Neurokinine 3 receptor antagonists as a novel treatment for menopausal hot flashes PROF. DR. H. DEPYPERE Menopauze kliniek, Universitair Ziekenhuis, Gent.
Neurokinine 3 receptor antagonists as
a novel treatment for menopausal hot
flashes
PROF. DR. H. DEPYPERE
Menopauze kliniek, Universitair Ziekenhuis, Gent.
Proposed Mechanism of
Action
• Mittleman-Smith et al., PNAS 2012 &
Endocrinology 2015
• NK3R expressing KNDy & POA neurons
modulate heat dissipation in OVX rat
• Jayasena et al., SciRep 2015
• NKB induces hot flushes in
premenopausal women
• Crandall et al., Menopause 2017
• genetic variation in Tacr3 (‘NK3R’)
associated with hot flashes in
menopausal women
Rance et al. (2013)
Front Neuroendocrinol 34:211 Key References
Figure used with author permission
Methode: study design en deelnemers
• Gerandomiseerde, placebo-gecontroleerde, dubbel
blinde, two way cross over trial met als doel controle
van de doeltreffendheid van NK3R antagonist
Julia K Prague: Lancet 2017 389: 1809-20
• Deelnemers:
40-62 jr
>6 hot flushes/24 uur
Geen menses > 12 maanden
Geen medicatie voor hot fluses <8 weken voorafgaand
outcome
• Primaire outcome:
– # hot flushes tijdens 4e week van behandeling.
– Vergelijking #hot flushes 4e week met de 2e week van de
baseline periode.
– Meting hot flushes
1. Tally Chart (streepjes zetten)
2. Tally Counter (app voor smartphone)
– Optellen voor en na slapen gaan van het aantal flushes
• Secundaire outcome
Ernst van de hot flushes
Subjectieve last
Geassocieerde menopauzale klachten
LH pulsatie
# hot flushes gemeten via huid aangevoerde monitor
• Gemiddelde van de 4e week van behandeling
werd vergeleken met de 2e week van de baseline
periode
68 gerekruteerde
28 patiënten die de
volledige studie
doorlopen hebben
(dropout 24%)
Resultaten
# wekelijkse hot flushes gedaald tov placebo:
45% pp decrease (p<0,0001)
Ernst van hot flushes gedaald, last, subjectieve
effect, huid geleide monitoring
Verbetering vasomotorische sympt,
psychosociale verbetering, fysieke verbetering.
Géén verbetering op seksueel gebied
Géén verandering in LH pulsatie wel amplitude,
E2 onveranderd
• Compliance : “hoog”
• Bijwerkingen:
•
• 3 pt ALT/AST stijging met normaal
bilirubine (normalisatie na stoppen R)
• CAVE: Transaminase stijgingen
Discussie
• Verbetering op primaire en secundaire eindpunten
• Therapie bestaat uit een goed verdraagzame
behandeling
• Stijging in transaminasen, billirubine normaal
• Objectieve en subjectieve verbetering: gelijkaardige
resultaten
Discussie (2)
• Kleine groep deelnemers
• Grotere drop out dan verwacht
• Unicentrische studie
47, Rue Adrienne Bolland,
6041 Gosselies, Belgium
Tel. +32 71 348 500
Fax +32 71 348 519
www.ogeda.com
Clinical Evaluation of the NK3 Receptor Antagonist
Fezolinetant (a.k.a. ESN364) for the Treatment of
Menopausal Hot Flashes
Herman Depypere1, Dirk Timmerman2, Gilbert Donders3, Peter Sieprath4,
Steven Ramael5, Jean Combalbert5, Hamid R. Hoveyda5, Graeme L. Fraser5
1 Breast and Menopause, Ghent University Hospital, Gent, Belgium 2 Dept Obstetrics and Gynaecology, University Hospitals, Leuven, Belgium
3 Femicare vzw, Clinical Research for Women, Tienen, Belgium 4 Ziekenhuis Oost-Limburg, Genk, Belgium
5 OGEDA SA
Fezolinetant (‘ESN364’)
Oral, proprietary NK3R Antagonist Ph-1: Efficacy in Premenopausal
Women
• Medicinal Chemistry
• Hoveyda et al. (2015), J Med Chem
58:3060
• Hoveyda et al. (2015), ACS Med
Chem Lett 6:736
• Preclinical Pharmacology
• Fraser et al. (2015), Endocrinol
156:4214
• Clinical Pharmacology
• Fraser et al. (2016), JCEM 101:417
0 4 8 1 2 1 6
0 . 0
0 . 4
0 . 8
1 . 2
1 . 6
T i m e ( h )
Ra
tio
LH
:F
SH
18 0 m g
P l a c e b o
2 0 m g
6 0 m g
p<0.05 @ 4h for all dose groups
Menopausal HF Trial Design: fezolinetant (Phase II)
Endpoints
Primary Endpoint (FDA Guidance)
HF Frequency and Severity at wks 4, 12
Secondary Endpoints
Patient Questionnaires:
QoL, Sleep, Bother, Productivity
Safety and Pharmacokinetics
Hormones: LH, FSH, estradiol, SHBG
Trial design
Timing
8 Double
blind Sites
12
Weeks
80
Patients
2
Cohorts: 90mg (BID) vs. PBO
Patients with ≥49
moderate/severe HF/week
at baseline
Daily self-reporting of HF with
weekly data compilation
Enrollment complete ahead of
schedule, Top-line data in
12/2016
12w Treatment 2w FUP
Subject Demographics
Placebo 90 mg b.i.d.
Mean Values (N = 44) (N = 43)
------------ ----------- ----------
AGE (years) 53.7 53.3
HEIGHT (cm) 163.6 165.7
WEIGHT (kg) 70.8 69.0
Body Mass Index (kg/m²) 26.5 25.1
Daily Hot Flash Frequency 10.3 11.5
Daily Hot Flash Severity 2.37 2.36
87 patients randomised in total
4 patients withdrew consent for various reasons
(personal-social, perceived lack of efficacy,…)
2 patients discontinued due to adverse event
1 patient discontinued due to violation of
inclusion criteria
80 patients completed the study in
the ITT population (40/40)
Effect on Frequency of Moderate + Severe Hot Flashes
Average Daily HF Frequency Reported as per FDA Guidelines
fezolinetant 90mg BID (N=40)
placebo (N=40)
Baselin
e
Week 4
Week 8
Week 1
2
0
2
4
6
8
HF
RD
IS
P l a c e b o (N = 4 0 )
f e z o l i n e t a n t 9 0 m g B I D (N = 4 0 )
n o t s i g n i f i c a n t
Week 4: 14/40 patients have ZERO HF in FEZO group
(vs 2/40 in placebo group)
BA
SE
LI N
E
W
EE
K 2
W
EE
K 4
W
EE
K 6
W
EE
K 8
W
EE
K 1
0
W
EE
K 1
2
FU
P W
K2
0
3
6
9
12
HF
Fr
eq
ue
nc
yp < 0 . 0 0 0 1
Quality of Life: HFRDIS Questionnaire
Measured by the Hot Flash Related Daily
Interference Scale (HFRDIS):
Psychometrically sound and validated measure for assessing the
impact of hot flashes on daily activities and overall quality of life in
clinical practice
HFRDIS (mean score ± SEM)
0
2
4
6
HF
RD
IS
fezolinetant 90mg BID (N=40)
placebo (N=40)
Baselin
e
Week 4
Week 8
Week 1
2
0
2
4
6
8
HF
RD
IS
P l a c e b o (N = 4 0 )
f e z o l i n e t a n t 9 0 m g B I D (N = 4 0 )
n o t s i g n i f i c a n t
Baselin
e
Week 4
Week 8
Week 1
2
0
2
4
6
8
HF
RD
IS
P l a c e b o (N = 4 0 )
f e z o l i n e t a n t 9 0 m g B I D (N = 4 0 )
n o t s i g n i f i c a n t
p <0.001
Leeds Sleep Evaluation Questionnaire
LSEQ: Quality of Sleep ± SEM
0
2
4
6
LS
EQ
fezolinetant 90mg BID (N=40)
placebo (N=40)
Baselin
e
Week 4
Week 8
Week 1
2
0
2
4
6
8
HF
RD
IS
P l a c e b o (N = 4 0 )
f e z o l i n e t a n t 9 0 m g B I D (N = 4 0 )
n o t s i g n i f i c a n t
Baselin
e
Week 4
Week 8
Week 1
2
0
2
4
6
8
HF
RD
IS
P l a c e b o (N = 4 0 )
f e z o l i n e t a n t 9 0 m g B I D (N = 4 0 )
n o t s i g n i f i c a n t
p <0.001
• Getting to sleep (GTS) How would you compare
getting sleep using the medicine with how you
usually get to sleep without the medicine? p<0.01
• Quality of sleep (QOS) How would you compare
the quality of sleep using the medicine with your
usual sleep? p<0.001
• Awakening from sleep (AFS) How did your
awakening feel after being medicated compared
with your usual pattern of awakening without the
medicine? p<0.05
• Behaviour following wakening (BFW) How did
you feel when you woke up? p=0.08
p <0.001
Greene Climacteric Scale
GCS total score ± SEM
GC
S t
ota
l
• GCS is a 21 item four-point Likert scale that
investigates symptoms related to different
areas affected by menopause
– Psychological, somatic, libido, vasomotor
symptoms
• It is a brief measure of menopause
symptoms used to assess changes in
different symptoms, before and after
menopause treatment
• Higher scores = worse symptoms
fezolinetant 90mg BID (N=40)
placebo (N=40)
Baselin
e
Week 4
Week 8
Week 1
2
0
2
4
6
8
HF
RD
IS
P l a c e b o (N = 4 0 )
f e z o l i n e t a n t 9 0 m g B I D (N = 4 0 )
n o t s i g n i f i c a n t
Baselin
e
Week 4
Week 8
Week 1
2
0
2
4
6
8
HF
RD
IS
P l a c e b o (N = 4 0 )
f e z o l i n e t a n t 9 0 m g B I D (N = 4 0 )
n o t s i g n i f i c a n t
p <0.001
-15
-10
-5
0
Sheehan Disability Scale
SDS global functional impairment
-15
-10
SD
S G
lob
al
Fu
ncti
on
al
Imp
air
me
nt
• Measure of functional impairment for number of
psychiatric disorders (eg, panic, social phobia,
major depression, alcoholism)
• Measures impact of treatment on disability in both
trials and practice
• The scale has 5 sub-scales relating to interference
with:
– work-related activities
– social life & activities
– family life & home responsibilities
– days lost at work
– unproductive work days
• Higher scores = worse symptoms
-5
0
fezolinetant 90mg BID (N=40)
placebo (N=40)
Baselin
e
Week 4
Week 8
Week 1
2
0
2
4
6
8
HF
RD
IS
P l a c e b o (N = 4 0 )
f e z o l i n e t a n t 9 0 m g B I D (N = 4 0 )
n o t s i g n i f i c a n t
Baselin
e
Week 4
Week 8
Week 1
2
0
2
4
6
8
HF
RD
IS
P l a c e b o (N = 4 0 )
f e z o l i n e t a n t 9 0 m g B I D (N = 4 0 )
n o t s i g n i f i c a n t
p <0.001
Effect on Plasma LH Levels
SC
RB
L
W
k 4
W
k 8
W
k 1
2 P
re
W
k 1
2 3
h P
os
t
FU
P
0
10
2 0
3 0
4 0
5 0
LH
(IU
/L
)
P l a c e b o
f e z o l i n e t a n t 9 0 m g B I D
* * *
* * * *
Plasma LH levels significantly
inhibited (as expected)
relative to baseline (‘BL’)
20% ↓ at 12h post-dose
50% ↓ at 3h post-dose (assumed
Cmax for drug)
%decrease in plasma LH similar
in pre- and post-menopausal
subjects
LH: a biomarker of efficacy in treatment of HF
95% of Patients with ↓30% in Plasma LH have ≥70% ↓ in HF Score
B a s e l i n e w k - 12 , 3 h p o s t - d o s e
0
12
2 4
3 6
4 8
Pla
sm
a L
H (
IU
/L
)
P l a c e b o
f e z o l i n e t a n t
16 %
5 0 %
0 5 0 10 0 15 0
0
5 0
10 0
15 0
2 0 0
P e a r s o n C o r r e l a t i o n , p < 0 . 0 0 0 1
( N = 8 0 p a t i e n t s )
% B a s e l i n e L H
( 3 h p o s t - d o s e )
%B
as
elin
e H
F S
co
re
(a
t w
ee
k 1
2)
L H 3 0 %
H F S c o r e 7 0 %
Pharmacokinetic Analysis
• Pharmacokinetics measured at steady-state
Day 21 in women volunteers (Ph I)
Day 84 in post-menopausal (Ph II)
• Peak and trough drug concentrations in HF trial
exactly as would be predicted from Phase I data
• No sign of drug accumulation with repeat dosing
Drug-Plasma Exposure Fezolinetant Exposure equivalent in
pre- and post-menopausal women
0 3 6 9 12 15 18 2 1 2 4
0
5 0 0
10 0 0
15 0 0
2 0 0 0
T i m e ( h )
Fe
zo
lin
et
an
t (
ng
/m
L)
9 0 m g B I D ( P h I I , N = 3 8 )
6 0 m g Q D ( P h I , N = 6 )
18 0 m g Q D ( P h I , N = 6 )
60 mg (QD) decreases LH; LH is a biomarker for efficacy on HF
PK/PD analysis supports testing of once-daily dosing for VMS
Safety Data: HF Trial (Ph II) – adverse event profile
Placebo fezolinetant 90 mg
Total number of subjects with: n % n %
At least one treatment emergent adverse event (TEAE) 35 79.5 29 67.4
At least one serious TEAE 1 2.3 0 0.0
At least one mild TEAE as worst severity 20 45.5 19 44.2
At least one moderate TEAE as worst severity 15 34.1 10 23.3
At least one TEAE where treatment was stopped 0 0.0 2 4.7
At least one TEAE considered to be treatment related 11 25.0 13 30.2
More patients reported TEAE in the placebo group than in fezolinetant group
Fezolinetant trial (Ph II) in menopausal hot flashes
• Primary Endpoint: HF frequency (↓93%), HF severity (↓70%), p<0.0001
– rapid onset of action; significant effects at first week (p<0.001); efficacy maintained
• Secondary Endpoint: all 4 questionnaires positive in favour of drug (p<0.05, each)
– Improvements in QoL, sleep quality, HF bother and professional/personal productivity
• Validation of plasma LH as conservative biomarker of drug efficacy on hot flash
– LH ↓50%, no changes on estradiol, FSH, SHBG
• PK/PD Analysis supportive of once-daily dosing
• Clear Safety Profile
First Demonstration of efficacy for an NK3R Antagonist in HF Trial
conducted according to FDA Guidelines
Acknowledgements
• OGEDA Team
• Medicinal Chemistry
• Hamid Hoveyda et al. Compound invention, optimization & scale-up
• ADME/PK &
Pharmacology
• Sophie Noel, Catherine Sorlet
et al. ADME/PK characterization
Preclinical pharmacology
• Clinical Advisory Board
• Rick Legro (Penn State)
• Hugh Taylor (Yale)
• Herman Depypere (Ghent)
• Bart Fauser (Utrecht)
• Philippe Bouchard (Paris)
• Clinical Development
• Steven Ramael
• Cindy Van Sande, Julie Van Peer Clinical Phase Study Management