GOLDEN-505 STUDY EASL INVESTOR EVENT. Vienna April 24, 2015

Transcription

1 GOLDEN-505 STUDY EASL INVESTOR EVENT Vienna April 24,

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3 GOLDEN-505 STUDY EASL Investor Event Agenda Introductory remarks NASH Disease/ epidemiology and physiopathology GOLDEN505 Study Design Statistical analysis GOLDEN-505 Results Results in global population Results in Phase 3 target population Phase 3 design Next steps and concluding remarks J-F. Mouney V. Ratziu V. Ratziu P. Lehert V. Ratziu B. Staels S. Megnien J-F. Mouney 3

4 THE NASH LANDSCAPE IN 2015 V. RATZIU PRINCIPAL INVESTIGATOR AND INTERNATIONAL COORDINATOR OF THE GOLDEN-505 STUDY 4

5 The NASH Landscape in 2015 Epidemiology NAFLD ~80 MM adults (US) NASH > 30 MM adults (US) NASH with NAS 4 25 MM adults (US) > 30% of adult population > 10% of adult population > 8% of adult population * Established NASH disease defined by NAS score 4 represents 85% of NASH population ** NASH is a $30-40B market worldwide 85% of NASH population* > $30 B market worldwide** 5

6 The NASH Landscape in 2015 Progression to NASH: the severe form of NAFLD NAFLD STEATOHEPATITIS = NASH Steatosis / Inflammation / Hepatocyte ballooning STEATOSIS F0 F1 F2 F4 F3 Cirrhosis No or minimal fibrosis 6

7 The NASH Landscape in 2015 Progression to NASH: the severe form of NAFLD 25% of the general population 70% in diabetic and obese patients Same survival as the general population NAFLD 12% of population has NASH STEATOSIS All-cause mortality HEALTHY LIVER Liver-related mortality NASH CVD Cardiovascular mortality Leading cause of death in NASH CIRRHOSIS T2D Neoplasia Matteoni, Gastro 1999, Adams, Gastro 2005, Ekstedt, Hepatol 2006, Ong, J Hepatol 2008, Dunn AJG 2008, Sorderberg, Hepatology 2010, Targher NEJM

8 NASH as an indication for liver transplantation Data from UNOS Registry NASH : second cause of LT waitlist registrants NASH : less likely to undergo LT NASH : less likely to survive for 90 days on the waiting list Wong, Gastroenterology 2015

9 HCC in NASH and liver transplant UNOS database , 61,868 adults with LT including 10,061 with HCC In 2012 : HCV 43.5%, 13.5%. Second and fastest growing etiology Wong, Hepatology 2014

10 The NASH Landscape in 2015 NASH is associated with cardiometabolic disease (2/2) Masuoka & Chalasani (2013) Ann NY Acad Sci CVD is the leading cause of death in NASH patients 10

11 Pharmacological Targets of GFT505 in NASH Insulin resistance FFA + insulin+ cytokines Steatosis + metabolic dysregulation Innate immunity ER stress Oxidative stress Mitochondrial dysfct Innate immunity Inflammation Cell injury Stellate cell activation fibrosis Multiple sources, courtesy Arun Sanyal 11

12 GOLDEN-505 STUDY DESIGN V. RATZIU 12

13 GOLDEN-505 Study Design First true Multi-centric International Study in NASH (1/2) Inclusion criteria on liver Biopsy Presence of NASH defined by at least 1 in each component (steatosis, inflammation, ballooning) = NAS score of 3 and above Why include early NASH: At the time of design, need to treat all patients to get better understanding in NASH First study with GFT505 in NASH patients, need to evaluate full range of disease Centralized reading Rigorous methodology Centralized reading for both inclusion biopsy and end-of-treatment biopsy Adequacy of sample checked by central pathologist 13

14 GOLDEN-505 Study Design First true Multi-centric International Study in NASH (2/2) Recruitment of 274 randomized treated patients (FAS) 237 patients with 2 biopsies (ITT) 9 countries, 56 active sites 37 sites in Europe, 19 sites in US Staggered design (first cohort 80mg/plac, second cohort 120mg/plac) Why so many sites: Feasibility on recruitment Potential reluctance from patients for 2 biopsies in a 1-year period Primary endpoint: Reversal of NASH without worsening of fibrosis after 52 weeks of treatment Relevant endpoint according to FDA/AASLD recommendation Joint Workshop 14

15 GOLDEN-505 HISTOLOGY: STATISTICAL ANALYSIS PROF P. LEHERT, PHD FACULTY OF MEDICINE, UNIVERSITY OF MELBOURNE, AUSTRALIA FACULTY OF ECONOMICS, UCL MONS, LOUVAIN, BELGIUM 15

16 GOLDEN-505: Histology Main Analysis in the Global Population Statistical considerations Blind statistical analysis plan Independent validation/review of the statistical analysis Main analysis Statistical analysis procedure Statistical analysis plan discussed and agreed with FDA Prior to code breaking Reviewed by third party statistician 16

17 GOLDEN-505: Histology Main Analysis in the Global Population Phase 2 characteristics Widest range of baseline severity : 3 NAS 8 2 doses 80mg and 120mg, step-down assumption (80mg 120mg) Limited sample size (phase 2), multicenter (>50 sites) and unbalanced treatment-center distribution Unconstrained standard care in each site Selection Intent to treat (n=237; randomized treated, and 2 biopsies) Full analysis set (n=274; randomized treated, missing biopsies considered as non responders) 17

18 GOLDEN-505: Histology Main Analysis in the Global Population Statistical principles Main endpoint : NASH resolution (binary) Factor : treatment (placebo, GFT80, GFT120) Covariate : NAS baseline NAS = obvious main predictor EMA-CHMP, PTC 2013; ICH-E9, section 5.5 Center ICH-E9, 3.2 Mixed model, small centers ICH-E9, 5.7 Unbalanced multicenter study 18

19 GOLDEN-505 HISTOLOGICAL RESULTS: GLOBAL POPULATION V. RATZIU 19

20 GOLDEN-505: Histology Results in the Global Population Primary endpoint: Reversal of NASH without worsening of fibrosis Descriptive analysis: responder rate by categories of baseline severity Baseline severity N =237 Placebo GFT mg Severe (6-8) 72 0% 14.8% Moderate (4-5) % 27.5% Mild (3) % 36.4% High placebo response rate in mild NAS 3 patients 20

21 GOLDEN-505: Histology Results in the Global Population Primary endpoint: Reversal of NASH without worsening of fibrosis Confirmatory test ITT n=237 Risk ratio 95%CI P value GFT120 vs Placebo GFT80 vs placebo FAS n=274 Risk ratio 95%CI P value GFT120 vs Placebo GFT80 vs placebo Statistically significant dose-dependent beneficial effects on histological end-points in the global population 21

22 GOLDEN-505: Histology Main analysis CONCLUSIONS Dose effect - Placebo GFT505 80mg < GFT mg - GFT mg = Minimum Effective Dose Clinically and Statistical Significant Benefit of GFT mg in doubling the response rates (RR 2) Confirmed on both Intent To Treat and Full Analysis Set populations 22

23 GOLDEN-505 NEW HISTOLOGICAL RESULTS: PHASE 3 TARGET POPULATION V. RATZIU 23

24 GOLDEN-505: Histology Results in the NAS 4 Population: Additional analyses without center adjustment Centers with 3 arms, NAS 4 population Population NAS 4 : inclusion criteria in previous trials Centers with patients in the 3 groups (placebo, 80 mg, 120 mg) in 9 countries (Europe and USA) Enables the analysis of sites with a balanced distribution between treatment groups Situation recommended in the organization of clinical trials Distribution of treatment groups «by block» to avoid a center effect 24

25 GOLDEN-505: Histology Results in the NAS 4 Population: patients from all centers with 3 groups (n=120) (1/2) Resolution of NASH w/o worsening of fibrosis Placebo GFT mg p value 5% 29% 0.01 Decrease of NAS 2 21% 48% 0.02 Mean change in NAS Significant beneficial effects on major NASH histology endpoints 25

26 GOLDEN-505: Histology Results in the NAS 4 Population: patients from all centers with 3 groups (n=120) (2/2) Subjects with improvement Placebo GFT mg p value Steatosis 18% 36% NS Ballooning 23% 45% 0.02 Inflammation 33% 55% 0.05 Significant beneficial effects on histology of NASH lesions 26

27 Change in Score GOLDEN-505: Histology Efficacy in GFT505 responders (Global Population) 0,5 Beneficial on NASH components and fibrosis improvement in Responders to GFT505 GFT mg Responders GFT mg Non responders 0-0,5-1 -1,5-7,96 p=0.06 *** ** *** -2-25,45-2,5-3 *** NAS Steatosis Ballooning Inflammation Fibrosis 5% NASH components ** : p<0.01 *** : p<

28 GOLDEN-505 LIVER PROTECTION V. RATZIU 28

29 GOLDEN-505: Liver Protection Analysis of Biomarkers of Hepatic damage evolution Beneficial hepatic effects of GFT505 (statistically significant) Decrease in liver enzymes Decrease in inflammatory markers Composite scores for NAFLD & Fibrosis are statistically significant Fatty liver index, steatotest NAFLD Fibrosis score, fibrotest : Early sign of fibrosis improvement Effects on hepatic biomarkers demonstrate beneficial impact on the liver 29

30 GOLDEN-505: Liver Protection Results on Biomarkers: Liver Enzymes Effect size GFT mg vs placebo (Absolute change - U/L) ALAT GGT ALP -9,45 p=0,06-23,85-29,31 *** *** Decrease of liver enzymes consistent with beneficial impact on the liver *** : p<

31 GOLDEN-505: Liver Protection Results on Composite Scores for NAFLD/Fibrosis Effect size GFT mg vs placebo (Absolute change) FIBROTEST STEATOTEST NAFLD-Fibrosis score -0,05 *** -0,11 *** -0,25 ** ** : p<0.01 *** : p<0.001 Effects on the composite scores consistent with benefit on liver histology and indication of an antifibrotic effect 31

32 GOLDEN-505: Liver Protection Results on Biomarkers: Inflammatory Markers Effect size GFT mg vs placebo (Relative change - %) Fibrinogen Haptoglobin hs-crp -7,96 *** -25,45 *** -42,12 Decrease of inflammation markers consistent with anti-inflammatory effects on the liver *** : p<

33 GOLDEN-505 CARDIOMETABOLIC PROTECTION B. STAELS 33

34 GFT505 has Pleiotropic Activities PPARα and δ Regulate Numerous Pathways Essential in NASH i Fibrogenesis (TGFβ1, αsma, Col1α1) i Oxidative stress (CAT, SOD) i Inflammation(MCP-1, IL-6, TNFα) i steatosis (h lipid utilization) i Oxidative stress (CAT, SOD) i ALT, GGT, ALP h Hepatic hemodynamics LIVER DYSFUNCTION FIBROSIS CVD RISK i Atherogenic lipid profile i Endothelial dysf. (ET-1, RGS5, Nox) i Vessel Ox stress (CAT, GPx1, HO1) i Vessel inflam (ICAM1, MCP1) h Triglyceride clearance (APOC3) i VLDL-APOB & ildl-apob i sd-ldl cholesterol level h HDL cholesterol level (APOA1/A2) h NEFA utilization (ACOX, CPT1, EHHADH) i NEFA level (lipolysis, β-oxidation) LIPID METABOLISM PPARα/δ GLUCOSE HOMEOSTASIS INFLAMMATION i NF-κB, i TLRs i TNFα, IL-1β i IL-6, CRP, SAA, HG, fibrinogen i Kupffer cell activation (BCL6) h Insulin sensitivity (Fgf21) i Hepatic glucose output (PEPCK, FAS, ACC, PDG, G6PDH) i insulin

35 GOLDEN-505: Cardiometabolic Protection Analysis of Cardiometabolic Biomarkers Beneficial cardiometabolic effects of GFT505 confirmed (statistically significant) Lipids : decrease in «bad» lipids with high cardiovascular risk (in particular decrease in LDL-cholesterol), increase in cardio-protective lipids Improvement in glycemic parameters, particularly in diabetics Significant improvement in CV risk PROCAM score Beneficial effects on top of standard treatment (statins, anti-diabetic drugs, etc.) FDA/AASLD recommendation (Hepatology 2014) NASH is associated with type II diabetes, increased cardiovascular risk and cancerrelated mortality (74-76). For this reason, it seems important to monitor LDL- and HDLcholesterol, triglycerides, and diabetes control (e.g. hemoglobin A 1C ) in phase 2b and 3 NASH trials. It is imperative that any drug developed for NASH be at least neutral from a cardiovascular risk perspective and ideally also reduce cardiovascular risks. Consistent beneficial cardioprotective profile demonstrated in NASH patients 35

36 GOLDEN-505: Cardiometabolic Protection Results on Biomarkers: Lipid Parameters Effect size GFT mg vs placebo (Absolute change - mmol/l) ** 0,11-0,24 *** -0,17 *** -0,43-0,55 *** *** TG CHOL HDL-C LDL-C VLDL-C Cardioprotective lipid profile demonstrated ** : p<0.01 *** : p<

37 Relative Change (%) Absolute Change (% HbA1c) GOLDEN-505: Cardiometabolic Protection Results on Biomarkers: Glycemic Parameters in Diabetics HbA1c Effect size GFT mg vs placebo (Absolute change) 0 0 Glycemic parameters in diabetics Effect size GFT mg vs placebo (relative change %) FPG Fasting Insulin Fructosamin C-peptide FFA -5-0,5-0,46 * ,11 ** ,03 * ,8-26,34 p=0,06 * ,3 ** -35 Absolute Change (% HbA1c) Relative Change (%) Beneficial effects in T2D NASH patients, consistent with insulin sensitivity * : p<0.05 ** : p<

38 GOLDEN-505 HIGHLY FAVORABLE SAFETY S. MEGNIEN 38

39 GOLDEN-505: Highly Favorable Safety Tolerance of GFT505 Very good tolerance confirmed after one year of treatment No weight gain No cardiac events, no deaths No signal on cancer No signal for pruritus Very good tolerance profile, essential for a long-term treatment 39

40 GOLDEN-505 COMPARISON GOLDEN/FLINT/PIVENS S. MEGNIEN 40

41 Comparison GOLDEN/FLINT/PIVENS Results in the NAS 4 Target Population Patients with a NAS score 4 The target population for treatment, according to KOLs Inclusion criteria in previous trials Corresponds to the target population to be included in Phase 3 studies with GFT505 Analysis of NASH patients with NAS score 4 allows comparison of the histological results of GFT505, Pioglitazone, and OCA in the same type of population 41

42 Comparison GOLDEN/FLINT/PIVENS Efficacy in Patients with NAS score 4 NASH RESOLUTION (%) PLACEBO VITAMINE E PIOGLITAZONE PLACEBO OCA PLACEBO GFT505 PLACEBO GFT505 PIVENS FLINT GOLDEN-505 GOLDEN ARMS SITES VIT E / PIO 24 months OCA 18 months Clear beneficial effect of GFT505 on relevant NASH histology endpoint 5 GFT months 42

43 Comparison GOLDEN/FLINT/PIVENS Efficacy in Patients with NAS score 4 DECREASE OF NAS 2 (%) PLACEBO VITAMIN E PIOGLITAZONE PLACEBO OCA PLACEBO GFT505 PLACEBO GFT505 PIVENS FLINT GOLDEN-505 GOLDEN ARMS 3-ARMS SITES SITES VIT E / PIO 24 months OCA 18 months GFT months Clear beneficial effect of GFT505 on NASH histology 43

44 Comparison GOLDEN/FLINT/PIVENS Results in the NAS 4 Target Population Efficacy comparable to OCA on NASH histological end-points in the Phase 3 target population (NAS score 4) Better cardiometabolic profile Better safety/tolerability profile Phase 3 in preparation 44

45 GOLDEN-505 PHASE 2 & PHASE 3 NEXT STEPS STUDY DESIGN S. MEGNIEN 45

46 NEXT STEPS Phase 2 Conclusions Phase 2 study met its objectives Confirmation of GFT505 treatment effect on histology Determination of minimum effective dose Cardio-metabolic benefit for NASH patients and treatment of co-morbidities Confirmation of excellent safety profile Further analyses of phase 2 data ongoing To explore responder profile To explore biomarkers Subgroup analyses 46

47 Study population: High-risk patients Phase 3 Study Design Ongoing Outline (1/2) NASH with a NAS score 4 Activity score Ballooning + Inflammation 3 Fibrosis stage 2-3 Cardiometabolic risk Subpart H Histological primary endpoint Reversal of NASH Duration 18 to 24 months of treatment Long term outcome F2-F3 patients Time to cirrhosis Up to 48 months of treatment Ongoing discussions on design with FDA & EMA 47

48 Phase 3 Study Design Ongoing Outline (2/2) General design Approximately 1500 patients Placebo plus 1 or 2 doses of GFT505 Dose linearity between 80 mg and 120 mg 120 mg is an efficient and safe dose Possible to use a higher dose Phase 3 study in cirrhotic patients HVPG ~200 patients/arm Pediatric plan in preparation Ready for Phase 3 48

49 AGENDA 2015 CONCLUSION J-F. MOUNEY CHAIRMAN & CEO GENFIT 49

50 GOLDEN-505 & Phase 3: Agenda 2015 April 2015 Investigator Events at EASL Summer 2015 Meetings with agencies (FDA/EMA) Summer 2015 Publication in an internationally-renowned scientific journal End 2015 Phase 3 initiation 50

51 THANK YOU