GENFIT OVERVIEW. September 2016

Transcription

1 GENFIT OVERVIEW September

2 Disclaimer Important information and forward looking statements THIS PRESENTATION HAS BEEN PREPARED BY GENFIT AND IS FOR INFORMATION PURPOSES ONLY. THE INFORMATION AND OPINIONS CONTAINED IN THIS PRESENTATION SPEAK ONLY AS OF THE DATE OF THIS DOCUMENT, UNLESS OTHERWISE INDICATED HEREIN. GENFIT IS NOT UNDER ANY, AND UNDERTAKES NO, OBLIGATION TO UPDATE OR KEEP CURRENT THE INFORMATION CONTAINED IN THIS PRESENTATION AND ANY OPINIONS EXPRESSED THEREIN IS SUBJECT TO CHANGE WITHOUT NOTICE. CERTAIN OF THE INFORMATION CONTAINED HEREIN CONCERNING ECONOMIC TRENDS AND PERFORMANCE IS BASED UPON OR DERIVED FROM INFORMATION PROVIDED BY THIRD-PARTY CONSULTANTS AND OTHER INDUSTRY SOURCES. WHILE GENFIT BELIEVES THAT SUCH INFORMATION IS ACCURATE AND THAT THE SOURCES FROM WHICH IT HAS BEEN OBTAINED ARE RELIABLE, GENFIT HAS NOT INDEPENDENTLY VERIFIED THE ASSUMPTIONS ON WHICH PROJECTIONS OF FUTURE TRENDS AND PERFORMANCE ARE BASED. IT MAKES NO GUARANTEE, EXPRESS OR IMPLIED, AS TO THE ACCURACY AND COMPLETENESS OF SUCH INFORMATION. THIS PRESENTATION CONTAINS CERTAIN FORWARD-LOOKING STATEMENTS. ALTHOUGH GENFIT BELIEVES ITS EXPECTATIONS REFLECTED IN SUCH FORWARD-LOOKING STATEMENTS ARE BASED ON REASONABLE ASSUMPTIONS, THESE FORWARD-LOOKING STATEMENTS ARE SUBJECT TO NUMEROUS RISKS AND UNCERTAINTIES, WHICH COULD CAUSE ACTUAL RESULTS TO DIFFER MATERIALLY FROM THOSE EXPRESSED IN, OR IMPLIED OR PROJECTED BY, THE FORWARD-LOOKING INFORMATION AND STATEMENTS. THESE RISKS AND UNCERTAINTIES INCLUDE AMONG OTHER THINGS, THE UNCERTAINTIES INHERENT IN RESEARCH AND DEVELOPMENT, INCLUDING RELATED TO BIOMARKERS, RESULTS OF CLINICAL DATA FROM THE RESOLVE-IT TRIALS, REVIEW AND APPROVALS BY REGULATORY AUTHORITIES, SUCH AS THE FDA OR THE EMA, REGARDING ELAFIBRANOR AND BIOMARKERS, THE SUCCESS OF ANY INLICENSING STRATEGIES, GENFIT S CONTINUED ABILITY TO RAISE CAPITAL TO FUND ITS DEVELOPMENT, AS WELL AS THOSE DISCUSSED OR IDENTIFIED IN THE PUBLIC FILINGS WITH THE AMF MADE BY GENFIT, INCLUDING THOSE LISTED UNDER SECTION 4 RISK FACTORS ( FACTEURS DE RISQUE ) OF THE COMPANY S 2015 REGISTRATION DOCUMENT WHICH IS AVAILABLE ON GENFIT S WEBSITE ( AND ON THE WEBSITE OF THE AMF ( OTHER THAN AS REQUIRED BY APPLICABLE LAW, GENFIT DOES NOT UNDERTAKE ANY OBLIGATION TO UPDATE OR REVISE ANY FORWARD-LOOKING INFORMATION OR STATEMENTS. 2

3 GENFIT A BIOPHARMACEUTICAL COMPANY 3

4 GENFIT: Innovative company in diagnostic & treatment of metabolic & inflammatory diseases Public company focused on metabolic diseases & associated complications, including liver related disorders Elafibranor (GFT505) lead program Phase 2b completed, first-in-class PPAR α/δ candidate for NASH Biomarker program in NASH/NAFLD: diagnostic, disease progression, and companion tool. World-leading expert in nuclear receptor based drug discovery Revenue-generating alliances with multiple major pharmaceutical companies Founded in 1999 (Lille, France Cambridge, US) 110 employees Since 2006, Euronext Paris - compartment B (GNFT) Lead program in NASH: Elafibranor, first-in-class molecule, Fast-track designation, Accelerated approval Subpart H (FDA) and Conditional approval (EMA) Rich pipeline addressing other key unmet needs: PBC, fibrosis, auto-immune diseases 4

5 GENFIT s pipeline is well-diversified, with R&D efforts well distributed between late stage and early stage programs Lead Programs Research programs Inlicensing program Indication Program MOA Program maturity NASH PBC NASH Pediatric, NASH Cirrhosis, etc. NASH Liver fibrosis/ cirrhosis Auto immune diseases Gastroenterology indications Elafibranor (GFT505) Elafibranor (GFT505) Elafibranor (GFT505) Combo therapy Repositioning Hit-to-lead TGFTX4 TGFTX1 Biomarker Diagnostic PPAR α/δ agonist PPARα/δ agonist PPAR α/δ agonist Multiple Undisclosed Undisclosed RoRγ inverse agonist First patients Phase 3 Q Validation steps Q Phase 2 start in 2016 Different phases Undisclosed Phase 2-ready Early 2017 Start Preclinical H Start Preclinical Q Undisclosed Undisclosed Undisclosed 5

6 THE NASH LANDSCAPE IN

7 NASH: The liver manifestation of metabolic syndrome Obesity prevalence Type 2 Diabetes prevalence 66% of obese or diabetic patients >50 years in the US have NASH with advanced fibrosis Prevalence of NASH in the adult US population is 12% WHO - IDF - Ng, Lancet 2014 Rinella, JAMA Williams, Gastro

8 NASH, the severe form of NAFLD, leads to liver fibrosis, cirrhosis & HCC Waitlist registrations for liver transplantation New HCC cases US Wong, 2015 Reported HCC cases were derived from reported liver cancer cases SEER database 8

9 NASH, the severe form of NAFLD, leads to liver fibrosis, cirrhosis & HCC NASH is the underlying cause of progressive fibrosis resulting from necroinflammation, and leads to cirrhosis Estimated 20 millions US adult patients with NASH & advanced fibrosis Matteoni, Gastro 1999 Adams, Gastro 2005 Ekstedt, Hepatol 2006 Ong, J Hepatol 2008 Dunn, AJG 2008 Sorderberg, Hepatol 2010 Targher, NEJM 2010 Williams, Gastro 2011 Chalasani, Gastro 2012 Torres, Clin Gastro Hepatol 2012 Wree, Nat. Rev Gastroenterol Hepatol 2013 Rinella, JAMA 2015 Bazick, Diabetes Care

10 PHASE 2b GOLDEN-505 BACKGROUND & STUDY DESIGN 10

11 Elafibranor, first-in-class, has Pluripotent Activities PPARa and d Regulate Multiple 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 11

12 Rationale for Treating NASH with Elafibranor, a Dual PPARα/δ Agonist with Multiple Activities Cariou et al. 2011, Diabetes Care, 34(9): Cariou et al. 2013, Diabetes Care, 34(9): Staels et al. 2013, Hepatology, 58(6):

13 GFT505 Improves Liver & Peripheral Insulin Sensitivity Effects on Insulin Sensitivity MoA (Clamp Study) GFT Phase IIa: patients with HOMA>3.0; 2month-treatment, GFT505 (80mg/day) vs. placebo in cross-over design Hepatic MoA: The response of the liver to insulin action is significantly increased in the GFT505 treated group (cf. decrease of Hepatic Glucose Production) Peripheral effects: Improved insulin sensitivity (increase in Glucose Infusion Rate) 13

14 HISTOLOGICAL RESULTS PUBLISHED IN GASTOENTEROLOGY 14

15 Data from Phase 2b Trial of Elafibranor Published in Gastroenterology GOLDEN-505: The first international clinical trial with Resolution of NASH without worsening of fibrosis as the Primary endpoint (56 centers, 9 countries, 52 weeks) The publication highlights the resolution of NASH without fibrosis worsening with 120mg Elafibranor This result is confirmed both in intention-to-treat population as well as in subgroups of moderate/severe NASH patients, based on the recommended definition of NASH resolution now used for clinical trials In addition, the publication confirms that Elafibranor significantly improves the cardiometabolic risk profile and is safe, well-tolerated The online version is available here: Elafibranor, an Agonist of the Peroxisome Proliferator-activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening 15

16 Elafibranor 120mg Has Significant Effect vs Placebo in Both Global and NAS 4 Populations (ITT) GOLDEN-505 study,

17 NASH and Hepatocyte Ballooning are Clear Risk Factors, and Appropriate Targets to Prevent Disease Progression NASH Ballooning NASH and hepatocyte ballooning identified as histological features correlated with clinical outcomes and mortality. In-line with the clinical use of Elafibranor. Angulo, Gastroenterology

18 Mean change versus baseline Elafibranor Responders Have Significant Histological Responses 1 Elafibranor 120mg Responders vs Elafibranor 120mg Non-Responders 0,5 0-0,5-1 -1,5 # # ### -2-2,5-3 -3,5 ### ### Patients who resolved their NASH showed significant reduction in liver fibrosis while non-responders did not show any change from baseline NAS Steatosis Ballooning Inflammation Fibrosis NASH components Elafibranor 120 mg Responders Elafibranor 120 mg Non responders #: p<0.05 ###: p<

19 % patients Changes in Hepatocyte Ballooning and Lobular Inflammation Drive Fibrosis Response % patients % patients Steatosis Ballooning Inflammation Fibrosis Improvers Fibrosis Worseners Fibrosis Improvers Fibrosis Worseners Fibrosis Improvers Fibrosis Worseners N=4 N=49 N=128 N=56 90 N=7 N=78 N=129 N=23 N=9 N=72 N=138 N= Change in steatosis score NS p=0.03 p< Change in ballooning score Change in lobular inflammation score In GOLDEN505 after only 1 year: Changes in hepatocyte ballooning and lobular inflammation are associated with fibrosis response (% of patient who improved or worsened their fibrosis score) No association between change in steatosis score and fibrosis response P-value derived from Khi2 after grouping of extreme with low counts 19

20 Activity Index Correlates with Change in Fibrosis Score and Response: NASH Resolution Induces Fibrosis Improvement % patients Activity Index = Ballooning Score + Inflammation Score fibrosis score Fibrosis Improvers Fibrosis Worseners Mean±SE 1,5 70 N=7 N=39 N=77 N=82 N=27 N= p< Change in activity Index (Ballooning + Inflammation) 1 R² = 0,946 0,5 Activity Index ,5-1 -1,5 In GOLDEN505 after only 1 year: Changes in in Activity Index is highly correlated with changes in fibrosis P-value derived from Khi2 after grouping of extreme with low counts 20

21 The Right Target : Fibrosis or NASH? Two Simple Analogies to Really Understand the Disease Paradigm Underlying Cause = Primary Target For Pharmaceutical Drugs Measure of Progression Clinical Outcome HIV HCV Abacavir, dolutegravir, etravirine, rilpivirine, etc. Sofosbuvir, simeprevir, dasabuvir, etc. FIBROSIS CIRRHOSIS NASH Elafibranor, unique molecule with proven resolution of NASH in ITT in Ph2b Arun Paris Nash Symposium

22 LIVER ACTIVITY MARKERS AND SCORES 22

23 Effect size vs placebo (Absolute change) Elafibranor has efficacy on composites scores, liver and inflammatory markers Effect size vs placebo (U/L) Effect size vs placebo (g/l or log- HsCRP) Elafibranor 120mg vs placebo on composite scores Elafibranor 120mg vs placebo on liver markers Elafibranor 120mg vs placebo on inflammatory markers FIBROTEST *** STEATOTEST *** NAFLD-Fibrosis score p= ,1-0, ** *** *** ALT AST GGT ALP -0,3-0,4 p=0.09 *** ** Fibrinogen Haptoglobin HsCRP (log) The effect size vs placebo was calculated and expressed as LSMean±Standard Error. ** : p< *** : p<

24 CARDIOMETABOLIC PROTECTION MARKERS 24

25 CVD risk in NASH patients is under high scrutiny by regulatory agencies and experts alike FDA/AASLD recommendation (Hepatology 2015) NASH is associated with type II diabetes, increased cardiovascular risk and cancer-related mortality (74-76). For this reason, it seems important to monitor LDL- and HDL-cholesterol, 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. Elafibranor has beneficial effects on top of standard of care (statins, anti-diabetic drugs, etc.) 25

26 The NASH Patient: Characterized by a High Cardiovascular Risk NASH is highly prevalent in obesity NASH is associated with atherogenic dyslipidemia and increased CV risk NASH is associated with type 2 Diabetes Central role of the liver in NASH and its complications New generation therapies should improve global risk management 26

27 Cardiovascular Diseases, Leading Cause of Death in NASH Patients Angulo, Gastro

28 Effect size vs placebo (Absoute change - mmol/l) Elafibranor Improves CV Risk Factors: TG, Cholesterol, LDL-C, Remnant-C, HDL-C 0,2 Elafibranor 120mg vs placebo on lipid markers *** 0,1 0-0,1-0,2-0,3-0,4 *** ** -0,5-0,6-0,7-0,8 *** *** *** TG Total-Chol Non-HDL-Chol LDL-Chol Remnant-Chol VLDL-Chol HDL-Chol The effect size vs placebo was calculated and expressed as LSMean±Standard Error. ** : p<0.01 *** : p<

29 Metabolic Syndrome, Insulin Resistance, and NASH Often Closely Associated in Patient Condition In patients with bland steatosis who had fibrosis progression, steatosis evolved to steatohepatitis and the majority were diabetic or became diabetic at follow-up. This suggests that rather than being distinct entities, steatosis and steatohepatitis represent different stages in the evolution of NAFLD, and that increases in insulin resistance might be a key factor in the progression from steatosis to steatohepatitis with fibrosis. McPherson, J Hepatol Kanwar, Clin Liver Dis

30 Effect size vs placebo (% of baseline) Elafibranor Improves Glucose Homeostasis / Insulin Sensitivity in Type 2 Diabetic NASH Patients Effect size vs placebo (%) Elafibranor 120mg vs placebo Elafibranor 120mg vs placebo 0 0-0, ,1-20 ## -0,2-0,3-30 # -0, , # ## # -0,6-0,7-0,8 # HbA1c GFT # FPG Insulin HOMA-IR FFA Fructosamine C-peptide Significant decrease in HbA1C vs placebo The effect size vs placebo was calculated and expressed as LSMean±Standard Error. # : p<0.05 ## : p<

31 Elafibranor improves NASH by acting on all cell types involved in NASH Parenchymal cells KC Elafibranor EC HSC PPRE FAO decreases Liver fat NFkB AP-1 decreases Inflammation Fibrosis increases Insulin Sensitivity Elafibranor decreases Fibrosis Elafibranor improves Vaso-reactivity E T -1 Elafibranor decreases Inflammation 31

32 HIGHLY FAVORABLE SAFETY OF ELAFIBRANOR 32

33 Elafibranor has very good safety and tolerability profiles, essential for a long-term treatment Very good tolerance confirmed after one year of treatment No Death and no Major Cardiovascular Events (MACE) No effect on body weight No signal on cancer No meaningful change in safety markers and hematology No signal for pruritus Elafibranor 80mg Elafibranor 120mg Placebo Total Adverse event N=93 N=89 N=92 N=274 Nausea Vomiting Diarrhoea Headache Fatigue/asthenia Creatinine increase Abdominal pain Myalgia Decreased appetite Rash Pruritus

34 GENFIT GLOBAL NASH MANAGEMENT 34

35 GENFIT focuses on global management of NASH patients DIAGNOSIS Development of non-invasive biomarkers Identification of patients who should receive therapeutic intervention TREATMENT Therapy to meet unmet need Resolution of histological NASH Safe and well tolerated for long term treatment Beneficial cardioprotective profile for global management of NASH patients Elafibranor enters phase 3 35

36 GENFIT s new algorithms are more predictive than existing scores to identify NASH patients for treatment Identification of NASH patients with NAS 4 with F2 or F3 fibrosis Important for the patient: non-invasive diagnosis for treatment Important for the physician: facilitated diagnosis of patients to treat Important for the NASH market: to meet full potential GENFIT is developing proprietary biomarker algorithms to identify, diagnose and follow-up patients Innovation with bioinformatics and mirnas FDA position on NASH diagnosis there is an urgent unmet need to develop biomarkers that facilitate the diagnosis, identification of populations at risk, assessment of disease progression or regression, and/or response to treatment. Page

37 Launch of Phase 3 in early 2016 Study population: High-risk patients NASH with a NAS 4 Fibrosis stage F2 and F3 (F1 + cardiometabolic risk) Subpart H (interim analysis) Histological primary endpoint: NASH resolution, corresponding to ballooning=0, inflammation=0-1, without worsening of fibrosis (1 point increase) Central reading for all biopsies (inclusion & follow-up) Key secondary endpoint: improvement of histological fibrosis, to be considered as an additional labeling claim Duration 18 months of treatment All patients followed until the occurrence of a pre-defined number of progressions to cirrhosis and other liver related events General design Approximately 1000 patients in interim analysis (total of ~2000 patients) 2 arms: Elafibranor 120mg & Placebo 37

38 Launch of Phase 3 in early 2016 Design details 250 centers SUBPART H ANTICIPATED MARKET AUTHORIZATION ~1000 patients Approx 2000 patients FIRST TREATMENT PERIOD EXTENSION PERIOD Placebo Elafibranor 120mg Placebo Elafibranor 120mg 2:1 2:1 TRIAL INITIATION Q WEEK INTERIM ANALYSIS PRIMARY ENDPOINT: NASH RESOLUTION WITHOUT WORSENING OF FIBROSIS END OF STUDY Occurrence of a pre-defined number of events including progression to cirrhosis Prevention of NASH associated clinical events, including cirrhosis resulting from progressive fibrosis 38

39 Large unmet needs, Large market size THANK YOU FOR YOUR SUPPORT PATIENTS EXPERTS & INVESTIGATORS INVESTORS 39

40 Appendix ABOUT: - LDL and CVD Risk Profile - Glucose Homeostasis and Insulin Sensitivity - OCA Japanese Trial - Pruritus 40

41 Elafibranor decreases LDLc along with a beneficial CV risk profile, while Ocaliva worsens CV risk via increased LDLc after 12 weeks Slide presented by INTERCEPT Pharmaceuticals GENFIT s comment +21% Ocaliva After 12 weeks Treatment (1) (1) Brent A Neuschwander-Tetri, The Lancet 2014 «It is imperative that any drug developed for NASH be at least neutral from a cardiovascular risk perspective and ideally also reduces cardiovascular risks» (HEPATOLOGY 2015) 41

42 Elafibranor improved glucose homeostasis and insulin sensitivity in NASH patients, while Ocaliva shows no benefit in FLINT or even worsening based on HOMA-IR NO BENEFIT or even WORSENING vs. placebo for HbA1c and HOMA-IR (2) Ocaliva IMPROVEMENT vs. placebo (1) UNTREATED/ DRUG NAïVE PATIENTS ON TOP OF STANDARD OF CARE Magnitude of therapeutic response correlates with baseline severity The relevant question is not how PPARα/δ agonism performs vs. fibrates, but rather whether NASH drugs are beneficial for NASH patients (1)Ratziu, Gastroenterology 2015 (2) Brent A Neuschwander-Tetri, The Lancet

43 Japanese Trial With OCA: No Trend on Fibrosis, but an Increase of Pruritus, and in LDL Fibrosis Pruritus 50% 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% Placebo 10mg 20mg 40mg 0% Placebo 10mg 20mg 40mg No sign of efficacy on fibrosis*, one of the co-primary endpoint of the REGENERATE Phase III trial. Dose dependent increase of pruritus as side effect. No indication of any trend. LDL But some «change in lipid parameters consistent with Western population», i.e. increase in LDL (no specific data disclosed). 43

44 Japanese Trial With OCA: No efficacy on NASH resolution endpoint 50% Delta of 2 (NAS) 50% NASH Resolution 40% 40% 30% 30% 20% 20% 10% 10% 0% Placebo 10mg 20mg 40mg 0% Placebo 10mg 20mg 40mg «Delta of 2» on NAS score : not considered as a relevant registrational endpoint by regulatory agencies for Phase III in NASH. No efficacy on NASH resolution, one of the coprimary endpoint of the REGENERATE Phase III trial. Only statistically significant result: obtained for a high dose (40mg) which will not be tested in REGENERATE (a 10mg has instead been added compared to the FLINT trial). 44

45 Pruritus is a Real Concern for a Silent and Chronic disease like NASH, with Potential Impact on Patient Outcome and Health Expenditures Sub-optimal adherence and persistence is a significant issue for people with diabetes Complications from diabetes lead to a significant increase in comorbidities and associated healthcare costs Improved adherence and persistence can reduce costs of complications by 4-15 percent FDA website The IMS Institute For Healthcare Informatics 45