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