estetrol (e4) development update: a new horizon for · 2020-05-07 · human breast epithelial cells...
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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
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
Prof JM Foidart, University of Liège and Mithra Pharmaceuticals, Liège, Belgium
Introducing the first natural estrogen with selective tissue
action (NEST) in menopause
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
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
Arnal JF et al. Physiol Rev. 2017 Jul 1;97(3):1045-1087
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)
Arnal JF et al. Physiol Rev. 2017 Jul 1;97(3):1045-1087
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
What are the Potential Benefits of using E4?
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
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
2. Low Carcinogenic Impact
E2 E2
E4 E4
Gompel A by courtesy and Gérard C. et al Oncotarget. 2015 Jul 10; 6(19): 17621–17636
2. Low Carcinogenic Impact
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
2. Low Carcinogenic Impact
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
What are the Potential Benefits of using E4?
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
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
What are the Potential Benefits of using E4?
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
- 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
Valera et al. Mol Cell Endocrinol. 2018 (in press)
*** 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.
Valera et al. Mol Cell Endocrinol. 2018 (in press)
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
%
4. Lower Changes in Hemostasis Biomarkers in Women receiving E4 15 mg + DRSP 3 mg
Data on file Mithra Pharmaceuticals
Sex Hormone Binding Globulin (SHBG) Cycle 6 - Baseline
SH
BG
Change (
%)
4. Lower Changes in Hemostasis Biomarkers in Women receiving E4 15 mg + DRSP 3 mg
Data on file Mithra Pharmaceuticals
Change of APC resistance (Thrombin generation)1,2
Cycle 6 – Baseline (Mean change)
4. Lower Changes in Hemostasis Biomarkers in Women receiving E4 15 mg + DRSP 3 mg
Data on file Mithra Pharmaceuticals
What are the Potential Benefits of using E4?
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
Data on file Mithra Pharmaceuticals
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 risk of drug-drug interactions
Low breast stimulation, pain, and
low carcinogenic impact
Low impact on triglyceride levels
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
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
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
Data on file Mithra Pharmaceuticals
E4 2.5 mg
E4 15 mg
E4 5 mg
Placebo
E4 10 mg
VMS Severity
Data on file Mithra Pharmaceuticals
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
Data on file Mithra Pharmaceuticals
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)
Data on file Mithra Pharmaceuticals
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
Data on file Mithra Pharmaceuticals
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
Data on file Mithra Pharmaceuticals
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
Data on file Mithra Pharmaceuticals
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
*
Data on file Mithra Pharmaceuticals
Menopause Rating Scale
0
5
10
15
20
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
Baseline Week 4 Week 12
Mean
M
RS S
core
Data on file Mithra Pharmaceuticals
Baseline Week 12
0
20
40
60
80
100
120
140
160
Mean
mm
ol/
mo
l
SHBG
**
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
**
*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
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
mm
ol/
mo
l
Triglycerides
0
0.5
1
1.5
2
2.5
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
mm
ol/
mo
l
High density lipoprotein-C
0
1
2
3
4
5
6
7
8
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
mm
ol/
mo
l
Total cholesterol (C)
0
1
2
3
4
5
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
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
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
mm
ol/
mo
l
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
HOMA - Insulin Resistance
E4 decreased HbA1c suggesting improved Glucose Tolerance
Data on file Mithra PharmaceuticalsBaseline Week 12
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
[mIU
/L
Insulin concentration
mm
ol/
mo
l
HbA1c
*
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
**
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)
Fasting glucose
Ind
ex
0.00
20.00
40.00
60.00
80.00
100.00
120.00
140.00
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
%
Antithrombin
0
20
40
60
80
100
120
140
160
0
50
100
150
200
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
%
Factor VIII Activity [%]
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
%
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
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
%
Protein S, Free [%]
*
0
5
10
15
20
25
30
35
40
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
[UG
/L]
Tissue factor pathway inhibitor
Data on file Mithra PharmaceuticalsBaseline Week 12
0
100
200
300
400
500
600
700
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
pm
ol/
ml
Prothrombin Fragments 1 + 2
Mean values (+SD ) are shown in all 3 graphs*p<0.05 vs placebo at Week 12 | **p<0.001 vs placebo at Week 12 (W12)
0
200
400
600
800
1,000
1,200
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
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
E4 2.5 mg E4 5 mg E4 10 mg E4 15 mg Placebo
Screening
Visit 2
Visit 3
Visit 4 (EOT)
Visit 5 (EOS)
Mean
en
do
metr
ial th
ick
ness
(m
m)
Safety - Endometrium
Data on file Mithra Pharmaceuticals
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
Arnal JF et al. Physiol Rev. 2017 Jul 1;97(3):1045-1087
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
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
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