Estetrol (E4) development update: a new horizon for · 2020-05-07 · Human breast epithelial cells are 100 fold more sensitive to E2 E4 antagonizes the proliferation elicited by

Estetrol (E4) development update:

a new horizon for

post-menopausal women?Symposium held at the16th IMS congress, Vancouver Canada

6-9 June 2018

Agenda

10:05 Estetrol: Towards the development of a new generation of

hormonal therapy: update on clinical development

Prof RA Lobo, Department of Obstetrics and Gynecology, Columbia University, New York, USA

09:35 Introducing the first natural estrogen with selective tissue

action (NEST) in menopauseProf JM Foidart, University of Liège and Mithra Pharmaceuticals, Liège, Belgium

09:20 Welcome and introductionProf R Reid, Department of Obstetrics and Gynaecology, Queen's University, Kingston, Canada

10:35 Q&A and Closing remarks Prof R Reid, Department of Obstetrics and Gynaecology, Queen's University, Kingston, Canada

Disclosures

Member of Advisory Board

Merck

Pfizer

Bayer

Mithra

Allergan

R&D company dedicated to providing innovation in women's health

Focus on fertility, contraception, and menopause

Innovation streams

Develops products based on its natural estrogen platform: Estetrol (E4)

Develops long acting therapies: rings, IUDs, and implants

Lead candidates

Contraception: 5th generation oral contraceptive, Estelle® (E4 15mg/DRSP 3mg)

Next generation hormone therapy, Donesta® (E4)

Founded in 1999 as a spin-off of the University of Liège

HQ in Liège, Belgium - 200 people

Mithra Pharmaceuticals

Currently used Estrogens are Aged Molecules

No significant improvement for almost 80 years

Natural Human Estrogens

* Extensive variable data / depending on particle size

1965: Discovery of E4 by Egon Diczfalusy at the Karolinska Institute in Stockholm,

Sweden

2001: Herjan Coelingh Bennink started E4 R&D

2015: Mithra Pharmaceuticals, Liège, Belgium acquired all rights of E4 development

and licensed oncology development to Pantarhei Bioscience

2016: Phase 3 European and North American trials in contraception

and Phase 2b trial in menopause

History of Estetrol (E4)

Agenda




09:35

Prof JM Foidart, University of Liège and Mithra Pharmaceuticals, Liège, Belgium

Introducing the first natural estrogen with selective tissue

action (NEST) in menopause



Introducing the first natural estrogen with selective tissue action (NEST)

in menopauseProf JM Foidart, University of Liège and Mithra Pharmaceuticals

Liège, Belgium

JM Foidart is a member of the Board of Mithra and

chairman of the scientific committee

Disclosures

Natural Human Estrogens

* Extensive variable data / depending on particle size

Physiological Role of Estetrol (E4)?

Physiology of Estetrol (E4)

Estetrol (E4)

Is produced by the fetal liver,

crosses the placenta, is detected

from the 9th week of gestation in

maternal urine. Fetal plasma

levels are 12 times higher than

those of the mother

Circulates at high concentrations

(up to 30 nM) in fetal plasma

Has a very long half-life (2832

hours)

Pharmacokinetics of Estetrol (E4) versus E2

Oral E4 Oral E2

Affinity for ERα LOW (IC50: 170 x1010 ) HIGH (IC50: 5.2 x1010)

Affinity for ERα/ERβ

5 1

T1/2 2832 hours 2 hours

Oral bioavailability >70% 1%

Binding to circulating proteins

LOW

No binding to SHBG

=> At least 50% free active fraction

HIGH

SHBG (37%) and albumin (61%)

=> 12% free active fraction

Active metabolitesNo evidence of active or

carcinogenic metabolites

Active E1, E3, catechol

estrogens (precursors of carcinogenic

quinones) and inactive metabolites

(high inter-subject variability)

E4 Pharmacokinetics in Postmenopausal Women

Coelingh Bennink HJT et al., Climacteric. 2017 Jun;20(3):285-289 | Visser M et al., Climacteric. 2008 1 (suppl 1):31-40

High and dose proportional

oral bioavailability

Low interindividual

variations of plasma levels

T1/2 ~28 hours

Tmax ~ 3040 min

Dose dependent Cmax

No safety concerns

The two forms of the Estrogen Receptor-α (ER-α)

The two forms of the Estrogen Receptor-α (ER-α)

Activation of the Membrane ERα by E2 increases: NO production by endothelial cells proliferation of normal & malignant breast cells

angiogenesis migration & invasion of malignant breast cells

Arnal JF et al. Physiol Rev. 2017 Jul 1;97(3):1045-1087

Estetrol (E4) reduces Migration and Invasion by Breast Cancer Cells

Giretti MS et al. Front Endocrinol (Lausanne). 2014;5: 80 | Gérard C et al. J Endocrinol. 2015 Jan;224(1):85-89

Mouse Models of Selective Loss of Function

Billon-Gales et al. Proc Natl Acad Sci U S A. 2011 Aug 9; 108(32):13311–13316 | Adlanmerini M et al. Proc Natl Acad Sci U S A. 2014 Jan 14; 111(2):E283–E290


Estetrol (E4) is an estrogen with a

distinctive profile of ERα activation

Estetrol (E4) is a NEST

E4 activates the nuclear ERα, but is

an antagonist of the membrane ERα

E4 is the first Natural Estrogen with

Selective Action in Tissues (NEST)


The use of Transgenic Mice coupled with Pharmacological Agents Allows to Precisely Predict the Profile of Activity of E4 in Human

Brain Breast

Bone Vagina Uterus CV-system

Tumoral angiogenesis

E4 - A Major Breakthrough in Basic Research and Clinical sciences, at the Heart of Multiple National and International Academic Collaborations

What are the potential

benefits of using E4 in

comparison to

currently available

estrogens?

Low risk of drug-drug interactions

Low carcinogenic impact

Low impact on triglyceride levels

Neutral Impact on markers of VTE risk & beneficial impact on

experimental models of thrombosis

Favorable influence on renin-angiotensin-aldosterone loop

What are the Potential Benefits of using E4?

1. Low Risk of Drug-drug Interactions

% inhibition of cytochrome P450 enzymes

CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4

EE <10 <10 82 <10 45

E2 19 <10 63 <10 <10

E4 <10 <10 <10 <10 <10

E4 does not interact with

the CYP450 family

The risk of drug-drug

interactions is low

Visser M et al., Climacteric. 2008 1 (suppl 1):31-40








2. Low Carcinogenic Impact

Gompel A by courtesy and Gérard C. et al Oncotarget. 2015 Jul 10; 6(19): 17621–17636

Human breast epithelial cells are

100 fold more sensitive to E2

Human breast epithelial cells are

100 fold more sensitive to E2

E4 antagonizes the proliferation

elicited by E2

Significantly different from single E2

treatment p<0.05 (#); p<0.01 (##)

Enhancement of MCF-7 breast

cancer cells proliferation requires

1001000 fold higher doses of

E4 than E2


E2 E2

E4 E4

Gompel A by courtesy and Gérard C. et al Oncotarget. 2015 Jul 10; 6(19): 17621–17636


Dose dependent

prevention of breast tumor

development with E4

Mean number of mammary tumors per animal at necropsy (+SEM)

Coelingh Bennink, HJT et al. Climacteric. 2008;11(sup1):29 | Visser M et al. Horm Mol Biol Clin Investig. 2012 Apr 1;9(1):95-103


Mean number of mammary tumors per animal at necropsy (+SEM)

Baseline

4

5

0

Mean

nu

mb

er

of

tum

ors

3

2

1

Necropsy

## ## ##

## ##

#

**

**

Vehicle

OVX

TAM 1.0 mg

E4 1.0 mg

E4 1.0 mg

E4 10.0 mg

E4 inhibits growth of

existing tumors

Coelingh Bennink, HJT et al. Climacteric. 2008;11(sup1):29 | Visser M et al. Horm Mol Biol Clin Investig. 2012 Apr 1;9(1):95-103

Neo-adjuvant E4 Breast Cancer Study

Double-blind, randomized, placebo controlled, proof- of-concept study

15 post- and 15 premenopausal women with ER+ breast cancer

Preoperative treatment for 14 days with 20 mg E4 per day or placebo

immediately followed by surgery

Effect of E4 on tumor biology (Ki67 and apoptosis)

Singer CF et al. Carcinogenesis. 2014 Nov;35(11):2447-2451

Significant increase in number of apoptotic cells

No change in proliferation (expression of Ki67)

Singer CF et al. Carcinogenesis. 2014 Nov;35(11):2447-2451

Anti-estrogenic Effects of E4 in Women with ERα Positive

Early Breast Cancer

Mixed estrogen

agonist / antagonist

• Weak estrogen agonist in in vitro breast cancer cell lines

• Strong E2 antagonism in vitro and in vivo models

Anti-proliferative

breast tumor

• DMBA rat model

• Prevention of breast tumor development and regression

of existing tumors

• Phase 1 breast cancer clinical study

E4 is a NESTSelective activation of nuclear ERα and blockade of

membrane ERα

E4 and the Normal or Malignant Breast - Summary








3. Low Impact on Triglyceride Levels

Percentage change from baseline triglyceride levels after 28 days of treatment

Elevated triglycerides levels

are associated with

coronary heart diseases

Coelingh Bennink. HJT et al. Menopause. 2017 Jun;24(6):677-685

E2 2 mg (n=10)

E4 2 mg (n=10)

E4 10 mg (n=10)

E4 20 mg (n=10)

E4 40 mg (n=9)

0

5

10

15

20

25

30

35

40

45





Neutral Impact on markers of VTE risk & beneficial

impact on experimental models of thrombosis


- E4 (death)

+E4 (survival)Venous Thromboembolism is induced by injection of

collagen (0.4 mg/kg) and epinephrine (60 μg/kg) into the jugular vein

p<0.05

Valera et al. Mol Cell Endocrinol. 2018 (in press)

4. Beneficial Effect in Experimental Models of VTE

Inferior Vena Cava was partially or completely ligated


*** p<0.01

4. Beneficial Effect in Experimental Models of VTE

p <0.05

A 1 × 4-mm strip of paper saturated with a 7% FeCl3 solution was

applied to the adventitia of the left carotid artery for 2 minutes then

removed. The right carotid was used as control. Blood flow was

monitored continuously throughout the procedure.


4. Beneficial Effect in Experimental Model of Arterial Thrombi Formation

4. Lower Changes in Hemostasis Biomarkers in Women receiving E4 15 mg + DRSP 3 mg

Mean percentage change from baseline at cycle 6

Data on file Mithra Pharmaceuticals

Mean

%



Sex Hormone Binding Globulin (SHBG) Cycle 6 - Baseline

SH

BG

Change (

%)



Change of APC resistance (Thrombin generation)1,2

Cycle 6 – Baseline (Mean change)











5. Favorable Influence on Renin-angiotensin-aldosterone loop

E4 protects against Angiotensin II induced

hypertension

Fontaine C et al. J. Am. Heart Assoc. 2018 (in press)

5. Favorable Influence on Renin-angiotensin-aldosterone loop

E4 is the First NEST and Different to Other Estrogens

Agonist on the nucleus

Beneficial effects on bone, vagina,

endometrium & cardiovascular system

Antagonist on the membrane

E4 blocks the estrogen receptor in breast

tumor angiogenesis

Mixed antagonist and agonist effects

On the liver and the breast


Low breast stimulation, pain, and

low carcinogenic impact


Neutral impact on markers of VTE risk

E4 is the First NEST

Natural

Estrogen with

Selective Action in

Tissues

Kluft C et al. Contraception. 2017 Feb;95(2):140-147 | Gerard C et al. Oncotarget. 2015;6(19):17621-36 | Visser M et al. Horm Mol Biol Clin Invest. 2012;9:95-103 | Visser M et al. Climacteric. 2008 11 Suppl 1:64-8

Mawet M et al. Eur J Contracept Reprod Health Care. 2015;20(6):463-75 | Apter D. et al. Contraception. 2016;94(4):366-73 | Data on file Mithra Pharmaceuticals

Estetrol (E4) offers a Unique Development Platform for Treatment of Menopause, the Prevention of Pregnancy and Other Indications

*HIE = Hypoxic Ischemic Encephalopathy

E4 - A Major Breakthrough in Basic Research and Clinical sciences, at the Heart of Multiple National and International Academic Collaborations

Agenda








Estetrol: Towards the development of a new generation of hormonal therapy:

update on clinical developmentProf RA Lobo, Department of Obstetrics and Gynecology

Columbia University, New York, USA

Mithra USA Advisory Board

Did not participate in current clinical trials, but has

assessed the analysed data

Consultant: Mithra, TherapeuticsMD, AMAG

Financial support for clinical trial to Columbia University:

TherapeuticsMD, Ogeda, Bayer, NIH

Disclosures

E4 is unique in that it is a “NEST”, not a SERM

The NEST concept has been studied extensively

E4: A Promising New Estrogen

Expected Benefits of E4 in Comparison to Currently Available Estrogens

Favorable

lipid profile

Low risk

of drug-drug

interactions

Favorable

breast profile

Favorable

thrombotic profile

Randomized, open-label, multiple-rising-dose study

Doses: E4 (2 mg, 10 mg, 20 mg, 40 mg) or E2V (2 mg)

Duration: 28 days

Objectives

Safety

Hot flushes (E4 2 mg, E4 10 mg, and E2V 2 mg groups)

Vaginal cytology

Phase 1 Clinical Trial Design

E4 2 mg and 10 mg decreased the Number of Hot Flushes

Coelingh Bennink HJT et al., Maturitas. 2016 Sep;91:93-100

0

2

4

6

8

10

12

14

2mg E2V 2 mg E4 10 mg E4

Me

an

nu

mb

er

of h

ot flush

es

pe

r d

ay

Screening Day 14 Day 28 Day 56 (follow up)

(n=4) (n=5) (n=8)

2 mg E2V

Patients with at least 35 VMS per week

E4 increased the Number of Superficial Cells

Parabasal cells

mean %

Intermediate cells

mean %

Superficial cells

mean %

Screening Day 28 Screening Day 28 Screening Day 28

E4

2 mg 40 3 47 81 4 18

10 mg 51 8 46 45 13 47

20 mg 29 0 65 60 3 40

40 mg 65 0 30 46 6 53

E2V 2 mg 32 0 64 74 5 26

Coelingh Bennink HJT et al., Maturitas. 2016 Sep;91:93-100

Phase 2 Clinical Trial

Multicenter Dose-Finding, Randomized,

Double-Blind, Placebo-Controlled Study

to Select the Daily Oral Dose of E4

for the Treatment of Vasomotor Symptoms (VMS)

in Post-Menopausal Women

Clinicaltrials.gov NCT0283431 | EudraCT 2015-004018-44

To select the minimum effective oral dose of E4 for the

treatment of VMS in post-menopausal women

Primary Objective

Secondary objectives included the evaluation of

different doses of E4 on genitourinary syndrome of

menopause symptoms/vulvar and vaginal atrophy, bone

turnover, parameters of health-related quality of life, and

safety parameters such as markers of coagulation

Secondary Objectives

Prospective, multicenter, randomized, placebo-controlled, double-blind

N=225

Five groups (1:1:1:1:1)

Up to 4 weeks washout (if needed)

E4 (2.5 mg, 5 mg, 10 mg, and 15 mg), or placebo for 12 weeks

Efficacy and safety assessments at week 4 and week 12

Dydrogesterone 10 mg once-daily for 14 days in non-hysterectomized women

Design

Change in weekly frequency of moderate to severe VMS

Change in severity of moderate to severe VMS

Primary Endpoints

Written informed consent

Postmenopausal women

40‒65 years

BMI 18‒35 kg/m2

≥7 moderate to severe hot flushes per day, or ≥50 moderate to severe hot

flushes in the week preceding randomization

Not hysterectomized if transvaginal ultrasonography (TVUS) showed a bi-

layer endometrial thickness ≤5 mm

Main Inclusion Criteria

A history of malignancy, thromboembolism or coagulopathy,

diabetes with poor glycemic control, and breast cancer

Women with a uterus and history or presence of uterine cancer,

endometrial hyperplasia, polyp or abnormal cervical smear

Main Exclusion Criteria

Change from baseline to week 12 in the genitourinary

syndrome of menopause symptoms

Vaginal dryness

Vaginal and/or vulvar irritation/itching

Dysuria

Vaginal pain associated with sexual activity

Vaginal bleeding associated with sexual activity

Vaginal maturation index

Vaginal pH

Secondary Endpoints (1)

Change from baseline to week 12 in Menopause Rating

Scale (MRS) score

Psychological symptoms, somato-vegetative symptoms, urogenital

symptoms

Change from baseline to week 12 in bone turnover

Change from baseline to week 12 in binding globulins,

lipids, glucose homeostasis, and coagulation

parameters

Secondary Endpoints (2)

Psychological symptoms:

Depressed, irritable, anxious, exhausted

Somato-vegetative symptoms:

Sweating/flush, cardiac complaints, sleeping disorders, joint

& muscle complaints

Urogenital symptoms:

Sexual problems, urinary complaints, vaginal dryness

Menopause Rating Scale

Safety parameters

Adverse event monitoring

Physical and gynecological examination

ECG and routine clinical laboratory tests

For non-hysterectomized subjects

Bi-layer endometrial thickness using TVUS

Bleeding pattern by daily diary recording

Safety Assessments

If bi-layer endometrial thickness ≥15 mm, and/or

abnormal uterine bleeding

Endometrial biopsy

Sequential 10 mg dydrogesterone once-daily

Endometrial hyperplasia

Withdraw subject

Treatment of hyperplasia as per local guidelines

Safety - Non-hysterectomized Women

Primary endpoints: ITT analysis

E4 versus placebo: change from baseline to week 4 and

baseline to week 12

Analysis of co-variance with treatment as a fixed effect and

baseline as a covariate

Alpha set 0.05

Statistics

Disposition of Subjects

E4

Total Placebo 2.5 mg 5 mg 10 mg 15 mg

Randomized 260 55 54 48 53 50

Treated 257 55 53 47 53 49

Completers 200 41 44 36 38 41

Discontinued 57 14 9 11 15 8

• Clinical trial conducted in Europe (Belgium, UK, Ireland, Czech Republic and Poland)

• Mean age: 54.2 4.4 years

Analysis Sets

E4

Total Placebo 2.5 mg 5 mg 10 mg 15 mg

ITT* 257 55 53 47 53 49

PP 179 37 39 35 34 34

* ITT population included women who took at least 1 dose of the study treatment and had 4 consecutive days of VMS diary data

at baseline and for 1 on-treatment week

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

Placebo E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg

E4 Plasma ConcentrationsM

ean

(+SD

) p

lasm

a c

on

cen

trati

on

(n

g/m

l)

E4 15 mg reduced VMS frequency

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

0 2 4 6 8 10 12

p<0.05

-65%

-84%

Weeks

Mean

% o

f ch

an

ge f

rom

base

lin

e

p<0.05


E4 2.5 mg

E4 15 mg

E4 5 mg

Placebo

E4 10 mg

VMS Severity


Mean

ch

an

ge f

rom

base

lin

e

-28%

-44%

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

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

p<0.05

p<0.05

Weeks

E4 2.5 mg

E4 15 mg

E4 5 mg

Placebo

E4 10 mg

E4 15 mg reduced VMS frequency


0

10

20

30

40

50

60

70

80

90

100

≥50% responder ≥75% responder

Resp

on

ders

(%

)

E4 15 mg Placebo

p<0.01 vs placebo

p<0.001 vs placebo

≥ 50% response ≥ 75% response

VVA Self-assessment

Vaginal pain

associated with

sexual activity

Dysuria

Vaginal and/or

vulvar

irritation/itching

Vaginal dryness

Baseline W12 Baseline W12 Baseline W12 Baseline W12

E4

2.5 mg 0.6 0.3 0.2 0.0 0.7 0.3 1.0 0.5

5 mg 1.0 0.5 * 0.2 0.0 0.6 0.4 1.3 0.7

10 mg 0.6 0.2 ** 0.2 0.1 0.7 0.3 1.0 0.5

15 mg 0.7 0.3 ** 0.3 0.3 0.5 0.4 1.1 0.5 *

Placebo 1.0 0.7 0.2 0.3 0.8 0.5 1.3 0.9

*p<0.05 vs placebo at Week 12 (W12) | **p<0.001 vs placebo at Week 12 (W12)


E4 increased the Number of Superficial Cells

Parabasal cells

mean %

Intermediate cells

mean %

Superficial cells

mean %

Baseline W12 Baseline W12 Baseline W12

E4

2.5 mg 13.6 1.1 73.2 64.8 13.2 34.1

5 mg 27.6 5.6 59.9 49.3 12.5 45.0

10 mg 17.2 0.7 69.8 44.1 13.0 55.2

15 mg 26.9 0.9 59.4 44.7 13.7 54.4

Placebo 22.3 16.0 69.0 68.7 8.6 15.3


E4 increased the Vaginal Maturation Index

0

10

20

30

40

50

60

70

80

90

****

** **

** p<0.001 vs placebo at Week 12

Vaginal Maturation Index

E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo

Baseline Week 12


Vaginal pH

Mean vaginal pH

Baseline Week 12

E4

2.5 mg 4.60 4.43

5 mg 4.84 4.61

10 mg 4.73 4.64

15 mg 4.61 4.48

Placebo 4.58 4.71


0

5

10

15

20

25

30

35

40

0

100

200

300

400

500

600

700

800

900

E4 decreased Bone Resorption

* p<0.05 vs placebo at Week 12

Baseline Week 12

E4 2.5 mg

E4 5 mg E4 10 mg E4 15 mg Placebo

µg

/L (

mean

+SD

)

µg

/L (

mean

+SD

)

C-terminal telopeptide (CTX-1) Osteocalcin

E4 2.5 mg

E4 5 mg E4 10 mg E4 15 mg Placebo

*


Menopause Rating Scale

0

5

10

15

20


Baseline Week 4 Week 12

Mean

M

RS S

core


Baseline Week 12

0

20

40

60

80

100

120

140

160

Mean

mm

ol/

mo

l

SHBG

**


**

*p<0.05 vs placebo at Week 12 | **p<0.001 vs placebo at Week 12 (W12)

0%

25%

50%

75%

100%

125%

150%

175%

Change from Baseline in SHBG for E4, E2, and CEE

E4 slightly increased SHGB

Matsui S et al. J Obstet Gynaecol. 2017 Jul;37(5):627-632 | Slater CC et al. J Reprod Med 2001 Dec;46(12):1052-1056 | Casson PR et al. Obstet Gynecol. 1997 Dec;90(6):995-8 | Shifren JL et al. Menopause. 2007

Nov-Dec;14(6):985-94 | Shifren JL et al. J Clin Endocrinol Metab. 2008 May;93(5):1702-1710 | Vehkavaara S et al. Circulation. 2000 Nov 28;102(22):2687-93 | Data on file Mithra Pharmaceuticals

E4 did not increase Triglycerides but increased HDL-C

0

0.5

1

1.5

2

2.5

3


mm

ol/

mo

l

Triglycerides

0

0.5

1

1.5

2

2.5


mm

ol/

mo

l

High density lipoprotein-C

0

1

2

3

4

5

6

7

8


mm

ol/

mo

l

Total cholesterol (C)

0

1

2

3

4

5


mm

ol/

mo

l

Low density lipoprotein-C

* ** **

Mean values (+SD ) are shown in all 4 graphs*p<0.05 vs placebo at Week 12 | **p<0.001 vs placebo at Week 12 (W12)

Data on file Mithra PharmaceuticalsBaseline Week 12

0

10

20

30

40

50

0

2

4

6

8

10

12

0

5

10

15

20

25

30

35

40

45

0

1

2

3

4

5

6


mm

ol/

mo

l


HOMA - Insulin Resistance

E4 decreased HbA1c suggesting improved Glucose Tolerance



[mIU

/L

Insulin concentration

mm

ol/

mo

l

HbA1c

*


**


Fasting glucose

Ind

ex

0.00

20.00

40.00

60.00

80.00

100.00

120.00

140.00


%

Antithrombin

0

20

40

60

80

100

120

140

160

0

50

100

150

200


%

Factor VIII Activity [%]


%

Protein C

E4 did not affect Coagulation Markers (1)

Data on file Mithra PharmaceuticalsBaseline Week 12Mean values (+SD ) are shown in all 4 graphs

0

20

40

60

80

100

120

140


%

Protein S, Free [%]

*

0

5

10

15

20

25

30

35

40


[UG

/L]

Tissue factor pathway inhibitor


0

100

200

300

400

500

600

700


pm

ol/

ml

Prothrombin Fragments 1 + 2


0

200

400

600

800

1,000

1,200


mm

ol/

mo

l

D-Dimer

E4 did not affect Coagulation Markers (2)

Safety – Endometrial Thickness at all Visits

0

2

4

6

8

10

12


Screening

Visit 2

Visit 3

Visit 4 (EOT)

Visit 5 (EOS)

Mean

en

do

metr

ial th

ick

ness

(m

m)

Safety - Endometrium


No endometrial hyperplasia

Endometrial thickness returned to baseline after

progestin therapy at 12 weeks

Safety – Treatment Emerging Adverse Events

0

5

10

15

20

25

Genital bleeding Pelvic pain Mastalgia Endometrial thickening

2.5 mg E4 5 mg E4 10 mg E4 15 mg E4 Placebo

Nu

mb

er

of

TEA

Es

*

*Reproductive system and breast disorder system organ class: TEAEs reported for 2 subjects Data on file Mithra Pharmaceuticals

>15 mm

15 mg appears to be most effective dose for VMS

All doses studied improved GSM/VVA

Positively influenced bone turnover

Triglyceride levels were not increased; increased HDL-C

Glucose tolerance was improved

No effects on coagulation parameters

No apparent safety concerns, and E4 was well tolerated

Summary: Effects of E4


The use of Transgenic Mice coupled with Pharmacological Agents

Allows to Precisely Predict the Profile of Activity of E4 in Human

Brain Breast

Bone Vagina Uterus CV-system

Tumoral angiogenesis

E4 is a promising natural estrogen for the

treatment of postmenopausal women

The selective tissue properties create a unique

safety profile that should enhance the

therapeutic utility of E4

Conclusion

Agenda








Q&A

Closing remarks

Prof R Reid, Department of Obstetrics and Gynaecology Queen's

University, Kingston, Canada

Estetrol (E4) development update: a

new horizon for

post-menopausal women?Symposium held at the16th IMS congress, Vancouver Canada

6-9 June 2018

Documents

Estetrol (E4) development update: a new horizon for · 2020-05-07 · Human breast epithelial cells are 100 fold more sensitive to E2 E4 antagonizes the proliferation elicited by