMART-1 -2 -3 and -5

Adverse reactions (incidence ge5) that were more common with DUAVIVE

Incidence of serious adverse reactions

35 with DUAVIVE 48 with placebo

DUAVEE [package insert] New York NY Pfizer Inc 2013

CE 045 BZA 20 (N=1224)

n ()

Placebo (N=1069)

n ()

Gastrointestinal disorders

Nausea 100 (8) 58 (5)

Diarrhea 96 (8) 57 (5)

Dyspepsia 84 (7) 59 (6)

Abdominal pain upper 81 (7) 58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms 110 (9) 63 (6)

Neck pain 62 (5) 46 (4)

Nervous system disorders

Dizziness 65 (5) 37 (3)

Respiratory thoracic and mediastinal disorders

Oropharyngeal pain 80 (7) 61 (6)

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Venous Thromboembolism (VTE) in

DUAVIVE Clinical Studies

bull Estrogen agonistantagonists (including BZA a component of DUAVIVE) and estrogens individually are known to increase the risk of VTE

bull In the clinical studies with DUAVIVE the reporting rates for VTE were low in all treatment groups

bull Adverse reactions of VTE reported by patients

bull Should VTE event occur or be suspected DUAVIVE should be discontinued immediately

bull Due to the low rates of events in both groups it is not possible to conclude that the risk of VTE with DUAVIVE is different from that seen with other estrogen therapies

DUAVEE [package insert] New York NY Pfizer Inc 2013

00 for DUAVIVE (n=1224)

01 for placebo (n=1069)

26

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull postmenopausal women (N = 1843) with menopausal

symptoms

bull Lipid (N = 1843) and coagulation (N = 590) variables were assessed in women receiving daily CE 045 mgBZA 20 mg CE 0625 mgBZA 20 mg BZA 20 mg CE 045 mgmedroxyprogesterone acetate (MPA) 15 mg or placebo for 12 months

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull CE 045 mgBZA 20 mg

bull CE 0625 mgBZA 20 mg

bull BZA 20 mg

bull and CE 045 mgMPA 15 mg decreased total cholesterol and LDL- cholesterol vs placebo (P lt 001 for all)

bull Both CEBZA doses and CEMPA increased high-density lipoprotein cholesterol compared with placebo (P lt 005 for all)

bull CE 045 mgBZA 20 mg had a neutral effect on triglycerides

bull CE 0625 mgBZA 20 mg and CEMPA increased triglycerides compared with placebo (P lt 005)

bull Skouby SO et al Menopause 2015 Jun22(6)640-9

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

Skouby SO et al Menopause 2015

Jun22(6)640-9

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Endometrial hyperplasia or malignancy occurred in lt1 of women

following up to 1 year of treatment with CEBZA12

Study Cumulative Incidence at month 12 (nN)

CE 045BZA 20 Placebo

SMART-11 000 (0336) 000 (0313)

SMART-52 030 (1335) 028 (1354)

Effects on the Endometrium

1 Pickar JH et al Fertil Steril 2009 2 Pinkerton at al J Clin Endocrinol Metab 2014

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Through the eyes of an amazone

Marie Mandy

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Breast tolerability profile similar to placebo following up to 2 years of treatment with CEBZA12

Pooled analysis of SMART clinical trials

CE 045BZA 20 (n=1585)

Placebo (n=1241)

Breast cancer incidence up to 2 years

(per 1000 woman-years)

100 (CI 000-321)

140 (CI 000-417)

Incidence of reported breast paintenderness up to 12 weeks

98-115 81-112

Incidence of abnormal mammogram at month 12

258 316

Mean change in breast density at month 12 (SMART-5)

ndash038 (n=186)

ndash032 (n=182)

Effects on the Breast

1 Pickar JH et al Menopause 2013 2 Pinkerton JV et al Obstet Gynecol 2013

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

CEBZA clinical overview - summary

bull In clinical trials CEBZA has demonstrated safety and efficacy in postmenopausal women with a uterus including the following

bull Significant reduction in number and severity of moderate to severe hot flushes1

bull Incidence of cumulative amenorrhea rate similar to placebo and significantly better than CEMPA2

bull Incidence of endometrial hyperplasia and breast tendernessdensity similar to that with placebo345

bull Incidence of adverse events and discontinuation rates similar to that with placebo6

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al

Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

CEBZA clinical overview - summary

Now women with a uterus who choose hormone therapy for management of menopausal symptoms have a choice

bull conventional estrogen-progestogen therapy or

bull a new combinationhellipconjugated estrogens paired with the SERM bazedoxifene

1 Pinkerton JV et al Menopause 2009 2 Pinkerton JV et al J Clin Endocrinol Metab2014 3 Pickar JH et al Fertil Steril 2009 4 Pinkerton at al J Clin Endocrinol Metab 2014 5 Pickar JH et al Menopause 2013 6 DUAVEE [package insert] New York NY Pfizer Inc 2013

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Conjugated EstrogensBazedoxifene (CEBZA)

US indication

bull DUAVEE is indicated in women with a uterus for

bull 11 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

bull 12 Prevention of Postmenopausal Osteoporosis

bull 13 Important Limitations of Use

bull Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary

bull When prescribing solely for the prevention of postmenopausal osteoporosis therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Conjugated EstrogensBazedoxifene (CEBZA)

EU indication

CEBZA is indicated for

bull Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate

bull The experience treating women older than 65 years is limited

bull Dose CE (045mg)Bazedoxifene (20mg)

Duavive SmPC

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Which women with a uterus

could benefit from estrogens

without the need for a

progestin

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Progestin intolerance is one of the main

factors for reduced compliance

bull About 20 of women receiving progestin-containing HT have significant progestin intolerance and half of these experience serious effects that prevent treatment continuation1

1 Panay N amp Studd J Human Reprod Update 1997

2 Panay N et al on behalf of the British Menopause Society and Womenrsquos Health Concern Menopause Int 2013

bull The 2013 British Menopause Society amp Womenrsquos Health

Concern recommendations on hormone replacement

therapy do recognise progestin intolerance as one of the

main factors for reduced compliance with HT 2

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Proportion of patients () with at least one bleeding episode in relation to time and to the

used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Breast density

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Adapted use of MHT

bull Lower dosage of estrogens

bull Other progestins

bull Better safety profile

bull Vaginal estrogen or SERMS

bull Non-hormonal therapy

bull Development of new products

bull SERMS + estrogens

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Most common adverse events leading to

discontinuation are related to progestins12

bull breakthrough bleeding

bull Low compliance

bull Increase in the number of US

bull Stress

bull Cost

bull uterine procedures

bull Unnecessary endometrial biopsies Hysteroscopies DampC Hysterectomies

bull Morbidity

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Proportion of patients who completed or discontinued treatment in relation to the used HT

Serge Rozenberg et al Hum Reprod 2009241739-1747

copy The Author 2009 Published by Oxford University Press on behalf of the European Society of

Human Reproduction and Embryology All rights reserved For Permissions please email

journalspermissionsoxfordjournalsorg

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Most common adverse events leading to discontinuation

are related to progestins

bull breast paintenderness

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Breast tenderness after initiation of CEE

CEE + MPA (WHI)

and mammographic density change

bullCrandall et al Breast Cancer Res Treat DOI 101007s10549-011-1803-9

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Breast density

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Hormone therapy use and mammographic

density in postmenopausal Norwegian women

bull Results differed when considering the combined effect of age and BMI

bull The effect of EPT on mammographic density was modified by age and BMI with no apparent association among the youngest women (aged 50-55) with the highest BMI (BMI ge 26)

bull A higher mammographic density was found in EPT users compared to never HT users particularly in women using high-dose NETA regimens Age and BMI modified the association between EPT use and mammographic density

bull Couto E et al Breast Cancer Res Treat 2011 Nov 4 [Epub ahead of print]

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Birads age HT Duration Risk

1 55-59 None 5 year risk 08 (95 CI 06- 09)

1 55-59

ET EPT 5 year risk 09 (95 CI 07 -11)

4 55-59

None 5 year risk 24 (95 CI 20 -28)

4 55-59

ET 5 year risk

30 (95 CI 26 -35)

4 55-59

EPT 5 year risk

42 (95 CI 37 -46)

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Breast Cancer Risk by Breast Density

Menopause and Postmenopausal Hormone

Therapy Use

Adapted from Kerlikowske et al JOURNAL OF CLINICAL ONCOLOGY 2010

bull Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT especially estrogen plus progestin

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull progestin-containing HT may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

A Nath and R Sitruk-Ware CLIMACTERIC 200912(Suppl 1)96ndash101

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Diabetes an epidemy

bull UK 1996 14 million of diabetics

bull UK 2015 32 million (6 of the population)

bull UK 2025 5 million

bull httpwwwdiabetescoukdiabetes-prevalencehtml

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Other progestin-related intolerance issues

bull Nausea

bull Depressive mood

bull Poor concentration

bull Hirsutism

bull Headache

bull Dizziness

bull Fluid retention

bull Weight gain Panay N amp Studd JWW Human Reprod Update 1997

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Medical condition which may be exacerbated by treatment with progestins

PMSPMDDdepression

bull Progesterone-induced PMD can be exacerbated by exogenous progestin administration and can occur in association with HT or OC administration1

bull Significantly higher negative mood scores have been observed during the addition of a progestin to an estrogen in a sequential HT regimen in postmenopausal women with a history of PMS compared to those without2

bull Women with a history of PMS or PMD exacerbation of depression using progestins may therefore benefit from a progestin free treatment for menopausal symptoms

1) Nevatte T et al Arch Womens Ment Health 2013 2) Bjoumlrn I et al Climacteric 2006 PMS premenstrual syndrome

PMDD premenstrual dysphoric disorder

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Conclusion

bull CEEBAZO is an additional regimen for menopausal symptoms it provides also a prevention for osteoporosis

bull It is suitable for women with a uterus who are unsatisfied with an EPT regimen or who you are unwilling to treat with an EPT regimen

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

For some postmenopausal women with a uterus there is a

need for progestin free treatment options

bull with demonstrated clinical efficacy

bull which protects the endometrium

bull improved tolerabilitysafety profile

In clinical practice this translates to women who are

intolerant of progestin-containing HT or have conditions

which may be exacerbated by treatment with progestins

Conclusion Medical need for alternative treatment option

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Medical condition which may be exacerbated by treatment with progestins

Depression

bull Progestin-containing HT has been associated with increases in depressive symptoms in some individuals1

bull There is a biochemicalphysiological plausibility for the association of progestins with depression234

bull Therefore postmenopausal women who also have a medical history of depressive disorders or depression could be inappropriate for treatment with progestin-containing HT

Pfizer Confidential

65

1) Girdler SS et al J Womens Health Gend Based Med 1999 2) Traish AM et al Korean J Urol 2014 3) Stroumlhle A et al Biol Psychiatry 1999 4) Romeo E et

al Am J Psychiatry 1998

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Women for whom progestin-containing HT

would not be considered appropriate

minus Women who are intolerant of progestin-containing hormone therapy

minus Women with pre-existing medical conditions that may be exacerbated by progestins

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Most common adverse events leading to discontinuation are related to progestins12

breakthrough bleeding

bull Increase in the number of uterine procedures (ie unnecessary endometrial biopsies)

breast paintenderness

bull Increase in the number of breast interventions

1 Steel SA et al Climacteric 2003 2 Ettinger B and Pressman A Am J Manag Care 1999 3 Komm BS Mirkin S

Pharmaceuticals 2012

4 Panay N amp Studd JWW Human Reprod Update 1997

bull Nausea bull Depressive mood bull Poor concentration bull Hirsutism bull Headache bull Dizziness bull Fluid retention bull Weight gain

Other progestin-related intolerance issues4

Unmet need with the treatment of postmenopausal symptoms

bull Alternatives to progestin are needed that will protect the endometrium while avoiding other progestin-associated effects and preserving the desired effects of estrogens in postmenopausal women3

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Which women with a uterus could benefit from

estrogens without the need for a progestin

bull Women who are intolerant of progestin-containing hormone therapy

bull Women with pre-existing medical conditions that may be exacerbated by progestins (eg women with a history of depression PMSPMDD increased breast density diabetes and metabolic syndrome)

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

History of the following conditions may make progestin inappropriate

bull Depression

bull PMSPMDD

bull High breast density

bull Diabetes and metabolic syndrome

PMS premenstrual syndrome

PMD premenstrual dysphoric disorder

Medical conditions that may be exacerbated by treatment with progestins

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Learning from WHI data

bull Hormone therapy (HT) is the conventional and established therapy option to effectively treat postmenopausal symptoms however it has been associated with some safety and tolerability concerns1 2

bull A review of WHI data suggests that many of the concerns with menopausal HT more often associated with EPT (CE+MPA) such as CHD risk increased breast density breast pain and breast cancer risk than with ET (CEE alone)2

1 Rolnick SJ Kopher RA DeFor TA et al Menopause 2005

2 Komm BS Mirkin S Pharmaceuticals 2012

WHI Womenrsquos Health Initiative trial

CHD coronary heart disease

CEE conjugated equine estrogens

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Efficacy and Safety of Constant Oestrogen

Pulsed Progestogen vs

Continuous Combined HRT

Adverse Events

17b-oestradiol 17b-oestradiol norgestimate NETA (n = 150) (n = 172) Breast discomfort 14 27 Abdominal discomfort 14 22 Uterine bleeding 15 12 Dysmenorrhea 3 8 Oedema 5 8

Adapted from S Rozenberg et al Human Reproduction 2000

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Medical condition which may be exacerbated by treatment

with progestins

Increased breast density

bull Increases in breast density are associated with progestin-containing HT which may adversely affect radiological detection of breast cancer1 and may be independently associated with an increased risk for the development of breast cancer2

bull The Postmenopausal EstrogenProgestin Interventions (PEPI) trial demonstrated that an increased mammographic breast density was associated with the use of E+P but not with the use of estrogen alone3

bull Women who already have high breast density may therefore be considered inappropriate for treatment with a progestin-containing HT

1) EU Core SPC for Hormone Replacement Therapy Products (CMDh1312003 Rev 4 June

2012)

2) De Villiers TJ et al on behalf of the International Menopause Society Climacteric 2013 16

3) Greendale GA et al J Natl Cancer Inst 2003

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Stroke

0 25 5 75 10 125

Fractures

Diabetes

Breast cancer

Cholecystitis

Venothrombotic episodes

Endometrial cancer

Lung cancer

Coronary heart disease

Colorectal cancer

Overall mortality

15 125 10 75 5 25

Benefits Risks

CE

CE MPA

Santen RJ et al J Clin Endocrinol Metab 2010

The basis of the Endocrine Society scientific statement for postmenopausal hormone replacement therapy (HRT) excess risks and benefits of HRT for 5 years in women aged 50ndash59 years or within 10 years of the start of menopause E=estrogen P=progestin

bull Younger women (aged 50ndash59 years) had more favorable results bull There are differences between CE alone and CEMPA arms bull Overall benefitrisk ratio of CE-alone appears to be more favourable than CEMPA

Reevaluation of WHI data (stratified by age) Risks and

Benefits of HRT Cases per 1000 Women per 5 Years of

Use

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Medical condition which may be exacerbated by treatment

with progestins

Diabetes and metabolic syndrome

bull Treatment of oestrogen deficiency symptoms with progestin-containing HT (unlike oestrogen alone) may be associated with increases in insulin resistance and deterioration in glucose tolerance123

bull Postmenopausal women with diabetes could be inappropriate for treatment with progestin-containing HT due to the potential risk of exacerbation of their condition

1) Panay N amp Studd JWW Human Reprod Update 1997

2) Godsland I et al Metabolism 1993

3) Sites CK et al J Clin Endocrinol Metab 2005

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Variations in Associated Breast Cancer

Risks Between CE alone and CEMPA

bull Use of CE alone for a median of 59 years was associated with a lower incidence of invasive breast cancer (151 cases 027 per year) compared with placebo (199 cases 035 per year HR 077 95 CI 062ndash095 P=002)

bull In the CE alone group fewer women died from invasive breast cancer (6 deaths 0009 per year) compared with controls (16 deaths 0024 per year HR 037 95 CI 013ndash091 P=003)

Anderson GL et al Lancet

Oncol 2012

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Bazedoxifene (BZA) specifically selected in

combination with conjugated estrogens

bull BZA has been specifically selected for its unique pharmacologic profile and effects on VMS and uterine tissue in particular123

1 Crabtree J et al Mol Cell Endocrinol 2008

2 Kharode Y et al Endocrinolology 2008

3 Duavive SmPC

Estrogen Receptor activity is dimmed

Estrogen Receptor activity is turned on

CEs are agonists BZA is an antagonist

In the uterus

bull The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone3 This means that progestins are not needed

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Extensive global clinical development program for

CEBZA

aIncludes additional pilot dose-finding study 203 1 Lobo RA et al Fertil Steril 2009 2 Pinkerton JV et al Menopause 2009 3 Kagan R et al Menopause 2010 4 Mirkin S et al Climacteric 2013 5 Pinkerton JV et al Obstet Gynecol 2013

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo

Effects of conjugated estrogensbazedoxifene on

lipid and coagulation variables a randomized

placebo- and active-controlled trial

bull At 12 months

bull Both CEBZA doses were associated with small but significant effects on hemostasis variables including reductions in antithrombin plasminogen activator inhibitor-1 and fibrinogen activity and an increase in plasminogen activity relative to placebo at 12 months Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups

bull CONCLUSIONS

bull This study provides reassurance that CEBZA does not adversely affect lipid metabolism or hemostatic balance In accordance the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo