elafibranor: a liver targeted pparαδ agonist for a … · 2017-11-27 · elafibranor: a liver...
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ELAFIBRANOR: A LIVER TARGETED PPARα/δ AGONIST FOR A GLOBAL MANAGEMENT OF NASH PATIENTSDean Hum1, Arun Sanyal2, Stephen A. Harrison3, Sophie Megnien1, Pierre Bedossa4, Alice Roudot1, Robert Walczak1, Remy Hanf1, Bart Staels5, 6, Vlad Ratziu7, 8
1GENFIT SA, Loos, France; 2Virginia Commonwealth University, Richmond; 3Department of Medicine, Gastroenterology & Hepatology Service, Brooke Army Medical Center, Fort Sam Houston, Texas, United States; 4Department of Pathology, Hôpital Beaujon, University Paris-Denis Diderot, Paris; 5Université Lille 2; 6INSERM U1011, European Genomic Institute for Diabetes (EGID), Institute Pasteur de Lille, Lille; 7Université Pierre et Marie Curie, Hôpital Pitié Salpétrière; 8Insititute of Cardiometabolism and Nutrition (ICAN), INSERM, UMRS 938, Paris, France
BACKGROUND
AIM
ELAFIBRANOR IN DISEASE MODELS OF NASH
ELAFIBRANOR IN DISEASE MODELS OF LIVER FIBROSIS
PHASE 2A: ELAFIBRANOR IS AN INSULIN SENSITIZER CONCLUSION
Elafibranor is new dual PPARα/δ agonist
Elafibranor Chemical Structure
S
O
OCOOH
Elafibranor is liver targeted.
By activating both PPARα and PPARδ in both parenchymal cells (hepatocytes) and non-parenchymal cells (Inflammatory cells and Stellate cells), elafibranor regulates essential pathways of NASH pathophysiology.
FIBROSIS
LIVER DYSFUNCTION
CVD RISK
LIPIDMETABOLISM
GLUCOSEHOMEOSTASIS
INFLAMMATION
PPAR α/δ
NF-κB, TLRs TNFα, IL-1β IL-6, CRP, SAA, HG, �brinogen Kup�er cell activation (BCL6)
Insulin sensitivity (Fgf21)Hepatic glucose output (PEPCK, FAS, ACC, PDG, G6PDH)Insulin
Triglyceride clearance (APOC3)VLDL-APOB & LDL - APOBsd-LDL cholesterol levelHDL cholesterol level (APOA1/A2)NEFA utilization (ACOX, CPT1, EHHADH)NEFA level (lipolysis, β - oxidation)
Steatosis ( Lipid utilization)Oxidative stress (CAT, SOD)ALT, GGT, ALPHepatic hemodynamics
Fibrogenesis (TGFβ1, αSMA, Col1α1)Oxidative stress (CAT, SOD)In�ammation(MCP -1, IL-6, TNFα)
Atherogenic lipid pro�leEndothelial dysf. (ET-1, RGS5, Nox)Vessel Ox stress (CAT, GPx1, HO1)Vessel in�am (ICAM1, MCP1)
GOLDEN-505: A 1-YEAR PHASE 2B IN NASH GOLDEN-505: A 1-YEAR PHASE 2B IN NASH
foz/foz mice fed a high fat diet
Randomisation on Body weight, Glycemia, insulinemia, AST & ALT
CHOWGFT#1 (n=11)
HFDGFT#2 (n=12)
HFD HFDGFT#3 (n=11)
18 weeks12 weeks
Switch to HFD at the age of 4-5 weeks
HFDGFT#4 (n=12) HFD + ELAFIBRANOR
foz/foz mice fed a high fat diet reproduced the pathophysiolgical process of human NASH leading to liver fibrosis.
On an installed NASH with fibrosis in foz/foz mice, elafibranor treatment totally resolved NASH (acting on steatosis, inflammation and ballooning) and also cleared liver fibrosis.
The anti-NASH activity of elafibranor consistently demonstrated in multiple disease models of NASH.
- foz/foz mice fed a high fat diet - Normal and diabetic mice fed a Methionine-Choline Deficient diet (MCD) - PPARα-KO/ApoE2-Ki mice fed a high fat diet - Choline Deficient L-Amino Acid defined diet (CDAA) in rat
Trichrome staining
Without elafibranor
Chow diet (control) High fat diet (pathological)
With elafibranor
T12w
+18w
T12w
CCl4 induced liver fibrosis
2 weeks CCl4Elafibranor
Vehicle
T0 T1w T2wReversion protocol: CCl4 induced liver fibrosis
*** *** ***
**
0,0
0,5
1,0
1,5
2,0
2,5
2 weeks 2+1 weeks 2+2 weeks
Fibr
osis
are
a (%
)
normal pathologic + Ctrl pathologic + GFT505 30mg/kg
***
******
T0 T1w T2wControl animals (no CCl4 induced fibrosis)
Pathological animals (with CCl4 induced fibrosis)Treated with elafibranor (30mpk) Not treated with elafibranor
Elafibranor reversed CarbonTetraChloride CCl4 induced fibrosis and favored the regeneration of the liver.
T0
T1w
T2w
Not treated with elafibranor
Control animals Pathological animals
Treated with elafibranor
A glucose clamp trial in insulino-resistant patients (GFT505-210-6)
Elafibranor-80mg Elafibranor-80 mg
Placebo8 weeks
Washout6 weeks
8 weeks
Glucose clamp Glucose clamp
Glucose clampGlucose clamp
Placebo
Patients (N=22): - HOMA-IR>3 but not diabetic
Main Objectives: - Hepatic insulin sensitivity (Hepatic glucose production at a low dose of insulin) - Peripheral insulin sensitivity (Glucose Infusion Rate at a high dose of insulin)
Design:An international Phase 2b RCT in NASH: 56 sites (US & 8 European countries)
InclusionLiver Biopsy
End-of-treatmentLiver Biopsy
SCREENING PERIOD
FOLLOW UP PERIOD
W34 W64
D0 W43W26 W52
Clinical & Lab evaluation
W8 W17
Placebo (N=92)
Elafibranor-80mg/d (N=93)
Elafibranor-120mg/d (N=89)
V1 V2 V3 V4 V5 V6 V7 V8 V9
Elafibranor-120mg resolved NASH without worsening of fibrosis
*Comparison elafibranor-120mg vs Placebo# Patients from centers with balanced randomization (i.e. at least 1 patient per treatment arm)
Patient population: - NAS≥3 with at minimum score of ≥1 in each of the three lesions (steatosis, ballooning and inflammation) at baselinePrimary outcome: - % Resolution of NASH without worsening of fibrosis - NASH resolution = Score of 0 for ballooning and 0-1 for inflammation - Worsening of fibrosis = any progression ≥1 stage
Significant effect of elafibranor-120mg vs placebo in the ITT population
In NAS=3: high rate of spontaneous resolution of NASH in the placebo group
Improved response to elafibranor-120mg vs placebo in the NAS≥4 population
Ratziu et al., Gastroenterology, 2016
Elafibranor-120mg improvedsecondary histological end-points
Responders vs Non-Responders in elafibranor-120mg group
0
10
20
30
40
50
60
NASH resolution
Reduction NAS>=2
Decreased Steatosis
Decreased Inflammation
Decreased Ballooning
% re
spon
ders
Placebo Elafibranor-120mg
OR=7.28P=0.02
OR=3.93P=0.01
OR=2.63P=0.10
OR=4.30P=0.05
OR=3.80P=0.02
-3,5
-3
-2,5
-2
-1,5
-1
-0,5
0
0,5
1
NAS Steatosis Ballooning Inflammation Fibrosis
Elafibranor -120mg Responders Elafibranor-120mg Non responders
###
#
#### ###
NASH components
Mea
n ch
ange
ver
sus b
asel
ine
A Post-hoc analysis of patients with NAS≥4 from centers with balanced randomization (i.e. at least 1 patient per treatment arm).
In the elafibranor-120mg treated group, about half of the patients experienced reduction of NAS≥2 and/or improvement of necro-inflammation (inflammation, ballooning).
Results are expressed vs baseline as mean±95% CI, #p<0.05, ###p<0.001
Patients who resolved their NASH showed significant reduction in liver fibrosis while non-responders did not show any change from baseline.
Elafibranor-120mg lowered plasma liver markers Elafibranor-120mg improved non-invasive scores of NASH and fibrosis
-40
-35
-30
-25
-20
-15
-10
-5
0
5
ALT AST GGT ALP
p=0.06
***
***
Effec
t size
vs p
lace
bo (U
/L)
The effect size vs placebo was calculated and expressed as LSMean±Standard Error. ***p<0.001
-0,4
-0,35
-0,3
-0,25
-0,2
-0,15
-0,1
-0,05
0
Fibrotest Steatotest NAFLD-fibrosis score
***
***
**
Effec
t siz
e vs
pla
cebo
(abs
olut
e ch
ange
)
The effect size vs placebo was calculated and expressed as LSMean±Standard Error. **p<0.01, ***p<0.001
Elafibranor is now in phase 3: RESOLVE-IT trial
Anti-inflammatory properties
Favorable effects on lipids :
-Decreased TG-Decreased LDL-C-Increased HDL-C
Improvement of liver dysfunction markers
Improvement of glucose homeostasis and insulin
sensitivity
GOLDEN-505:Elafibranor-120mg
induces: Resolution of histological NASH
+Reduction of CV risk
+Long term safety
Absence of safety concern
Phase 2a trials
Phase 2a trials
Phase 2a trials Phase 2a trials
Phase 2a trials
Efficacy in NASH acting on:-Steatosis
-Inflammation-Hepatocyte injury
- Fibrosis
Disease models
PHASE 3: RESOLVE-ITRecruiting
A very good safety and tolerability confirmed after 1 year of treatment
Adverse eventElafibranor-80mg
N=93Elafibranor-120mg
N=89Placebo
N=92Total
N=274Nausea 13 9 9 31
Vomiting 5 3 2 10Diarrhoea 6 5 4 15Headache 6 7 8 21
Fatigue/asthenia 9 5 6 20Creatinine increase 1 6 0 7
Abdominal pain 1 8 9 18Myalgia 5 2 2 9
Decreased appetite 3 5 0 8Rash 3 4 1 8
Pruritus 1 1 2 4
Elafibranor-120mg improved lipid profile and reduced CV risk
-0,8
-0,7
-0,6
-0,5
-0,4
-0,3
-0,2
-0,1
0
0,1
0,2
TG Total-Chol Non-HDL-Chol LDL-Chol VLDL-Chol HDL-Chol
***
***
***
***
**
***Elafibranor-120mg vs placebo on lipid markers
Remnant-Chol
Effec
t size
vs p
lace
bo(A
bsou
te ch
ange
-mm
ol/L
)
The effect size vs placebo was calculated and expressed as LSMean±Standard Error. **p<0.01, ***p<0.001
Elafibranor-120mg improvedglucose homeostasis and HbA1c in T2D
-80
-70
-60
-50
-40
-30
-20
-10
0
e
*
*
**
**
*
Effec
t size
vs p
lace
bo (%
of b
asel
ine)
-0,46
-0,8
-0,7
-0,6
-0,5
-0,4
-0,3
-0,2
-0,1
01
HbA1cSignificant
decrease in HbA1c vs placebo
Effec
t size
vs p
lace
bo (%
)
The effect size vs placebo was calculated and expressed as LSMean±Standard Error. *p<0.05, **p<0.01
$$$
** ***
P= 0,001
% o
f fibr
osis
area
Elafibranor improved hepatic insulin sensitivity (cf. decrease of Hepatic Glucose Production).Elafibranor improved peripheral insulin sensitivity (cf. increase in Glucose Infusion Rate).Elafibranor concomitantly improved, circulating liver markers, plasma lipids and inflammatory markers.
This poster summarizes key preclinical and Phase 2 clinical data demonstrating efficacy of elafibranor in treating NASH and supporting its assessment in RESOLVE-IT, a large international, randomized, placebo controlled Phase 3 trial in patients with NASH (NAS≥4) and fibrosis (F1-F3).
AIM
REFERENCES
No Death and no Major Cardiovascular Events (MACE)No effect on body weightNo signal on cancerNo meaningful change in safety markers and hematologyNo signal for pruritus
RESOLVE-IT design
END OF STUDYOccurrence of a
pre-defined number of events including progression
to cirrhosis (time-to-event)
~1,000 patients
Elafibranor-120mgPlacebo
FIRST TREATMENT PERIOD EXTENSION PERIOD
Elafibranor-120mgPlacebo
~2,000 patients
72-WEEK INTERIM ANALYSISPRIMARY ENDPOINT:
TRIAL INITIATIONQ1 2016 NASH RESOLUTION WITHOUT
WORSENING OF FIBROSIS
SUBPART HANTICIPATED MARKET
AUTHORIZATION~200centers
Study population: high-risk patients - NAS≥4 - Fibrosis stage: F2 and F3 (F1 + cardiometabolic risk)Interim analysis for conditional approval (subpart H for FDA)
Insulin induced effect on HGP (%)Elafibranor Placebo
p=0.0014
Glucose infusion rate (mg/kg/min)
Elafibranor Placebo
p=0.025
Cariou et al. Diabetes Care, 2011;34:2008-14 | Cariou et al. Diabetes Care, 2013;36:2923-30 Staels et al. Hepatology, 2013;58:1941-52 | Ratziu et al. Gastroenterology, 2016;150:1147-1159
ballooning grade
GFT#1 GFT#2
GFT#3 GFT#4
*p<0.05, ***p<0.001significant vs placebo**p<0.01, ***p<0.001
*p<0.05, **p<0.01, ***p<0.001
Ratziu et al., Gastroenterology, 2016
EASL NASH Monothematic Conference, Riga, 2016
= relevant endpointto prevent cirrhosis
Study collaboration with Isabelle A. Leclercq, Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Av E. Mounier 53, 1200 Brussels, Belgium
N NAS Placebo Elafibranor-120mg
OR* (CI 95%) P-Value*
274 NAS ≥ 3 (All) 12% 19% 2·31[1·02 - 5·24] 0·045*
234 NAS ≥ 4 9% 19% 3·52[1·32 - 9·40]
0·013*
120 NAS ≥ 4# 5% 26% 7.28 0.02*
204 NAS ≥ 4 (F1-F2-F3) 11% 20% 3·75[1·39 - 10·12] 0·009*
e