Genfit Sa · EURONEXT:GNFT

Genfit Sa — EASL Investor Event 2015

51 slides from Genfit Sa's conference presentation, Apr 24, 2015

  1. Slide 1: GOLDEN-505 Study EASL Investor Event

    GOLDEN-505 STUDY EASL INVESTOR EVENT Vienna April 24, 2015 1

  2. Slide 2: Disclaimer

    Disclaimer Important Information and Forward Looking Statements • GENFIT IS A PUBLIC COMPANY LISTED ON EURONEXT PARIS (COMPARTMENT B) STOCK EXCHANGE SINCE APRIL 17, 2014. GENFIT SHARES HAVE BEEN LISTED ON THE ALTERNEXT MARKET OF EURONEXT PARIS SINCE 2006. • THIS DOCUMENT DOES NOT CONSTITUTE OR FORM

  3. Slide 3: Agenda

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

  4. Slide 4: The NASH Landscape in 2015

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

  5. Slide 5: The NASH Landscape in 2015: Epidemiology

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

  6. Slide 6: Progression to NASH: the severe form of NAFLD

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

  7. Slide 7: Progression to NASH: the severe form of NAFLD

    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 • CVD HEALTHY LIVER Liver-related mortality • Cardiovascu

  8. Slide 8: NASH as an indication for liver transplantation

    NASH as an indication for liver transplantation Data from UNOS Registry 2004-2013 NASH : second cause of LT waitlist registrants NASH : less likely to undergo LT Wong, NASH : less likely to survive for 90 days on the waiting list Gastroenterology 2015

  9. Slide 9: HCC in NASH and liver transplant

    HCC in NASH and liver transplant UNOS database 2002-2012, 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. Slide 10: NASH is associated with cardiometabolic disease

    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. Slide 11: Pharmacological Targets of GFT505 in NASH

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

  12. Slide 12: GOLDEN-505 Study Design

    GOLDEN-505 STUDY DESIGN V. RATZIU 12

  13. Slide 13: GOLDEN-505 Study Design (1/2)

    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, nee

  14. Slide 14: GOLDEN-505 Study Design (2/2)

    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

  15. Slide 15: GOLDEN-505 Histology: Statistical Analysis

    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. Slide 16: Histology: Main Analysis in the Global Population

    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 t

  17. Slide 17: Phase 2 characteristics and selection

    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 •

  18. Slide 18: Statistical principles

    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

  19. Slide 19: GOLDEN-505 Histological Results: Global Population

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

  20. Slide 20: Results in the Global Population: responder rates

    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 GFT505 120mg Severe (6-8) 72 0% 14.8% Moderate (4-5) 130 19.5% 27.5% Mi

  21. Slide 21: Results in the Global Population: confirmatory test

    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 1.94 1.08-3.48 0.027 GFT80 vs placebo 1.68 0.92-3.05 0.091 FAS n=274 Risk ratio 95%CI P value GFT120 vs P

  22. Slide 22: Histology Main Analysis Conclusions

    GOLDEN-505: Histology Main analysis CONCLUSIONS  Dose effect - Placebo ≤ GFT505 80mg < GFT505 120mg - GFT505 120mg = Minimum Effective Dose  Clinically and Statistical Significant Benefit of GFT505 120mg in doubling the response rates (RR≅2)  Confirmed on both Intent To Treat and Full Analysis Se

  23. Slide 23: GOLDEN-505 New Histological Results: Phase 3 Target Population

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

  24. Slide 24: Results in the NAS≥4 Population: analyses without center adjustment

    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) • E

  25. Slide 25: NAS≥4 Population, 3-group centers (1/2)

    GOLDEN-505: Histology Results in the NAS≥4 Population: patients from all centers with 3 groups (n=120) (1/2) Placebo GFT505 120mg p value Resolution of NASH w/o 5% 29% 0.01 worsening of fibrosis Decrease of NAS≥2 21% 48% 0.02 Mean change in NAS -0.38 -1.1 0.02  Significant beneficial effects on maj

  26. Slide 26: NAS≥4 Population, 3-group centers (2/2)

    GOLDEN-505: Histology Results in the NAS≥4 Population: patients from all centers with 3 groups (n=120) (2/2) Subjects with Placebo GFT505 120mg p value improvement Steatosis 18% 36% NS Ballooning 23% 45% 0.02 Inflammation 33% 55% 0.05  Significant beneficial effects on histology of NASH lesions 26

  27. Slide 27: Efficacy in GFT505 responders

    GOLDEN-505: Histology Efficacy in GFT505 responders (Global Population) Beneficial on NASH components and fibrosis improvement in Responders to GFT505 0,5 GFT505 120 mg Responders GFT505 120 mg Non responders 0 -0,5 Change in Score p=0.06 -1 -7,96 *** ** -1,5 *** -25,45 -2 -2,5 5% *** -3 NAS Steatos

  28. Slide 28: GOLDEN-505 Liver Protection

    GOLDEN-505 LIVER PROTECTION V. RATZIU 28

  29. Slide 29: Analysis of Biomarkers of Hepatic damage evolution

    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,

  30. Slide 30: Results on Biomarkers: Liver Enzymes

    GOLDEN-505: Liver Protection Results on Biomarkers: Liver Enzymes Effect size GFT505 120mg vs placebo (Absolute change - U/L) ALAT GGT ALP -9,45 p=0,06 -23,85 *** -29,31 *** *** : p<0.001  Decrease of liver enzymes consistent with beneficial impact on the liver 30

  31. Slide 31: Results on Composite Scores for NAFLD/Fibrosis

    GOLDEN-505: Liver Protection Results on Composite Scores for NAFLD/Fibrosis Effect size GFT505 120mg 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 histol

  32. Slide 32: Results on Biomarkers: Inflammatory Markers

    GOLDEN-505: Liver Protection Results on Biomarkers: Inflammatory Markers Effect size GFT505 120mg vs placebo (Relative change - %) Fibrinogen Haptoglobin hs-CRP -7,96 *** -25,45 *** -42,12 *** : p<0.001  Decrease of inflammation markers consistent with anti-inflammatory effects on the liver 32

  33. Slide 33: GOLDEN-505 Cardiometabolic Protection

    GOLDEN-505 CARDIOMETABOLIC PROTECTION B. STAELS 33

  34. Slide 34: GFT505 has Pleiotropic Activities

     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) FIBROSIS i Oxidative stress (CAT, SOD) i Atherogenic lipid profile i ALT

  35. Slide 35: Analysis of Cardiometabolic Biomarkers

    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-prote

  36. Slide 36: Results on Biomarkers: Lipid Parameters

    GOLDEN-505: Cardiometabolic Protection Results on Biomarkers: Lipid Parameters Effect size GFT505 120mg vs placebo (Absolute change - mmol/L) ** 0,11 -0,17 -0,24 *** *** -0,43 *** -0,55 *** TG CHOL HDL-C LDL-C VLDL-C ** : p<0.01 *** : p<0.001  Cardioprotective lipid profile demonstrated 36

  37. Slide 37: Results on Biomarkers: Glycemic Parameters in Diabetics

    GOLDEN-505: Cardiometabolic Protection Results on Biomarkers: Glycemic Parameters in Diabetics HbA1c Glycemic parameters in diabetics Effect size GFT505 120mg vs Effect size GFT505 120mg vs placebo (relative change %) placebo (Absolute change) FPG Fasting Insulin Fructosamin C-peptide FFA 0 0 Absolu

  38. Slide 38: GOLDEN-505 Highly Favorable Safety

    GOLDEN-505 HIGHLY FAVORABLE SAFETY S. MEGNIEN 38

  39. Slide 39: Tolerance of GFT505

    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. Slide 40: GOLDEN-505 Comparison GOLDEN/FLINT/PIVENS

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

  41. Slide 41: Results in the NAS ≥4 Target Population

    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 NA

  42. Slide 42: Efficacy in Patients with NAS score ≥4: NASH resolution

    Comparison GOLDEN/FLINT/PIVENS Efficacy in Patients with NAS score ≥4 NASH RESOLUTION (%) 47 36 29 21 22 22 13 13 5 PLACEBO VITAMINE E PIOGLITAZONE PLACEBO OCA PLACEBO GFT505 PLACEBO GFT505 PIVENS FLINT GOLDEN GOLDEN-505 GOLDEN 3-ARMS GOLDEN-505 SITES 3-ARMS SITES VIT E / PIO OCA GFT505 24 months 18

  43. Slide 43: Efficacy in Patients with NAS score ≥4: NAS decrease

    Comparison GOLDEN/FLINT/PIVENS Efficacy in Patients with NAS score ≥4 DECREASE OF NAS≥2 (%) 48 45 43 36 34 25 21 21 19 PLACEBO VITAMIN E PIOGLITAZONE PLACEBO OCA PLACEBO GFT505 PLACEBO GFT505 PIVENS FLINT GOLDEN-505 GOLDEN GOLDEN-505 3-ARMS GOLDEN 3-ARMS SITES SITES VIT E / PIO OCA GFT505 24 months

  44. Slide 44: Results in the NAS ≥4 Target Population

    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. Slide 45: GOLDEN-505 Phase 2 & Phase 3 Next Steps

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

  46. Slide 46: Next Steps: Phase 2 Conclusions

    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 analyse

  47. Slide 47: Phase 3 Study Design Ongoing (1/2)

    Phase 3 Study Design Ongoing Outline (1/2) • Study population: High-risk patients • 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

  48. Slide 48: Phase 3 Study Design Ongoing (2/2)

    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 patient

  49. Slide 49: Agenda 2015 Conclusion

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

  50. Slide 50: GOLDEN-505 & Phase 3: Agenda 2015

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

  51. Slide 51: Thank You

    THANK YOU WWW.GENFIT.COM

Genfit — EASL Investor Event 2015 on 6ix