GENFIT Overview Focus on GFT505

Transcription

1 Apr v32fi GENFIT Overview Focus on GFT505 April

2 Disclaimer Important Information and Forward Looking Statements GENFIT IS A PUBLIC COMPANY LISTED ON EURONEXT PARIS (COMPARTMENT B) STOCK EXCHANGE SINCE APRIL 17, GENFIT SHARES HAVE BEEN LISTED ON THE ALTERNEXT MARKET OF EURONEXT PARIS SINCE THIS DOCUMENT DOES NOT CONSTITUTE OR FORM PART OF ANY OFFER FOR SALE OR SUBSCRIPTION OF OR SOLICITATION OF ANY OFFER TO BUY OR SUBSCRIBE FOR ANY SECURITIES. THE SHARES OF GENFIT HAVE NOT BEEN AND ARE NOT BEING REGISTERED UNDER THE U.S. SECURITIES ACT OF 1933, AS AMENDED (THE SECURITIES ACT ) AND NEITHER GENFIT, ITS SHAREHOLDERS OR THEIR AFFILIATES INTEND TO REGISTER ITS SHARES IN THE UNITED STATES OR TO CONDUCT A PUBLIC OFFERING OF SECURITIES IN THE UNITED STATES. SECURITIES MAY NOT BE OFFERED OR SOLD IN THE UNITED STATES UNLESS THEY ARE REGISTERED UNDER THE SECURITIES ACT, OR EXEMPT FROM REGISTRATION. BASED ON ITS HISTORIC AND EXPECTED OPERATIONS, COMPOSITION OF ASSETS AND MARKET CAPITALIZATION (WHICH WILL FLUCTUATE FROM TIME TO TIME), GENFIT DOES NOT EXPECT THAT IT WILL BE A PASSIVE FOREIGN INVESTMENT COMPANY WITHIN THE MEANING OF SECTION 1297 OF THE U.S. INTERNAL REVENUE CODE OF 1986, AS AMENDED, (A PFIC ) FOR THE CURRENT TAXABLE YEAR. HOWEVER, THE DETERMINATION OF WHETHER GENFIT IS A PFIC IS MADE ANNUALLY, AFTER THE CLOSE OF THE RELEVANT TAXABLE YEAR, AND, THEREFORE, IT IS POSSIBLE THAT GENFIT COULD BE CLASSIFIED AS A PFIC FOR THE CURRENT TAXABLE YEAR OR ANY FUTURE TAXABLE YEAR DUE TO CHANGES IN THE COMPOSITION OF ITS ASSETS OR INCOME, AS WELL AS CHANGES IN ITS MARKET CAPITALIZATION. THIS DOCUMENT INCLUDES CERTAIN STATEMENTS OF THE COMPANY WITH RESPECT TO THE COMPANY S HISTORICAL AND ANTICIPATED FUTURE PERFORMANCE. SUCH STATEMENTS REFLECT VARIOUS ASSUMPTIONS OF MANAGEMENT THAT MAY OR MAY NOT PROVE TO BE CORRECT AND INVOLVE VARIOUS RISKS AND UNCERTAINTIES. NO REPRESENTATIONS OR WARRANTIES ARE MADE AS TO THE ACCURACY OF SUCH STATEMENTS OF ANTICIPATED PERFORMANCE. 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. THE COMPANY BELIEVES THAT SUCH INFORMATION IS ACCURATE AND THAT THE SOURCES FROM WHICH IT HAS BEEN OBTAINED ARE RELIABLE. THE COMPANY CAN T GUARANTEE THE ACCURACY AND COMPLETENESS OF SUCH INFORMATION, HOWEVER, AND THE COMPANY HAS NOT INDEPENDENTLY VERIFIED THE ASSUMPTIONS ON WHICH PROJECTIONS OF FUTURE TRENDS AND PERFORMANCE ARE BASED. EXCEPT AS OTHERWISE INDICATED, THIS DOCUMENT SPEAKS AS OF THE DATE HEREOF. THE DELIVERY OF THIS DOCUMENT SHALL NOT, UNDER ANY CIRCUMSTANCES, CREATE ANY IMPLICATION THAT THERE HAS BEEN NO CHANGE IN THE AFFAIRS OF THE COMPANY AFTER THE DATE HEREOF. 2

3 GENFIT as of Today A Biopharmaceutical Company Public company focused on metabolic diseases & associated complications, including liver related disorders Lead program Phase IIb, first-in-class PPARα/δ candidate for NASH; Data expected by YE 2014 World-leading expert in nuclear receptor based drug discovery Revenue generating alliances with multiple major pharmaceutical companies Founded in 1999 (Lille, France Cambridge, US) 80 employees Listed on the Alternext market of Euronext (NYSE, Paris) since 2006 and transferred to the Euronext Paris regulated market - compartment B since April 17, 2014 (GNFT) 3

4 GENFIT in 2014 Strong R&D focused on metabolic related liver & GI diseases Lead Program: GFT505 a first-in-class PPARα/δ Phase IIb drug candidate for NASH CVD prevention in high-risk prediabetic & diabetic patients Non metabolic hepatic fibrosis and cirrhosis Phase IIb data by YE 2014 Phase III ready product by early 2015 FDA s Fast-Track designation for NASH Drug candidate programs (incl. RORγt, Rev-Erbα & RTK programs) for auto-immune & fibrotic diseases Proprietary molecules Comprehensive knowhow and capabilities to advance drug discovery programs from target validation to clinic Marketed drug : oral administration, single pill, once daily 4

5 GENFIT in 2014 Strong R&D focused on metabolic related liver & GI diseases Committed to biomarker approach NAFLD/NASH - Diabetes & prediabetes Identifying pertinent biomarkers in ongoing Phase IIb trial with histology proven NASH Risk-sharing drug discovery program with Sanofi Focused on mitochondrial dysfunction Potential notably in metabolic diseases (incl. T2D) and kidney diseases High-value milestones 5

6 Challenges in Metabolic Diseases Complications and Co-Morbidities - NASH Broad agreement among experts that the treatment paradigm of Metabolic Diseases needs to evolve Treatment of type 2 diabetics should not remain glucocentric Move to treat diabetics by treating the associated risk factors and co-morbidities NASH is a liver disease associated with metabolic diseases including pre-diabetes and diabetes NASH is a co-morbidity NASH is a multifaceted disease, thus best treated by targeting multiple activities 6

7 Challenges in Metabolic Diseases GFT505, A Therapeutic Solution for NASH RISK FACTORS Altered glucose metabolism Lipid Disorders Overweight, obesity Pro-inflammatory & oxidative stress Hypertension Liver Dysfunction Glucose reduction is not sufficient to avoid Type II diabetes complications PREDIABETES Organ Defects High need for products to treat complications and comorbid diseases associated with diabetes OADS METFORMIN SULFONYLUREAS GLITAZONES DPP-IV DIABETES Insulin Resistance Hyperglycemia COMPLICATIONS Retinopathy / Blindness Nephropathy Diabetic Foot NASH GFT505 CV Events 7

8 NASH, Non-Alcoholic Steato-Hepatitis A severe form of Non-Alcoholic Fatty Liver Disease 25% of the general population 70% in diabetic and obese patients STEATOSIS 12% of population has NASH HEALTHY LIVER Survival vs. the general population Hepatocellular Carcinoma Transplant Death NASH Liver-related mortality Cardiovascular mortality CIRRHOSIS Cirrhosis : an independent risk factor of death Matteoni, Gastro 1999, Adams, Gastro 2005, Ekstedt, Hepatol 2006, Ong, J Hepatol 2008, Dunn AJG 2008, Sorderberg, Hepatology 2010, Targher NEJM

9 NASH, Non-Alcoholic Steato-Hepatitis A severe form of Non-Alcoholic Fatty Liver Disease Simple steatosis (liver fat) is considered clinically benign NASH defined as having liver fat, inflammation and hepatocyte ballooning (cell damage) 12% of population has NASH NASH presents significant risk for liver fibrosis, cirrhosis and liver cancer NASH is associated with decreased overall survival, and increased liver related mortality NASH is an independent risk factor of CV events, and increases cardiovascular mortality Hepatologists can predict up to 80% if a patient has NASH based on standard clinical examination and routine liver function tests confirmed by biopsy Opinion leaders advocate that NASH patients need to be treated, and should not wait for later stage disease 9

10 Perspectives in NASH AASLD-FDA Public Workshop (Sept 5-6, 2013) NASH recognized as a high unmet need indication NASH rapidly becoming the leading cause of liver transplantation New data on Nash Prevalence in US: 12% of the general population 15-25% of NASH patients can progress to cirrhosis Fibrosis worsens the prognosis: Cirrhosis develops in 13.3% of NASH patient with mild to moderate fibrosis (F1-F2) Cirrhosis develops in 50% of NASH patient with advanced fibrosis (F3) Registration in US: Reversal of NASH without worsening of fibrosis is an acceptable clinical endpoint for Phase III trials Eligible for subpart H procedure (hard clinical end-points -> post marketing studies) Phase III trials should address NASH patients with established fibrosis 10

11 Competitive Landscape in NASH Clinical development pipeline Company Product MoA Phase Condition Next NASH catalyst Endpoint GENFIT GFT505 PPARα/δ agonist 2b NASH YE2014 reversal of histological NASH without worsening of fibrosis INTERCEPT (NIDDK) OCA FXR agonist (bile acid) 2b NASH YE2014 improvement of NAS (by 2 points) and no worsening of fibrosis RAPTOR (NIDDK) RP103 (DR cysteamine) cysteine-depleting agent 2b NAFLD in children 2015 improvement of NAS (by 2 points) and no worsening of fibrosis GILEAD Simtizumab Mab against LOXL2 2b Liver fibrosis/nash 2016 change in morphometric quantitative collagen PHENEX PX104 FXR agonist 2a NAFLD change in hepatic fat CONATUS Emricasan Caspase protease inhibitor 2a NAFLD/NASH change in ALT GALMED Aramchol synthetic Fatty Acid / bile acid conjugate 2a (completed) NAFLD/NASH change in liver triglyceride level GALECTIN GR-MD-02 galectin-3 inhibitor 1b NASH safety (+ evaluation of change in liver enzymes) Source: clinicaltrials.gov 11

12 GFT505 in NASH A Pluripotent Product Is Needed, GFT505 Can Meet the Need GFT505, New dual PPARα/δ product Over 600 patients or healthy volunteers treated with GFT505 to date Beneficial properties for NASH Improvement of glucose homeostasis & insulin sensitivity Improvement of markers of liver dysfunction Favorable effects on plasma lipids Efficacy on histological NASH parameters in disease models (fibrosis, steatosis, ) Absence of safety concern Anti-inflammatory properties 12

13 ALT (UI/L) 4+4 weeks 4 weeks GFT505 Reverses Liver Steatosis In Vivo Intervention Studies Relevant to the Treatment of NASH GFT505 leads to the complete regression of liver steatosis GFT505 treatment induces a reverse effect on liver transaminase levels Plasma ALT levels Control animals Examination of liver Pathological animals Pathological animals treated with GFT * *** *** *** N/A weeks weeks Ctrl MCD MCD + GFT505 Intervention protocol: Diabetic mice with induced liver steatosis (MCD Diet) 13

14 GFT505 Blocks Fibrosis In Vivo Intervention Studies Relevant to the Treatment of NASH GFT505 stops the development of liver fibrosis Intervention protocol: rat model of chemically (CCl4) induced liver fibrosis 14

15 Fibrosis area (%) GFT505 Reverses Fibrosis & Increases Liver Regeneration In Vivo Reversion Study on CCl4-Induced Liver Fibrosis in SD Rat GFT505 reverses CarbonTetraChloride (CCl 4 )-induced fibrosis and favors the regeneration of the liver 2,5 2,0 1,5 1,0 ** * *** *** * *** *** *** * 0,5 0,0 T0 T1w T2w 2 weeks 2+1 weeks 2+2 weeks normal Control animals pathologic (no + CCl Ctrl 4 induction pathologic of fibrosis) + GFT505 30mg/kg Pathological animals (with CCl 4 -induced fibrosis) Treated with GFT505 (30mpk) Not treated with GFT505 Reversion protocol: animal model of chemically (CCl4) induced liver fibrosis 2 weeks CCl4 T0 T1w T2w 2 weeks vehicle 2 weeks GFT505 (30 mpk) 15

16 GFT505 eliminates NASH and reverses fibrosis In vivo intervention study in foz/foz mice model of NASH Full results at AASLD congress (Boston, Nov 2014) In vivo intervention study reproducing the ongoing phase IIb clinical trial (foz/foz mice subjected to a high-fat diet) Intervention protocol: foz/foz mice model presenting established NASH with hepatic fibrosis High fat diet 18 weeks high fat diet +/- GFT505 GFT505 reverses steatosis, ballooning and inflammation GFT505 reverses fibrosis Average NAS of 5, hepatic fibrosis Obesity, Insulin resistance, Dyslipidemia GFT505 induces significant weight loss, improves diabetes parameters and plasma lipids 16

17 % of fibrosis area T12w+18w T12w GFT505 Reverses Hepatic Fibrosis NASH model (foz/foz mice on a high fat diet) Treatment with GFT505 results in a total reversion of hepatic fibrosis that was established due to high fat diet administration Control animals Pathological animals (HFD) (chow diet) Not treated with GFT505 Treated with GFT505 GFT-1 GFT-2 ** *** GFT-3 GFT-4 Trichrome staining $$$ GFT#1 (n=11) GFT#2 (n=12) GFT#3 (n=11) GFT#4 (n=12) 12 weeks CHOW HFD HFD HFD 18 weeks HFD HFD + GFT505 P= 0,001 Switch to HFD at the age of 4-5 weeks Randomisation on Body weight, Glycemia, insulinemia, AST & ALT 17

18 GFT505 Antifibrotic Activity A potential for the treatment of fibrotic diseases (incl. non hepatic ones) Full results at AASLD congress (Boston, Nov 2014) In vivo intervention studies on widely used model of IBD (crohn s disease & ulcerative colitis) GFT505 reduces fibrosis & protects from intestinal inflammatory injury in a model of DSS-induced chronic colitis in mouse Antifibrotic activity of GFT505 supported by effects on primary human stellate cells (inhibition of proliferation & of activation) A MoA related to the inhibition of a group of RTKs relevant to the fibrotic process 18

19 GFT505 Antifibrotic Activity Demonstrated in a IBD mouse model (DSS induced colitis) GFT505 reduces Dextran Sodium Sulfate -induced inflammation & fibrosis in the colitis model Score of intestinal fibrosis Score of intestinal inflammation Chronic colitis induced by 3 cycles of DSS Euthanasia 15 mice/group (C57bl6 mice) DSS H 2 O DSS H 2 O DSS H 2 O 5 days 8 days 5 days 8 days 5 days 7 days Vehicle or GFT505 3, 10 & 30mg/kg once daily 19

20 GFT505 Antifibrotic Activity Insights on the mechanism of action GFT505 demonstrates antifibrotic activity on Primary Human Stellate Cells Dose dependent inhibition of TGFβ induced stellate cell activation Dose dependent inhibition of PDGF induced stellate cell proliferation GFT505 antifibrotic properties are associated with the inhibition of structurally related RTKs by GFT505 The RTKs repressed by GFT505 belong to a group involved in the fibrotic process 20

21 GFT505 Improves Glucose Metabolism & Insulin Sensitivity GFT505 improves OGTT derived parameters, including AUC for glycemia, insulinemia and Free Fatty Acid levels GFT505 reduces HbA1c (-0.37% vs. baseline, p<0.05) GFT505 improves liver & peripheral insulin sensitivity h-Glycemia (mg/dl) AUC-Gluc (mg*h/dl) AUC-ins (UI*h) AUC-FFA (mmol*h/l) *** $ OGTT derived parameters vs baseline after 3 months NS *** GFT505 p=0.13 Placebo ** NS *** GFT Phase IIa: 97 drug-naïve diabetic patients 3 month-treatment - GFT505 (80mg/day) vs. placebo NS NS $$ NS 21

22 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) 22

23 Lipid parameters Effect size (% change) vs placebo GFT505 Positive Effects on Metabolic Parameters Favorable Effects on Plasma Lipids GFT505 decreases plasma triglycerides and non HDL-C levels GFT505 increases HDL-C These effects correlate with A reduction in pro-atherogenic apolipoproteins incl. ApoB An increase in ApoA2 anti-atherogenic HDL particle Consistently in all the trials GFT GFT GFT GFT TG CHOL HDL-C NON HDL-C 4 ** 9-8 ** -9 *** -12 ** -13 *** LDL-C ApoA2 ApoB *** 18 *** 7-8 * ** *** -14 *** GFT GFT ** *** 23

24 GFT505 favorable effects on Inflammation Markers and Markers of Liver Dysfunction Consistently in all the trials (GFT GFT GFT GFT ) GFT Phase IIa: 97 drug-naïve diabetic patients 3 month-treatment - GFT505 (80mg/day) vs. placebo GFT505 improves significantly markers of inflammation GFT Phase IIa: patients with HOMA>3.0; 2monthtreatment, GFT505 (80mg/day) vs. placebo in cross-over design and markers of liver dysfunction 24

25 No Safety Concerns Clear Advantage vs. Competitors Over 600 patients or healthy volunteers treated with GFT505 to date No serious adverse event nor dropout reported in the GFT505 treated groups, for periods of treatment up to 3 months No safety concern, no effect on PPAR related safety markers No change on red blood cell parameters: hemoglobin, hematocrit, red blood cell count Full toxicological package: No safety concern relevant to humans Completed Long-term GLP toxicity studies 26-week treatment in rats - 52-week treatment in monkeys No major safety concern identified up to the highest doses tested Completed 2-year Carcinogenicity studies (rats, mice) EMA validated protocol No carcinogenicity of relevance to human 25

26 GFT505 Development Plan in NASH Aligned to Register GFT505 Among the 1st Approved Drugs for NASH Proof of Safety & Efficacy Package COMPLETED Pivotal Phase IIb Ready for Phase III package Phase III Pivotal phase IIb in Europe & US 1-year treatment liver biopsy-based trial 270 patients / 56 centers 2 doses (80mg & 120mg) + placebo FDA preind meeting EMA scientific advice 2012 Submission US & Europe June-Oct 2012 First patient, First Visit Sept 2012 DSMB approval for second recruitment phase Oct 2013 => Completion of the enrollment End of treatment analysis YE2014 early

27 GFT Phase IIb trial design Criteria for evaluation After 52 weeks of daily administration of GFT505 (80 & 120 mg), comparison of changes vs baseline with those observed in the placebo group Primary endpoints Reversing histological steatohepatitis without worsening of fibrosis (i.e. progression to cirrhosis or bridging fibrosis) differences in % of responders in GFT505 groups vs. placebo Secondary endpoints Changes in NAS score Stage of steatosis, hepatic activity (inflammation, ballooning) Stage of fibrosis (NASH CRN scoring) - Fibrosis by morphometry Liver enzymes - Non-invasive markers of fibrosis & steatosis Lipid parameters, body weight, insulin resistance, inflammatory markers, safety markers (renal or cardiac function parameters), cardiovascular risk profile SAE, AE, physical examination, vital signs, medical history, ECG 27

28 GFT505 Moving Forward to NASH Approval FDA-AASLD Public Workshop (Sept 5-6, 2013) on trial designs and endpoints Target population: NASH patients with established fibrosis Eligible for approval based on surrogate endpoints ( subpart H procedure) Reversal of NASH without worsening of fibrosis could be acceptable FDA s Fast-Track designation for GFT505 in NASH (February 2014) Concerted definition of the most appropriate development plan with the FDA Accelerated review process 28

29 GFT505 Moving Forward GFT505 is predicted to be cost effective (Preliminary Markov model/ IMS-Health) Cost of NASH management offset by reduction of future later stage disease management Reduction of hepatic events Reduction of cardiovascular events A large market for treatments of NASH A forecast of 165M people with NASH by 2020 (5MM EU, NA, Japan & China) Addressable market of over 10 bn world-wide 29

30 Making the transition to a specialty biopharma for the metabolic related liver and GI diseases A strong R&D to develop innovative treatments and diagnostic tools A network of renowned KOLs, clinicians, experts in North America, Europe and Asia Addressing Market Access, Pharmaco-economy, Regulatory in EU & NA markets GFT505, an innovative treatment for NASH Potential for out-licensing Either on a worldwide basis Or on selected markets, while Genfit could retain rights on chosen territories Biomarkers / companion tool Drug candidate programs for autoimmune and fibrotic diseases in the Liver/GI area Positioned to evolve progressively into a business model combining R&D and products on selected markets, alone or with strategic partners 30

31 Financials Financial Statements to 31 December 2013 (million EUR) 12/31/13 Revenues from industrial alliances 1.90 Public funding of R&D expenses 3.92 Total revenues 5.97 Current operating result (10.42) Financial result 0.18 Pre-tax income (10.33) Net result (12.65) Gross cash

32 Thank you 32