11 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble

11

Intrinsa™

(testosterone transdermal system)Reproductive Health Drugs

Advisory Committee Meeting Gaithersburg, MDDecember 2, 2004

Procter & Gamble Pharmaceuticals

22

Introduction to Program and Regulatory Overview

Joan M. Meyer, PhD Senior Director, New Drug Development


I1C

33

What is Intrinsa? Transdermal patch delivering 300 mcg/day

testosterone when applied twice a week as continuous therapy

Proposed Indication:

Treatment of hypoactive sexualdesire disorder (HSDD) in surgically menopausal women receiving concomitant estrogen therapy

I2C

44

HSDD is a Condition thatAffects Many Women

A recognized medical condition

Associated with decreased desire, sexual activity and satisfaction

Distressing to these women

Can adversely affect a woman’s health, well-being, and relationship with spouse or partner

I14C

55

Agenda

Introduction Joan M. Meyer, PhD, P&GP

Clinical Efficacy Johna D. Lucas, MD, P&GP

Clinical Relevance Leonard D. DeRogatis, PhD, Johns Hopkins

Clinical Safety Johna D. Lucas, MD, P&GP

Hormone Data Glenn D. Braunstein, MD, UCLA

Medical Need Jan L. Shifren, MD, Harvard

Long-term Safety Michael Steinbuch, PhD, P&GP

Conclusions Joan M. Meyer, PhD, P&GP

I4C

66

Additional Participants

Ricardo Azziz, MD, MPH, MBA Chair, Department of OB/GYN

Cedars-Sinai Medical Center

Vernon Chinchilli, PhD Professor & Interim Chair, Department of Health Evaluation Sciences

Penn State College of Medicine

Maurie Gelfand, MD Professor of OB/GYN

McGill University

Robert Reid, MD Director of Reproductive Endocrinology

Kingston General Hospital

Alexander Walker, MD DrPH Senior Vice President of EpidemiologyIngenix

William White, MD Professor of MedicineUniversity of Connecticut School of Medicine

Nora Zorich, MD, PhD Vice President, R&D, P&GP

I5C

6

77

Intrinsa Comprehensive Clinical Development Program

3 Dermal Safety and Irritation Studies 9 Pharmacokinetic Studies

• Range of doses / dosing durations• Established T reference range

3 Phase II Studies• Dose-ranging• Multiple geographies, routes of E administration

4 Phase III Studies• 2 surgical menopause• 2 natural menopause

I6C

88

New Therapeutic Area Requires Special Studies

Instrument development and validation studies

Randomized, placebo-controlled withdrawal study

Clinical relevance study

Comprehensive safety program

I7C

99

Intrinsa™




1010

Phase III Surgical Menopause Efficacy Overview

Johna D. Lucas, MA, MD, FACOG

Medical Director

Procter & GamblePharmaceuticals

E1C

1111

Efficacy Agenda

Instrument development & validation Efficacy endpoints Description of trials Trial results

E2C

1212

Validated Study Instruments

Sexual Activity Log© (SAL©)• Weekly diary measuring sexual activity

Profile of Female Sexual Function© (PFSF©)• 30-day recall measuring domains of

sexual function Personal Distress Scale© (PDS©)

• 30-day recall measuring distress related to lack of interest in sex

McHorney CA et al. Menopause. 2004 Jul-Aug;11(4):474-83. Derogatis L. et al. J Sex Marital Ther. 2004 Jan-Feb;30(1):25-36

E32C

1313

PFSF & PDSDevelopment & Validation Program

Interviewed 250+ patients with HSDD Generated 450+ items Reduced items using psychometric criteria Tested remaining 83 items in 3 validation trials

• 325 women with HSDD• 255 age-matched controls

E3C

1414

PFSF & PDSDevelopment & Validation Program

Chose 37 best items for final PFSF (7 domains) and 7 items for final PDS based on assessments of data quality, domain structure and item redundancy

Domains had good reliability and validity Evaluated final version in a confirmatory validation

study (n= 251)• 59 surgically menopausal women with HSDD• 88 naturally menopausal women with HSDD• 104 age-matched controls with normal libido

E4C

1515

SAL Developed to Quantify Sexual Activity

Interviewed patients to understand how women quantify their sexual activity

Tested diary language to ensure universal understanding

Tested & revised SAL to minimize reporting error

Final instrument consistently well understood and shown to be valid and reliable

E7C

1616

Intrinsa Surgical Menopause Study Design

2 Phase II, 2 Phase III (SM 1 & SM 2)• 8-week pre-treatment baseline period• 24-week randomized double-blind placebo

controlled treatment period• All patients on concomitant estrogen• Inclusion / exclusion criteria same

All trials employed validated instruments Open label safety: weeks 25 ongoing

E10C

1717

Phase III Studies Concurrent multinational trials (US, Canada,

and Australia)• SM 1, 562 women, 52 sites• SM 2, 532 women, 51 sites

Objective• Assess efficacy / safety of transdermal

testosterone in SM women with HSDD Study population

• S/P hysterectomy and BSO • On oral or transdermal estrogen therapy• Hypoactive sexual desire disorder

E14C

1818

Endpoints of Phase III Program

Primary Endpoint • Satisfying sexual activity

Key Endpoints• Desire for sexual activity• Distress associated with low desire

Other Important Endpoints

E15C

1919

Key Inclusion Criteriafor HSDD Population

Post-operative onset of low sexual desire with significant distress

Bilateral oophorectomy and hysterectomy6 months prior to study

20-70 years old Stable dose of estrogen (oral or TD) for 3

months prior to study Stable monogamous relationship for 1 year

with partner present >50% of the time

E16C

2020

Key Exclusion Criteria for HSDD Population

Serious medical conditions Malignancy

- Breast or estrogen dependent (ever)

- Other (5 years) Depression or other psychiatric conditions Androgen or other confounding medications Dyspareunia Ongoing relationship disturbances

E17C

2121

1723 Screened

550 TTS

436 (80%)Completed

433 (79%)Completed

418 (96%) Placebo-TTS

Agreed toparticipate

419 (97%) TTS-TTSAgreed toparticipate

326 (78%)Completed

315 (75%)Completed

Disposition of Patients During Weeks 0-52Surgical Menopause 1 and 2

Weeks 0-24(24-week double-blindperiod)

Weeks 25-52(28-week open-label safety period)

1095 (64%) Randomized545

Placebo

8-week baseline period

E18C

2222

Patient Disposition at 24 Weeks

SM 1 SM 2

Placebo TTS Placebo TTS

No. Randomized 279 283 266 267

Completed, % 82 78 77 79

Discontinued, % 18 22 23 21

Adverse event 7 8 8 8

Voluntary/Other 11 14 15 13

E19C

2323

Demographics/Baseline Characteristics

SM 1 SM 2

Placebo TTS Placebo TTS

n=279 n=283 n=266 n=266

Age, yrs 49 49 50 48

Race, % Caucasian 87 91 92 89

Length of relationship, yrs 19 20 19 18

Time since BSO, yrs 8 9 9 9

Oral/TD estrogen, % 75/25 74/26 82/18 80/20

E20C

2424

HSDD Baseline Characteristics

SM 1 SM 2

Mean

Placebo

n=279

TTS

n=283

Placebo

n=266

TTS

n=266

Sexual desire score 20.7 19.9 23.2 21.4

Personal distress score 62.4 64.7 66.0 67.1

Total satisfying episodes*

2.9 2.8 3.2 3.0

* 4-week frequency

E21C

2525

0

0.5

1

1.5

2

2.5

4 W

k.

Fre

qu

en

cy

Ch

an

ge

Fro

m B

as

eli

ne

(S

EM

)

Placebo

TTS

SM 1

% IncreaseFrom Baseline 33% 74% 23% 51%

SM 2

Testosterone Patch Increased Total Satisfying Sexual Activity at 24 Weeks

E22C

p=0.0003

p=0.001

2626

Testosterone Patch Increased Desire at 24 Weeks

0

2

4

6

8

10

12

14

Me

an

Ch

an

ge

Fro

m B

as

elin

e (

SE

M)

Placebo

TTS

SM 1 SM 2

p=0.0006 p=0.0006

% IncreaseFrom Baseline 29% 56% 18% 49%

E23C

2727

-30

-25

-20

-15

-10

-5

0

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(S

EM

)

PlaceboTTS

SM 1 SM 2

% DecreaseFrom Baseline 40% 65% 48% 68%

p=0.0006 p=0.0091

Testosterone Patch Decreased Distress at 24 Weeks

E24C

2828Testosterone Patch Improved All PFSF Domains at 24 Weeks

0

5

10

15

20

25

Mea

n C

han

ge

Fro

m B

asel

ine

(SE

M)

Arousal PleasureOrgasm Reduced Concerns

Responsiveness Self-image

p=0.023

p<0.0001

p=0.0003

p=0.0006

p=0.0001

p<0.0001

Placebo

TTS

SM 1

E25C

2929

0

5

10

15

20

25

30

Mea

n C

han

ge

Fro

m B

asel

ine

(SE

M)

Arousal PleasureOrgasm Reduced Concerns

Responsiveness Self-image

p=0.0299

p=0.0004

p=0.0016

p=0.0002

p=0.002

p=0.0015Placebo

TTS

SM 2

Testosterone Patch Improved All PFSF Domains at 24 Weeks

E26C

3030

Increases in Other SAL Endpointsat 24 Weeks

0

0.5

1

1.5

2

2.5

3 Placebo

TTS

p=0.0036

p=0.0002

p=0.0132

Episodes Orgasms

4-W

k M

ean

Ch

ang

e F

rom

Bas

elin

e (S

EM

)

SM 1

Episodes Orgasms

p=0.0005

SM 2

% IncreaseFrom Baseline 9% 26% 37% 80% 3% 14% 23% 68%

E27C

3131

Testosterone Patch is Efficacious for Surgically Menopausal

Women with HSDD In surgically menopausal women with low

sexual desire, Intrinsa significantly:• ↑ Sexual desire • ↑ Satisfying sexual activity• ↓ Personal distress• ↑ Arousal, orgasm, pleasure, responsiveness and

sexual self image• ↓ Sexual concerns• ↑ Total sexual activity and number of orgasms

E31C

3232

Intrinsa™




3333

Clinical Relevance of Treatment Effects

Leonard R. DeRogatis, PhDDirector

Johns Hopkins Center for Sexual Health and Medicine

C1C

3434

Clinical Relevance of Treatment Effects

Evidence from Phase III Study

• All endpoints derived from concerns and experiences

of HSDD patients

• Decrease in personal distress is a direct marker of

relevant treatment impact

• Improvement of sexual function across all relevant

domains

Evidence from Clinical Relevance Study

C2C

3535

Anchoring Technique for Examining Clinical Relevance

Well-established through broad use Readily understood Patient-based. Uses direct questions

concerning patient benefit Patient perceptions of benefit are tied to study

endpoints through statistical analyses (ROC) Results define meaningful change (MCID)

which helps establish clinical relevance

C3C

3737

Anchoring Model ofClinical Relevance

PATIENT PATIENT PERCEPTIOPERCEPTIO

NN

ROCROCANALYSISANALYSIS

MCIDMCID RESPONDERESPONDERSRS

MeaningfulBenefit

Desire

Satisfying Activity

Distress

∆ PFSF

∆ PDS

Yes / No

%

%

%

Clinical Relevance Clinical Relevance StudyStudy

Phase III StudiesPhase III Studies

∆ SAL

C5C

3838

Clinical Relevance Study Design

132 women from Phase III trials

First, open-ended questions about experience in clinical study

Then, specific questions about benefits, if any

Question for anchoring analyses

• “Overall, considering everything we have talked about today, would you say that you experienced a meaningful benefit from the study patches?”

C6C

3939

Clinical Relevance Study Responders by Treatment

C7C

TTS PL p-value

52% 31% p=0.025

Self-identified Responders

4040

Clinical Relevance StudyMean Changes from Baseline

Reported overall meaningful benefit

Reported no overall meaningful benefit

Satisfying Sexual Activity 4.4 0.5

Desire 21.0 2.9

Distress - 36.5 - 8.8

C13C

4141

ROC Discrimination

0

0.2

0.4

0.6

0.8

1

0.00 0.20 0.40 0.60 0.80 1.00

Change > 1

AUC = 0.77

Tru

e p

ositi

ve r

ate

False positive rate

Satisfying Sexual Activity

C8C

4242

Clinical Relevance Results

PATIENT PATIENT PERCEPTIOPERCEPTIO

NN

ROCROCANALYSISANALYSIS

MCIDMCID RESPONDERESPONDERSRS

MeaningfulBenefit

Desire

SatisfyingActivity

Distress

≥ 8.9

≤ - 20

Yes

TTS PL50 vs 34 %

51 vs 39 %52 vs 31 %

p = 0.025

N = 132

All p < 0.0002

N =1095

Clinical Relevance Clinical Relevance StudyStudy

Phase III StudiesPhase III Studies

> 1 44 vs 30 %

TTS PL

C9C

4343

Interest in Continuing Treatment

0

10

20

30

40

50

60

70

80

Definitelynot

ProbablyNot

May/MayNot

Probably Definitely

Interest in Continuing Treatment

Per

cen

tag

e o

f P

atie

nts

Meaningful Benefit

No Meaningful Benefit

C10C

4444

Summary

Significantly more TTS patients than placebo patients experienced meaningful benefit

Anchoring using MCID values confirms similar proportions of responders in Phase 3 trials

Consistent results across all endpoints

• sexual desire

• satisfying sexual activity

• personal distress

C11C

4545

Conclusion

Consistent pattern of outcomes shows strong evidence of a clinically meaningful benefit, which translates into observable clinical relevance.

C12C

4646

Intrinsa™




4747

Phase III Surgical Menopause Safety Overview

Johna D. Lucas, MA, MD, FACOG

Medical Director

Procter & GamblePharmaceuticals

S1C

4848

Safety Focus Areas for Testosterone Therapy in Women

Androgenic skin changes

Weight Blood Pressure Liver Dysfunction Polycythemia

Cardiovascular Disease

Breast Cancer Other Adverse

Events Noted on Male Product Labels

S2C

4949

Phase III Trial Design

0-6 Months 7-12 Months

SM 1 SM 2 NM 1

NM 2

= primary safety data = additional safety data

DB

DB

DB

DB

OL

OL

S3C

n = 532

n = 562

DB = Double Blind OL = Open Label

5050

Exposure to Testosterone Patch Phase II & III Studies

Number of Patients

Surgical Menopause

Natural Menopause

Total

Exposure*

ICH Guideline

Minimum≥ 300 mcg/day 300 mcg/day

At least 1 dose 1288 517 1805

≈ 6 months 957 388 1345 300-600

≈ 12 months 494 136 630 100

≈ 18 months 127 0 127

Total patient months

10742 3350 14092

S4C

*exposure as of 6/04

5151

Safety Evaluations

Adverse Events (AEs)• Overall• Serious AEs• Withdrawals due to AEs

Androgenic Assessments and Adverse Events Adverse Events of Special Interest Weight and Vital Signs Laboratory Evaluations

• Liver Function• Cardiovascular Risk Factor Assessments• Hematology

Breast Cancer

S5C

5252Overall Adverse Event Summary

24 WeeksSM 1 SM 2

% of Patients

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Patients with AEs 79.6 77.7 74.1 74.4

Serious AEs / Deaths 2.5/0 2.5/0 2.3/1 1.9/0

Withdrawals due to AEs 6.8 8.5 8.3 8.3

Most Common AEs

Application-site reaction 39.1 31.1 28.9 29.7

Upper respiratory infection

9.3 9.9 7.5 8.3

Headache 7.5 9.9 5.3 5.6

S6C

5353S7C

Androgenic Effects at 24 Weeks

Acne Hirsutism Alopecia

Clitoromegaly Voice deepening

• 94% of events were mild• 78% of these patients had only one event• Time to event similar to placebo

5454

Acne Assessments & AEs 24 Weeks

SM 1 SM 2

% of PatientsPlacebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Acne: Clinical Assessments

(Change from baseline)

<0 98.1 97.3 98.7 97.5

1-2 1.9 2.7 1.3 2.5

3 0 0 0 0

Acne: AEs 6.1 6.0 4.1 7.5

Acne Scale: Palatsi

S8C

5555Facial Hair Assessments & AEs

24 WeeksSM 1 SM 2

% of Patients

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Facial Hair Clinical Assessments (Change from baseline )

Chin < 0 95.8

95.8 95.8 93.0

1-2 4.2 4.2 4.2 7.0

3 0 0 0 0

Upper lip < 0 93.9 94.3 95.0 94.2

1-2 6.1 5.7 5.0 5.3

3 0 0 0 0.4

Hirsutism: AEs 6.5 5.7 5.3 9.0Hirsutism Scale: Facial measures of Ferriman-Gallwey/Lorenzo

S9C

5656

Other Androgenic AEs24 Weeks

SM 1 SM 2

% of Patients

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Alopecia 3.2 3.2 2.6 5.3

Voice Deepening

2.9 2.5 1.5 3.0

Clitoromegaly 0 0 0 0.4

S10C

5757

SM 1 SM 2

% of Patients

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Acne 0 0 0 0.8

Alopecia 0.4 0.4 0.8 1.5

Hirsutism 0 0.7 0 0.8

Voice Deepening

0 0 0 0.8

Clitoromegaly 0 0 0 0.4

Androgenic AE Withdrawals 24 Weeks

S11C

5858

AEs of Special Interest 24 Weeks

SM 1 SM 2

% of Patients

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Breast Tenderness

2.5 2.5 3.4 2.3

Hot Flushes 2.2 2.1 2.3 1.9

Weight Gain 1.1 1.4 1.9 2.6

S12C

5959

Weight and Blood Pressure24 Weeks

SM 1 SM 2Baseline

from Baseline

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Weight (kg) 75.93

-0.24

74.76

0.18

75.00

-0.19

72.91

0.30

Systolic BP

(mmHg)

120.7

-0.2

120.6

0.2

120.9

-0.9

121.0

0.1

Diastolic BP

(mmHg)

76.1

-1.2

75.5

-0.1

75.3

-0.3

75.8

0.1

S13C

6060

Other Adverse Events 24 Weeks

SM 1 SM 2

% of Patients

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Anxiety 1.4 1.4 1.9 2.3

Edema 0.7 1.4 0.8 0.8

Aggression 0.7 0.4 0.8 0.4

Abnormal LFTs 0 0.7 0 1.5

S16C

6161

Liver Function Test AEs 24 Weeks

S17C

Isolated bilirubin elevations (n=2) Mild transaminase elevations (n=3)

• 2 resolved on testosterone• 1 remained just above ULN on testosterone

(52 weeks) and repeat after discontinuation

Moderate transaminase elevation (n=1)• Resolved on testosterone after concomitant drug

discontinued

6262

Liver Function Tests24 Weeks

SM 1 SM 2

Mean Baseline/

from Baseline

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Alk phos (U/L) 81

-1.7

80

-1.0

79.2

0.0

78.3

-0.6

ALT SGPT (U/L) 22.3

-0.2

21.1

0.4

21.4

0.6

20.7

0.8

AST SGOT (U/L) 22.4

0.0

21.6

0.7

22.2

0.6

21.6

0.8

Bilirubin (mg/dL) 0.46

-0.02

0.45

0.01

0.43

0

0.44

0

S18C

6363

Hematology 24 Weeks

SM 1 SM 2

Mean Baseline

from Baseline

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Hematocrit (%) 40

0.1

40

0.5

40

0.3

40

0.5

Hemoglobin (g/dL) 13.5

0.01

13.4

0.14

13.6

0.09

13.6

0.16

Platelet count (x1000/mcL)

263

-6.5

265

-6.2

262

-4.8

266

-1.9

S32C

6464Hemoglobin Changes With Testosterone Therapy 24 weeks (SM 1 and SM 2)

___

Hem

oglo

bin

- 24

wk

(g/d

L)

Baseline Value (g/dL)Treatment Group - TTS

S34C

6565

Carbohydrate Metabolism 24 Weeks

SM 1 SM 2

Mean Baseline/

∆ from Baseline

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

Glucose (mg/dL) 87

-1.6

86

-0.8

86

-0.4

86

-0.1

HbA1C (%) 5.3

0.03

5.3

0.02

5.3

0.02

5.3

0.05

Insulin (IU/mL) 9.3

0.2

7.6

1.3

8.2

1.5

8.3

2.0

S22C

6666 Serum Lipids 24 Weeks

SM 1 SM 2

Mean Baseline

from Baseline

Placebo

N=279

TTS

N=283

Placebo

N=266

TTS

N=266

T Chol (mg/dL) 215

-2.9

217

-2.8

217

-1.9

219

-3.6

HDL (mg/dL) 64

1.6

61

0.4

65

1.2

63

0.8

LDL (mg/dL) 122

-2.7

125

-0.1

124

-2.1

125

-2.3

Trig (mg/dL) 150

-9

156

-17

148

-9

155

-13

S26C

6767

Coagulation EvaluationsSM 1 24 Weeks

Placebo

N=279

TTS

N=283

Baseline∆ from

BaselineBaseline

∆ from Baseline

PT (sec) 10.9 -0.2 10.8 -0.1

APTT (sec) 29.2 -0.5 29.4 -0.4

Fibrinogen (mg/dL) 381 11.4 387 9.7

PAI activity (U/ml) 8.4 -0.6 7.6 -0.6

PAI antigen (ng/mL) 22.1 1.5 21.9 -1.6

tPA antigen (ng/mL) 5.6 1.3 5.5 1.1

ATIII (functional) 104.0 1.8 105.0 1.4

S31C

6868

Evaluation of Patients with Cardiac Risk Factors

At least three of the following:• BMI >30 kg/m2

• Triglycerides ≥ 150 mg/dL

• HDL < 50 mg/dL

• Blood Pressure ≥ 130/85 mmHg

• Fasting Glucose ≥ 110 mg/dL

S30C

6969Overall AE Summary SM Open-Label Weeks 25-78

S36C

SM 1 and SM 2 Integrated

TTS Exposure

% of Patients

6 mosPTTSN=418

12 mosTTS TTS

N=419

12 mosP TTS TTS

N=167

18 mosTTS TTS TTS

N=154

Patients with AEs

56.2 58.0 53.9 51.3

Serious AEs 1.7 1.7 3.0 0.6

Withdrawals due to AEs

6.0 8.4 5.4 5.2

Androgenic AE withdrawals

2.9 4.1 1.2 2.6

Weeks 53-78Weeks 25-52

7070

Adverse Event SummaryNatural Menopause Trials

NM 1

24 Weeks

NM 252 Weeks

Interim data 1:2 Randomization

% of PatientsPlacebo

N=273

TTS

N=276

Placebo

N=117

TTS

N=241

Patients with AEs 72.9 79.0 79.5 81.3

Serious AEs/Deaths 1.5/02.5/0.7

6.8/0 3.3/0

Withdrawals 7.0 8.0 12.8 12.9

Most common AEs

Application site reactions 39.6 26.4 34.2 31.5

Upper respiratory infections

14.3 15.6 22.2 21.2

Breakthrough Bleeding 6.6 2.9 10.0 7.0

S37C

7171

Androgenic Adverse Events Natural Menopause Trials

NM 124 Weeks

NM 252 Weeks


% of patients

Placebo

N=273

TTS

N=276

Placebo

N=117

TTS

N=241

Acne 4.0 6.5 4.3 7.1

Alopecia 2.9 1.4 4.3 6.2

Hirsutism 6.2 10.5 6.8 7.9

Voice Deepening 2.6 2.9 4.3 2.9

Clitoromegaly 0 0.4 0.9 0.4

S38C

7272

NM 124 Weeks

NM 252 Weeks


% of patients

Placebo

N=273

TTS

N=276

Placebo

N=117

TTS

N=241

Acne 0.4 0 0.9 0.4

Alopecia 1.1 0 0 1.2

Hirsutism 0 0 0.9 0.8

Voice Deepening

0.4 0 0 0

Clitoromegaly 0 0.4 0 0

Androgenic AE WithdrawalsNatural Menopause Trials

S39C

7373

Reported Cases of Breast CancerPatient

numbersObserved

Cases

Surgical Menopause Phase II

Placebo 159 1

TTS 364 0

Surgical Menopause Phase III

Placebo TTS 545 2

Placebo TTS TTS

TTS TTS 549

1

0

Natural Menopause Phase III

Placebo 390 0

TTS 517 0

S40C

7474

Breast Cancer Cases

Case #1 (placebo) 50 year old diagnosed with invasive ductal

carcinoma diagnosed during the initial placebo period

Case #2 (placebo TTS) 63 year old diagnosed with invasive

metastatic adenocarcinoma diagnosed after 5 weeks of TTS treatment (axillary mass, normal mammogram)

S41C

7575

Breast Cancer Cases

Case #3 (placebo TTS TTS) 56 year old diagnosed with tubulolobular

carcinoma after 37 weeks TTS treatment (area noted on baseline mammogram)

Case #4 (placebo TTS) 50 year old diagnosed with DCIS after 24

weeks TTS treatment (new mammographic finding)

S42C

7676

Breast Cancer Summary

Total number of observed cases is within range expected based on the number and risk profile of women

Observed cases in patients with least exposure

S43C

7777

Safety Data Summary

Overall AEs, serious AEs, and withdrawals due to AEs similar for TTS and placebo

Androgenic effects are infrequent, generally mild, and rarely led to withdrawal

No changes in lab values except small change in red cell mass

S44C

7878

Favorable Safety Profile

Testosterone patch was well tolerated No serious safety concerns identified Androgenic adverse events

• Generally mild • Low withdrawal rate• Easily self monitored

S45C

7979

Intrinsa™




8080

Phase III Surgical MenopauseHormone Data

Glenn D. Braunstein, MDProfessor, Department of Medicine

The David Geffen School of Medicine at UCLAChairman, Department of Medicine

Cedars-Sinai Medical Center

H1C

8181

Hormone Data Agenda

How testosterone circulates in the blood and its availability to tissues

Impact of Intrinsa on serum testosterone and SHBG

Correlation of testosterone with efficacy & safety

Endometrial and breast safety

H2C

8282

How Testosterone Circulates in the Blood

SHBG Bound65-80% Albumin Bound

18-35%

Free1-2%

H3C

8383

Reference Range for Testosterone Levels

No accepted reference range available for women

Testosterone levels in women vary widely

Range determined based on 161 pre-menopausal women aged 18-49

0

1

2

3

4

5

6

7

8

9

10

Fre

e T

Co

nc

(p

g/m

L)

Time

H4C

8484

Placebo TTS

Intrinsa Increased Median Free TLevels to Within Reference Range

(Combined SM 1 & SM 2)

0

1

2

3

4

5

6

7

8

9

10

0 24 0 24 52

Fre

e T

Co

nc

(p

g/m

L)

Study Visit (Weeks)

Whiskers describe the 10th and 90th percentiles; dots represent the median valuesDashed lines denote reference ranges in premenopausal women

H6C

8585

0

2

4

6

8

10

12

14

16

18

0 24 0 24 52

Ser

um B

io-T

Con

c (n

g/dL

)

Placebo TTS

Intrinsa Increased Median Bioavailable T to Within Reference Range


Study Visit (Weeks)


H7C

8686

0

20

40

60

80

100

120

140

160

0 24 0 24 52

Ser

um T

otal

-T C

onc

(ng/

dL)

Placebo TTS

Total Testosterone Levels Did Not Exhibit Continued Accumulation


Study Visit (Weeks)


H8C

8787

0

40

80

120

160

200

0 24 0 24 52

Ser

um S

HB

G C

onc

(nm

ol/L

)

Placebo TTS

Serum SHBG Stable Over One Year(Combined SM 1 & SM 2)

Study Visit (Weeks)


H9C

8888

s in Free T Are CorrelatedWith s in Efficacy

H13C

Phase II (pooled)

Phase III(pooled) NM1

Total Satisfying Activity 0.21* 0.17* 0.21*

Desire 0.28* 0.22* 0.19*

Personal Distress -0.25* -0.16* -0.15*

Spearman correlation coefficient

*p < 0.05

8989

Investigating Hormones and Safety

Effect on estrogens and estrogen responsive tissues

Reported and observed androgenic effects

Clinical laboratory measurements

H14C

9090

0

20

40

60

80

100

120

0 24 0 24 52

Ser

um T

otal

Est

radi

ol C

onc

(pg/

mL)

Placebo TTS

No Change in Serum Estradiol Concentrations With Intrinsa


Study Visit (Weeks)

Whiskers describe the 10th and 90th percentiles; dots represent the median values

H15C

9191

No Evidence of Significant Effects on Breast and Endometrium

Karolinska Study – 6 months• Mammographic breast density not different

from placebo • Breast epithelial proliferation not different

from placebo• Significant decrease in stromal cell proliferation with TTS

Natural Menopause Study – 12 months• no increase in endometrial hyperplasia

No Intrinsa-related estrogen side effects in safety database

H16C

9292

Relationship between Maximum Free T and Androgenic Effects

Pooled Phase II and Phase III studies Trend test examined incidence of

androgenic AEs vs. maximum free T Facial hair the only AE that was

statistically associated with free T Facial hair also associated with increases

in objective assessment scores

H17C

9494

Relationship Between Free T and Important Laboratory Parameters

Examined laboratory parameters related to liver function, lipids, carbohydrate metabolism, hematology, and clotting factors

Changes for patients within the highest decile of free T compared to placebo were small and clinically insignificant

H22C

9595

Intrinsa Hormone Summary

Surgically menopausal women with HSDD had low baseline T

TTS increased free, bioavailable & total T

No evidence of T accumulation over 12 months

No changes in estradiol, estrone & SHBG

Higher exposure to free and total T not associated with clinically significant lab changes

H18C

9696

Intrinsa Hormone Summary

Median free and bioavailable T levels raised into pre-menopausal reference range

Changes in T levels correlated with increase in satisfying sexual events, increase in desire, and decrease in personal distress

Available one year data showed: • No evidence of safety concerns with increased T

• Higher free T associated with small increases in facial hair in pooled trials

H19C

9797

Intrinsa™




9898

Hypoactive Sexual Desire Disorder in Menopausal Women

Jan L. Shifren, MD

Assistant Professor of Obstetrics, Gynecology,and Reproductive BiologyHarvard Medical School

Director of the Menopause Program,Vincent Ob/Gyn Service

Massachusetts General Hospital

D1C

9999

Women’s International Study of Health and Sexuality (WISHeS)

Self-report mail survey on general, menopausal, & sexual health

2467 US & 2050 EU women, ages 20-70 520 surgically & naturally menopausal women

in US with partners Three validated instruments:

• SF-36 • Profile of Female Sexual Function (PFSF)• Personal Distress Scale (PDS)

Leiblum SR, et al., International Society for the Study of Women’s Sexual Health,Oct. 10-13, 2002, Vancouver, Canada Leiblum SR, et al. Menopause. 2002;9:474.

D4C

100100

Menopausal Women with HSDD Report Decreased Sexual Activity

Leiblum SR, et al., American Society of Reproductive Medicine, Oct 16-19, 2004, Philadelphia, PA

0

2

4

6

8

10

No

. o

f ev

ents

in

pas

t

30 d

ays

womaninitiates

partnerinitiates

HSDD Normal desire

*

*Statistically significant different from HSDD (p<0.0001)

D2

101101

Women with Low Desire Are Significantly Less Satisfied with Their Sex Lives

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

0 - 20 21 - 40 41 - 60 61 - 80 81 - 100

Desire Domain Score (PFSF)

Sa

tisfa

ctio

n W

ith S

ex L

ife

r=0.49p<0.0001

Leiblum SR, et al., Second International Consultation on Erectile and Sexual Dysfunctions, June 2003, Paris, Fr

D7C

102102

Women Less Satisfied with Their Sex Lives Are Less Satisfied with Their Relationship or Marriage

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

Completely

Dissatisfied

Somewhat

Dissatisfied

Neither

Satisfied or

Dissatisfied

Somewhat

Satisfied

Completely

Satisfied

Satisfaction with Sex Life

Rel

atio

nsh

ip S

atis

fact

ion r=0.56

p<0.0001

D8C

Leiblum SR, et al., Second International Consultation on Erectile and Sexual Dysfunctions, June 2003, Paris, Fr

103103Greater Percentage of HSDD Menopausal Women Report Negative Feelings Due to Their Condition

N=343N=73

Normal Desire (%)

Hypoactive Sexual Desire Disorder (%)

I felt ______ because of my lack of interest in sex

449*Ashamed

456*Low self-esteem

889*I was letting my partner down

1088*Unhappy

579*Frustrated

570*Troubled

874*Hopeless

664*Less feminine

459*Like a sexual failure

* p<0.0001 Leiblum SR, et al., International Society for the Study of Women’s Sexual Health, Oct 28-31, 2004, Atlanta, GA

D9C

104104

Menopausal Women with HSDD Have Diminished Health Status as Measured by the SF-36

*p<0.001Leiblum SR, et al., International Society for the Study of Women’s Sexual Health, Oct 28-31, 2004, Atlanta, GA

0

20

40

60

80

100

Physic

al F

unctio

n

Role P

hysic

al

Bodily P

ain

Gener

al H

ealth

Vitalit

y

Social

Funct

ion

Role E

motio

nal

Men

tal H

ealth

Me

an

HSDD Normal Desire

*

*

*

*

*

**

D10C

105105

Focus on Physiology

Socio-CulturalInfluences

Psychology

Interpersonal Relationships

Physiology• Medical & neurological problems• Gynecological & urogenital problems • Estrogen deficiency• Androgen insufficiency

D22C

106106

400

300

200

100

0

Premenopausal Menopausal

Te

sto

ste

ron

e p

g/m

L

Judd et al. Am J Obstet Gynecol. 1974;118:794.

*p<0.001

**

Testosterone Levels Decrease After Oophorectomy

Baseline

After Oophorectomy

D23C

107107

Physician Response to Lack of Treatment Options

In 2003, 21% of the total prescriptions for branded male testosterone products were written for women*

• Represents 145,000 prescriptions

In 2002-03, there were 1,315,000 prescriptions written for compounded or generic testosterone products for women*

*National Disease and Therapeutic Index, IMS Health, 2003

D18C

108108

Improvement in TTS-treated Patients at

24 Weeks (SM 1 & SM 2)

Endpoint BaselineChange from

Baseline

Satisfying Sexual Activity (4 wk)

2.9 +1.8

Desire 20.7 +10.8

Distress 65.7 -22.7

D24C

109109

Conclusion

HSDD has a significant impact onwomen’s lives

Intrinsa presents a meaningful treatment option for women with HSDD, since it improves sexual desire and activity, and reduces distress

Intrinsa offers an important treatment option for physicians who have no approved therapies for HSDD

D20C

110110

Intrinsa™




111111

Intrinsa Long-term Safety Plan

Michael Steinbuch, PhD

Director, Pharmacovigilanceand Epidemiology


LT1C

112112

No Safety Signals Observedin Intrinsa Trials

Phase II/III Studies found no safety signal• 18 months in SM women• 12 months in NM women

LT2C

113113

Phase IV Safety Study Options

Observational studies

Randomized controlled trials (RCTs)

Patient registries

LT3C

114114

Observational Studies

Advantages• Ideal for rapid signal detection

• Real world setting

• Large numbers of patients

• Ability to adjust for confounding variables

• Evaluate all patients exposed to Intrinsa

LT4C

115115

FDA Feedback

Issues raised by FDA • Inability to capture medical claims data on

women over 65 • Inadequate statistical power to detect

possible safety signal P&G response

• Women over 65 represent 2% to 3% of potential Intrinsa users

• Study will have adequate power

LT5C

116116

Ingenix® LabRx

Comprehensive longitudinal database • Hospital, physician, pharmacy, laboratory

Open formulary (United Healthcare) Validation of endpoints (85% abstraction rate)

Timely claims processing (90% within 4 mos)

Stable patient population (85% retention/yr)

Experienced research staff Proven track record

LT6C

117117

Examples of Analysis Based on Ingenix Data at 2 Years Post-launch

FDA-accepted protocols for cardiovascular outcomes in:• Oral contraceptive users• Oral anti-diabetic therapies

Other outcomes in current, FDA-accepted Ingenix®

postmarketing safety studies• Allergic reactions• Vascular insufficiency of the intestine• GI surgery• Pregnancy and pregnancy outcome

LT7C

118118

Intrinsa Observational Study

Objective: Compare event rates in Intrinsa users vs nonusers

Design: Prospective cohort with 3:1 matching over a 5 year duration

Exclusion criteria: None Endpoints:

• Cardiovascular disease (CVD)• CHD (fatal, nonfatal MI)• Stroke (fatal, nonfatal)• Venous thromboembolic disease (DVT, PE)• Composite CVD endpoint

• Breast cancer

LT8C

119119

Ingenix Patient Population

10,000,000 patients

135,000 menopausal women taking estrogen

Estimated 5,500 Intrinsa users

19,000 potential users of Intrinsa

600,000 menopausal women

LT9C

120120

Power Considerations for Cardiovascular Events

Assumptions:• 5500 new treated patients per year• 0.15% event rate per year*• 50% discontinuation per year• 15% disenrollment per year• alpha=0.05, one-sided test

* JAMA. 2004;291:1701-1712

LT10C

121121

Power for Signal Detection

Year from launch

RRPerson- years

for IntrinsaPower

1 2.0 2837 58%

2 1.9 8148 82%

3 1.7 14510 85%

4 1.6 21320 87%

5 1.5 28319 85%

LT11C

122122

Robustness of Observational Study

Collaborative protocol development• External experts and FDA

Blinded medical expert panel will adjudicate endpoints

Independent safety review board will analyze, interpret and report results to FDA and P&GP

First data at 18 months post-launch

LT12C

123123

Phase IV Safety Study Options

Observational studies

Randomized controlled trials (RCTs)

Patient registries

LT13C

124124

Randomized Controlled Trial Option

Advantages• Ideal for hypothesis testing and

determination of cause/effect• Random allocation minimizes confounding

Disadvantages• Not real world (i.e., inclusion/exclusion criteria)

• Recruitment and retention• Timeliness

LT14C

125125

Patient Registry Option

Advantages• Signal detection• Large number of exposed patients• Real world setting• Recruitment ease

Disadvantages• No comparison group

LT15C

126126

Summary

P&GP is committed to continued monitoring of long-term safety of Intrinsa

Ingenix® LabRx is one of the largest and most comprehensive insurance claims databases

Novel approach• Implementation at launch• External expert design• Independent safety review board

• execute, analyze and report to FDA

Optimal study design for timely signal detection

LT16C

127127

Intrinsa™




128128

Closing Remarks

Joan M. Meyer, Ph.D. Senior Director, New Drug Development


W1C

129129

1) Do the efficacy data represent a clinically meaningful benefit?

Yes We assessed three related, but independent

endpoints Efficacy assessments were patient-centered The results were statistically significant and

highly consistent across all studies and endpoints

The randomized withdrawal trial reinforced the pharmacologic effect of the drug

130130

2) Is the patient exposure adequate to demonstrate long-term safety?

Yes

Number of Patients

Surgical Menopause

Natural Menopause

Total

Exposure

ICH Guideline

Minimum≥ 300 mcg/day 300 mcg/day

At least 1 dose 1288 517 1805

≈ 6 months 957 388 1345 300-600

≈ 12 months 494 136 630 100

≈ 18 months 127 0 127

Total patient months

10742 3350 14092

131131

3) Are there safety concerns or unanswered questions that need to

be studied? It is not uncommon to have unanswered

questions at approval Points to consider:

• No safety signals have been seen• Androgens and estrogens have been used for years

in women• We have proposed a rigorous independent post-

marketing safety study to supplement traditional PV• Labeling will reflect current knowledge

132132

4) Are the efficacy and safety data adequate to support approval of TTS?

Yes

Documents

11 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble