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The Hong Kong Association for the Study of Liver D 11/25/18 The Hong Kong Association for the Study of Liver D NAFLD Therapeutics: How Will We Treat NASH 5-Years from Now? The Hong Kong Association for the Study of Liver D Hong Kong Association for the Study of Liver Disease, Hong Kong, November 2018 Prof Quentin M. Anstee PhD, FRCP Professor of Experimental Hepatology & Honorary Consultant Hepatologist, The Hong Kong Association for the Study of Liver D Institute of Cellular Medicine, Newcastle University, UK. The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D Disclosure Slide Research Grant Funding Abbvie, Allergan/Tobira, Astra Zenica, GlaxoSmithKline, Novartis Pharma AG, Pfizer Ltd., Vertex. Active Research Collaborations (including research supported through the EU IMI2 LITMUS Consortium*) Abbvie, Antaros Medical*, Allergan/Tobira, AstraZenica, Boehringer Ingelheim International GMBH*, Ellegaard Gottingen Minipigs AS*, Eli Lilly & Company Ltd.*, Exalenz Bioscience Ltd.*, Genfit SA*, GlaxoSmithKline, HistoIndex, Intercept Pharma Europe Ltd.*, iXscient The Hong Kong Association for the Study of Liver D Ltd.*, Nordic Bioscience*, Novartis Pharma AG*, Novo Nordisk A/S*, One Way Liver Genomics SL*, Perspectum Diagnostics*, Pfizer Ltd.*, Sanofi-Aventis Deutschland GMBH*, SomaLogic Inc.*, Takeda Pharmaceuticals International SA*. Consultancy Abbott Laboratories, Acuitas Medical, Allergan/Tobira, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genfit SA, Gilead, Grunthal, Imperial Innovations, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Kenes, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, Novartis, Novo Nordisk A/S, Pfizer Ltd., Poxel Pharma, Raptor Pharma, Servier, Viking Pharma. Speaker Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Genfit SA, Gilead, Integritas. The Hong Kong Association for the Study of Liver D This lecture contains discussion of off-label/investigative use of commercial products, medical devices, biologic or pharmaceutical agents. The lecture is for academic purposes only and does not constitute any form of medical advice regarding use of these compounds in routine clinical practice or any form of financial advice/recommendation regarding the companies or the products discussed. The Hong Kong Association for the Study of Liver D 1 The Hong Kong Association for the Study of Liver D

The Hong Kong Association for the Study of Liver D 11/25/18 The Hong Kong Association for the Study of Liver D NAFLD Natural History The Hong Kong Association for the Study of Liver D Risk of Death or Transplantation Steatosis + Lobular NASH +/- Portal Advanced fibrosis Early fibrosis F2 F3 Steatosis F1 F4 Inflammation Inflammation & Cirrhosis The Hong Kong Association for the Study of Liver D “Dynamic” Steatotic/Steatohepatitic phase “Non-Linear” Fibrotic phase Steatohepatitis (NASH) is the biological driver of disease progression and fibrogenesis. The presence of advanced stage of fibrosis (F3-4) is the strongest predictor of long-term mortality . The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D Mortality Increases with Fibrosis Stage in NAFLD Systematic review and meta-analysis of 5 studies 1,495 NAFLD patients with 17,452 patient-years follow-up. All-Cause Mortality Liver-Related Mortality 38% Cardiovascular Disease The Hong Kong Association for the Study of Liver D 19% Non-Liver Malignancy Liver Disease 8% 1% Hepatocellular Carcinoma Liver Transplantation <1% The Hong Kong Association for the Study of Liver D Infections 8% Other 18% /Unknown 8% 26% Dulai et al, Hepatology 2017; Angulo et al., Gastroenterology 2015 The Hong Kong Association for the Study of Liver D 2 The Hong Kong Association for the Study of Liver D

The Hong Kong Association for the Study of Liver D 11/25/18 The Hong Kong Association for the Study of Liver D Targeting NAFLD: Four Principles of Treatment 1. Target Obesity – Lifestyle: Diet and Physical exercise The Hong Kong Association for the Study of Liver D – Bariatric Surgery 2. Target the Metabolic Syndrome – reduce CVD risk whilst selecting medication with additional ‘liver directed’ benefits – Insulin resistance/Type 2 diabetes mellitus – Hypertension – Dyslipidaemia The Hong Kong Association for the Study of Liver D 3. Target the liver disease – ameliorate steatohepatitis and prevent progression to fibrosis and cirrhosis 4. Minimise down-stream complications such as HCC The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D Lifestyle Changes: Current Evidence Weight Loss Improves NAS (NASH) • Weight reduction through diet and exercise Promrat, Hepatology 2010 should be recommended because if sustained it improves: The Hong Kong Association for the Study of Liver D – Cardiovascular risk profile Hallsworth 2011 & 2015 – Steatosis Hallsworth 2011 & 2015; Houghton 2017; Sullivan 2012; Wong 2013; Promrat, 2010; Vilar-Gomez 2015 – Steatohepatitis (7-9% weight loss) Promrat 2010; Weight Loss Improves Fibrosis Stage Vilar-Gomez 2015 – Fibrosis (>10% weight loss) Vilar-Gomez 2015 Vilar-Gomez, Gastroenterology 2015 The Hong Kong Association for the Study of Liver D • NAFLD patients lack confidence to exercise and may not be ready to make and sustain the necessary lifestyle changes Frith, 2010; Centis, 2013 The Hong Kong Association for the Study of Liver D 3 The Hong Kong Association for the Study of Liver D

The Hong Kong Association for the Study of Liver D 11/25/18 The Hong Kong Association for the Study of Liver D Bariatric Surgery The Hong Kong Association for the Study of Liver D N = 82 cases with confirmed NASH and f/u Biopsy at 1-Year The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D Targeting the Liver Disease - PHARMACOLOGICAL The Hong Kong Association for the Study of Liver D THERAPY FOR NAFLD…? Currently there are no licenced pharmacological treatments specifically for NAFLD The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D 4 The Hong Kong Association for the Study of Liver D

The Hong Kong Association for the Study of Liver D 11/25/18 The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D Targeting Insulin Resistance & Oxidative Stress with Currently Available Agents The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D Currently Available Pharmacological Compounds Targeting Insulin Resistance Compound Mechanism of Trial Name Company Primary Endpoint(s) Action Investigator Metformin Multiple Multiple Studies Various The Hong Kong Association for the Study of Liver D Led PIVENS* Investigator Reduction in NAS ≥2 without Pioglitazone PPARγ agonist Led fibrosis worsening Multiple Studies LEAN* Novo Resolution of NASH without Liraglutide GLP-1 analogue Nordisc† / IL fibrosis worsening (NCT01237119) Targeting Oxidative Stress The Hong Kong Association for the Study of Liver D Com Compou ound Mechanism Me sm of Tr Trial Name Company Com Primary Endpoint(s) Pr Ac Action on PIVENS* Investigator Improvement in NAS ≥2 Vitamin E Anti-oxidant Led without fibrosis worsening TONIC* † Note Disclosures *Phase IIb. The Hong Kong Association for the Study of Liver D 5 The Hong Kong Association for the Study of Liver D

The Hong Kong Association for the Study of Liver D 11/25/18 The Hong Kong Association for the Study of Liver D Pioglitazone & Vitamin E for NASH: The Phase 2b PIVENS Study 247 non-diabetic adults with biopsy proven NASH Primary Endpoint = 2-point NAS reduction (inc. reduced ballooning) with no worsening of fibrosis The Hong Kong Association for the Study of Liver D Inclusion: P = 0.001* Pioglitazone 30mg/day (N = 80) NAS ≥ 4, F ≤3 OR 3.14 FOLLOW-UP SCREENING Vitamin E 800 IU/day (N = 84) PERIOD PERIOD P = 0.04 Placebo (N = 83) OR 2.13 T -24 W24 W48 W72 W96 W0 96 Weeks The Hong Kong Association for the Study of Liver D Inclusion Liver End of Treatment Biopsy Liver Biopsy • Both agents improved steatosis & inflammation scores * Significance: • Only Vitamin E reduced ballooning P < 0.025 • Neither Vitamin E or Pioglitazone reduced fibrosis The Hong Kong Association for the Study of Liver D The Hong Kong Association for the Study of Liver D Pioglitazone for NASH: Further evidence 101 pre-diabetic/diabetic adults with biopsy proven NASH Primary Endpoint = 2-point NAS reduction (inc. reduced ballooning) with no worsening of fibrosis P < 0.001 60 Inclusion: The Hong Kong Association for the Study of Liver D “Confirmed NASH” Pioglitazone 45 mg/day (N = 50) % Reaching Primary End-Point ?NAS ≥3, F ≤3 50 SCREENING FOLLOW-UP + 500 kcal/day deficient diet PERIOD PERIOD 40 Placebo (N = 51) 30 T -24 W24 W36 W0 W12 W78 20 78 Weeks Inclusion Liver 10 The Hong Kong Association for the Study of Liver D End of Treatment Biopsy Liver Biopsy 0 Placebo • Pioglitazone produced a significantly higher resolution of Pioglitazone NASH but no improvement in fibrosis. Cusi et al, Ann Int Med 2016 The Hong Kong Association for the Study of Liver D 6 The Hong Kong Association for the Study of Liver D