neurokinine 3 receptor antagonists as a novel treatment...

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


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 )



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 )



p <0.001

Leeds Sleep Evaluation Questionnaire

LSEQ: Quality of Sleep ± SEM

0

2

4

6

LS

EQ


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 )



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 )



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


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 )



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 )



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


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 )



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 )



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

neurokinine 3 receptor antagonists as a novel treatment...

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