Therapy for NAFLD Are we getting there? Sanjay Bhagani Royal Free London/UCL

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1 Therapy for NAFLD Are we getting there? Sanjay Bhagani Royal Free London/UCL

2 What is NAFLD? Non-Alcoholic Fatty Liver Disease Wide disease range from simple steatosis to cirrhosis Steatosis Steatosis/inflammation Fibrosis Cirrhosis Steatosis NASH Cirrhosis 12-40% 15%

3 NAFLD: Potential consequences HCC Kotronen, Arterioscler Thromb Vasc Biol 2008

4 NASH is the Subtype of NAFLD that Primarily Progresses NASH progressive in a sub-set of NAFL patients Stable NAFLD Liver Failure NASH 10-15% Cirrhosis 40-60% 20-30% Death 65-75% 2%) HCC (Annual incidence Stable Ludwig 1980; Diehl 1988; Lee 1989; Powell 1990; Bacon 1994; Matteoni 1999; Angulo 1999; Caldwell 1999; Ponawala 2000; Contos 2001; Ong 2001; Bugianesi 2002; Ratziu 2002; Harrisson 2003; Marchesini 2003; Younossi 2004; Fassio 2004; Sanyal 2004; Ong 2005; Adams 2005; Ong 2006; Rafiq 2008; Stepanova 2010; Younossi 2012.

5 Fibrosis stage is predictive of survival 619 biopsy-proven NAFLD, FU 12.6 yrs 229 biopsy-proven NAFLD, FU 26 yrs F0 F1 F2-F3 F4 Controls F<3 F>2 Cause of death: cardiovascular 38-43%, cancer 19%, cirrhosis 4-8% HCC 1-5% Independent predictors: fibrosis, diabetes, tobacco, statin use Angulo P et al. Gastroenterology 2015 Ekstedt M et al. Hepatology 2015

6 The molecular engine that drives disease progression NASH Metabolic abnormality Apoptosis Inflammation Fibrosis Cirrhosis HCC Hepatic Fat Adapted from Arun Sanyal, NASH Symposium Paris June 2015

7 Appropriate End-points for therapeutics in NAFLD Early phase trials Populations with NASH or at high-risk of NASH Primary end-points based on mechanism of drug tested; e.g. reduction in hepatic fat by MR-Proton Density Fat Fraction, CAP Phase 3 studies Biopsy proven NASH (NAS score >2) with F2+ fibrosis Primary End-point Complete resolution of steatohepatitis and no worsening of fibrosis At least one point improvement in Fibrosis score with no worsening of steatohepatitis

8 Therapeutics for NASH Metabolic abnormalities Cell-stress/apoptosis and inflammation Antifibrotics Gut-Liver axis

9 NASH multiple potential targets Banini & Sanyal, Curr. Opin. Gastroenterol. 2017

10 What works and what doesn t work data to date Diet/exercise 5% weight loss improves steatosis 7% improvement in inflammation >10% for improvement in fibrosis Insulin sensitising agents Glitazones/Metformin?effective in pre-diabetics/t2dm Anti-lipid therapies Fibrates, statins may improve lipids BUT no/little effect on hepatic inflammation/fibrosis Anti-oxidants Vitamin E works (but risk of Prostate cancer??)

11 Other/upcoming agents for metabolic targets

12 Obetichocolic Acid (OCA) OCA) Semisynthetic bile acid analog (6α-ethyl-chenodeoxycholic acid) 100 times more potent than chenodeoxycholic acid in binding farnesoid X receptor Treatment with OCA has been associated with Improved insulin sensitivity Reductions in markers of liver inflammation and fibrosis Reductions in triglyceride levels Dose-related weight loss OCA was generally well tolerated; adverse effects were similar across treatment groups Increases in LDL and reductions in HDL Mudaliar S, et al. Gastroenterology. 2013;145:

13 % of Responders FLINT Phase 2 Trial Design The Farnesoid X Receptor Ligand Obeticholic Acid (OCA) in NASH Treatment (OCA vs. Placebo for 72 Weeks N=283) Fibrosis Improvement & No worsening of Steatohepatitis Lipid Parameters Measured 5 0 ** Total cholesterol LDL HDL Triglycerides % OCA Pla OCA Pla OCA Pla OCA Pla Baseline % Δ Baseline - 72 wks +6* -7* +9* -8* -1* +1* Δ Baseline - 96 wks P la c e bo O be tic holic Ac id Pruritus higher in OCA group (23% vs 6%) 1 dc d OCA Other AEs were similar to placebo and most SAE unrelated to therapy Brent A Neuschwander-Tetri, et al. Lancet

14 FLINT: Primary and Secondary Histological Endpoints 70% 60% 50% 45% 61% % of Patients with Improvement OCA Pbo P= P=0.001 P=0.006 P=0.03 P=0.004 P=0.08 P= % 46% LDL-C increased pruritus 40% 30% 20% 21% 38% 35% 31% 35% 19% 22% 13% 13% 12% 10% 0% Primary Endpoint Steatosis Lobular Inflammation Ballooning Fibrosis NASH resolution Portal Inflammation Neueschwander-Tetri BA et al. Lancet 2014

15 Elafibranor (GFT505): mechanism of action

16 One year elafibranor vs. placebo in NASH 16 Placebo (n = 92) ITT analysis Elafibranor 80 mg (n = 93) Elafibranor 120 mg (n = 89) p (120 mg vs placebo) Primary endpoint* 17 % 23 % 21 % 0,28 Placebo (n = 76) Post hoc analysis in NAS 4 Elafibranor 80 mg (n = 83) Elafibranor 120 mg (n = 75) p (120 mg vs placebo) Primary endpoint* 11 % 20 % 20 % 0,018 *Reversal of NASH without worsening of fibrosis Ratziu et al, Gastroenterology 2016

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20 Cell-stress/apoptosis and inflammation inhibitors

21 GS-4997 Alone (Apoptosis Signal-regulating Kinase (ASK- 1) Inhibitor) or in Combination with Simtuzumab Phase II Trial Phase 2, Randomized, Open Label Study Evaluating the Safety, Tolerability, and Efficacy of GS-4997 Alone or in Combination With Simtuzumab in NASH and Fibrosis Stages F2-F3 Intervention: Arm A: GS mg QD+SIM 125 mg SQ weekly for 24 wks Arm B: GS mg QD+SIM 125 mg SQ weekly for 24 wks Arm C: SIM 125 mg SQ weekly for 24 weeks NASH with F2-F3 Primary Outcomes: Adverse event of GS-4997 (Treatment-emergent SAE, worsening AST & ALT) Percent who prematurely discontinuation due to AE ClinicalTrials.gov. NCT

22 GS-4997, an inhibitor of apoptosis signal-regulating kinase (ASK1), alone or in combination with Simtuzumab - results Percent of Subjects 100 GS4997 (2 doses) + Sim vs Sim alone 2:2:1:1:1 randomization, Stratified by diabetes NASH, NAS 5, F mg ± SIM 6 mg ± SIM SIM /30 8/27 2/10 11/30 8/27 2/10 Fibrosis Improvement Fibrosis Improvement without NASH Worsening * 3 7 2/27 2/10 1/30 Progression to Cirrhosis Loomba R et al, AASLD 2016

23 CCR2 and CCR5 Promote Obesity-Induced Inflammation and Insulin Resistance Reproduced from Xu et al. Biomolecules 2015;5(3): by the authors; licensee MDPI, Basel, Switzerland. Taken from an open access article distributed under the terms and conditions of the Creative Commons Attribution License ( 11

24 1:1 Randomization 1:1 HEP DART 2015 CENTAUR: NASH with Fibrosis Phase 2b Study Global study 289 subjects enrolled Key eligibility criteria Biopsy diagnosis of NASH with fibrosis Enriched for patients with T2DM High BMI with >1 criteria of metabolic syndrome Bridging fibrosis and/or definite NASH Baseline CVC 150 mg Placebo Primary Analysis (Year 1) CVC 150 mg CVC 150 mg Placebo Final Analysis (Year 2) Primary endpoint 2-point improvement in NAS without worsening of fibrosis) Key secondary endpoint Resolution of NASH without worsening of fibrosis Other endpoints Change in fibrosis stage Collagen morphometry α-sma, CK-18 Validated fibrosis scores Noninvasive imaging and biomarkers Kidney function Screening biopsy Primary endpoint biopsy Final biopsy NCT

25 CENTAUR: primary endpoint not met but key secondary endpoint on fibrosis improvement met Placebo (N=144) 25% 20% 19% 15% 10% 5% CVC (N=145) 16% 25% 20% 15% 10% 5% 6% 8% P< % 20% 0% 2-point Improvement in NAS AND No Worsening of Fibrosis 0% Complete Resolution of NASH AND No Worsening of Fibrosis Improvement in Fibrosis Stage AND No Worsening of NASH PRIMARY ENDPOINT SECONDARY ENDPOINTS Sanyal A et al, AASLD 2016

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31 NASH* landscape: Segmentation by company NAFLD Pipeline X Interaction with company in progress Not available for partnering Covered by internal program Declined or MoA not interesting Antifibrotic BOT-191/BiOrion X ZGN-839/Zagfen Glucose metabolism X IVA-337/Inventiva NGM313/NGM Bio X FG-3019/FibroGen GS-0976/Gilead Nimbus NC-101/Naia Semaglutide/Novo ND-L02-s0201/Nitto Denko GR-MD-02/Galectin X MSDC-0602/Octeta KBP-042/Nordic Bioscience Simtuzumab/Gilead DS-102/Afimmune MN-001/MediciNova GRI-0621/GRI Bio PRX-106/Protalix GKT831/GenKyotex GS-4997/Gilead Emricasan/Conatus Cenicriviroc/Allergan/Tobira X Oxidative stress X X Elafibranor/Genfit PXS-4728/BI X MT-3995/Mitsubishi RTU-1096/Sucampo FXR/Allergan/Akarna EDP-305/Enanta INT-767/Intercept LJN452/Novartis/NIBR GS-9674/Gilead Aramchol/Galmed X Volixibat/Shire Obeticholic acid/intercept saroglitazar/zydus A4250/Albireo MGL-3196/Madrigal AZD4076/AZ NGM-282/NGM X X JKB-121/Taiwan J Pharma VK-2809/Viking IMM-124-E/Immuron Solithromycin/Cempra VK-0214/Ligand DRX-065/DeuteRx BMS /BMS TEV-45478/Teva X VLX103/Verlyx Lipid metabolism X IONIS-DGAT2Rx/Ionis X LY /Lilly BMS /BMS DUR-928/Durect NP-201 program/ngm/merck X RYI-018/Ruiyi Phase II Phase IIb Phase IIa Phase I Preclinical LMB-763/Novartis Other Anti-inflammatory UD-014/Ube Bertilimumab/Immune Therapeutics Sources: pipeline databases, company websites, competitive intelligence analysis. Preclinical: only selected projects to reach clinical development in 2016 are shown. More than one mode of action may be applicable for a given drug. *NASH compounds only. Projects with only NAFLD patients are not considered Immunomodulatory Drug/company (MoA) FDA Fast Track for NASH Breakthrough designation

32 Future markets.

33 Targeted therapies for NAFLD A better understanding of the pathaphysiology Biomarker development for prediction of progression, inflammation and fibrosis Imaging/sonographic modalities

34 Acknowledgements Patrick Ingiliz Manolis Tsotchasiz Maud Lemoine Laurent Sefarty Zobair Yaunossi