New treatments for NASH Vincent Wong Institute of Digestive Disease - PowerPoint PPT Presentation

New treatments for NASH Vincent Wong Institute of Digestive Disease The Chinese University of Hong Kong

Disclosures • Consultancy: AbbVie, Allergan, Gilead Sciences, Janssen, Perspectum Diagnostics, Pfizer • Lectures: Bristol-Myers Squibb, Echosens, Gilead Sciences, Merck

25% of the global population has non-alcoholic fatty liver disease (NAFLD) 24% 32% 24% 27% 13% 30% Modified from Younossi et al. Hepatology 2016;64:73

Natural history of NAFLD in Asia Fan JG, Kim SU, Wong VW. J Hepatol 2017;67:862

Management of NAFLD NASH-related Disease stage NAFL NASH cirrhosis ✓ ✓ ✓ Lifestyle modification ✓ ✓ ✓ Statin if indicated ✓ ✓ Pharmacological treatment ✓ Screening for HCC? varices and HCC For morbid For morbid For morbid Bariatric surgery obesity obesity obesity

Dulai et al. Hepatology 2017;65:1557

Lifestyle modification and resolution of NAFLD/NASH % ≥ 10% weight loss achieved in: - 19% of patients in a community cohort (Wong et al.) - 10% of patients in a hospital cohort (Vilar- Gomez et al.) Wong VW et al. J Hepatol 2013;59:536 Vilar-Gomez et al. Gastroenterology 2015;49:367

Pharmacological treatment of NASH Vitamin E Pioglitazone • Anti-oxidant • Insulin sensitizer • Reduces liver fat and • Reduces liver fat and inflammation inflammation • Causes weight gain ± • Neutral effects on insulin resistance fluid retention • Uncertain effects on the • May increase the risk of cardiovascular system bladder cancer and malignancy

Liraglutide (GLP-1 agonist) LEADER Trial Primary outcome: death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke GLP-1: glucagon-like peptide 1 Marso et al. NEJM 2016;375:311

Liraglutide for NASH (LEAN Study) Outcomes Liraglutide Placebo P N 23 22 Resolution of NASH 39% 9% 0.019 Down side: Improved ballooning 61% 32% 0.05 - Requires injections Improved steatosis 83% 45% 0.009 - GI upset Improved lobular inflammation 48% 55% 0.65 Improved fibrosis 26% 14% 0.46 Worsened fibrosis 9% 36% 0.04 Armstrong et al. Lancet 2016;387:679

Bile acids and NAFLD FXR Farnesoid X receptor Arab et al. Hepatology 2017;65:350

Obeticholic acid in NASH – FLINT study Primary outcome = NAS decrease ≥2 points without worsening of fibrosis at 72 weeks OCA (n=110) Placebo (n=109) 70 61 60 53 50 46 45 38 40 35 35 % 31 30 22 21 19 20 13 13 12 10 0 Primary Resolution of Fibrosis Steatosis Lobular Portal Ballooning outcome NASH improvement improvement inflammation inflammation improvement improvement improvement Neuschwander-Tetri et al. Lancet 2015;385:956

Safety of obeticholic acid OCA Placebo Pruritus 23% 6% Change in lipids (mmol/L) Total cholesterol 0.16 -0.19 HDL-C -0.02 0.03 LDL-C 0.22 -0.22 Triglycerides -0.22 -0.08 2 deaths in the OCA arm - Congestive heart failure and sepsis - Myocardial ischemia Neuschwander-Tetri et al. Lancet 2015;385:956

Relationship between cholesterol and bile acid synthesis https://commons.wikimedia.org/wiki/File:Bile_acid_differentiation.svg

GS-9674, a non-steroidal, intestine- selective FXR agonist Hepatic Triglycerides Treatment GS-9674 Vehicle Vehicle BID start 30 mg/kg BID 8 0 T r i a c y lg ly c e r id e ( µ m o l/g ) GS-9674 10 mg/kg QD * * GS-9674 30 mg/kg QD 6 0 GS-9674 30 mg/kg BID * 4 0 2 0 0 High-fat diet cynomolgus monkey model Serum Cholesterol Serum LDL-C Serum HDL-C 1500 1200 2 0 0 900 1 5 0 1000 mg/dL 600 1 0 0 500 300 * 5 0 * 0 0 0 0 5 10 15 20 0 5 10 15 20 0 5 1 0 1 5 2 0 French D, et al., AASLD 2016 (oral presentation) HDL-C, high-density lipoprotein-cholesterol; LDL-C; low-density lipoprotein-cholesterol.

Peroxisome proliferator-activated receptors (PPARs) Blaschke et al. Arterioscler Thromb Vasc Biol 2006;26:28

Elafibranor: a dual PPAR α / δ agonist • Improves insulin sensitivity and lipids • Well tolerated apart from abdominal pain (~10%) and small increase in serum creatinine Outcomes of the N Placebo Elafibranor Elafibranor P GOLDEN-505 Study 80 mg 120 mg Protocol-defined primary outcome: Absence of steatosis, lobular inflammation or ballooning without worsening of fibrosis Total 274 17% 23% 21% 0.28 NAS ≥4 234 11% 20% 20% 0.018 Modified definition: Resolution of NASH – Ballooning = 0 and lobular inflammation = 0-1 Total 274 12% 13% 19% 0.045 NAS ≥4 234 9% 13% 19% 0.013 Ratziu et al. Gastroenterology 2016;150:1147

Rationale of ASK1 inhibition for NASH • ASK1 pathway activated in NASH and correlates with fibrosis stage • In rodent models, ASK1 inhibition improves steatosis, inflammation and fibrosis • GS-4997 (selonsertib) is a selective, potent (EC 50 10.8 nM), small molecule inhibitor of ASK1 ASK1, apoptosis signal-regulating kinase 1 Loomba et al. AASLD Late-breaking Abstract #3

Fibrosis improvement with selonsertib treatment for 6 months Loomba et al. Hepatology 2017 [Epub ahead of print]

Cenicriviroc: a dual CCR2/5 antagonist Phase 2b CENTAUR study • Blocks Kupffer cell Primary analysis at Year 1 activation and macrophage % CVC (n=145) Placebo (n=144) recruitment 25 20 • Anti-inflammatory and anti- 20 fibrotic activity in animal 15 10 models 8 10 6 • Favorable safety profile 5 0 NASH resolution Fibrosis without improvement worsening of without fibrosis worsening of NASH Friedman et al. Hepatology 2017 [Epub ahead of print]

BMS-986036 (Pegylated FGF21) Improved liver fat by MRI-PDFF Improved liver stiffness by MRE Sanyal et al. AASLD 2017 #182

Drug development for NASH Active drug Placebo 2 nd liver biopsy Baseline liver biopsy in 1-2 years Follow-up for long-term Conditional approval if: clinical outcomes - NASH resolution without worsening of fibrosis OR - Fibrosis improvement without worsening of NASH

Challenges in drug development • Heavy reliance on liver biopsy • Competition for suitable subjects • Studies underpowered for clinical outcomes • The introduction of the first NASH treatment(s) will affect retention and management of subjects in ongoing or subsequent trials

Mechanisms and effects of NASH drugs Drug Mechanism Resolution Fibrosis of NASH regression ✓ Vitamin E Anti-oxidant X ✓ Pioglitazone PPAR-gamma agonist X ANTI-INFLAMMATORY ✓ Liraglutide GLP-1 agonist X METABOLIC ✓ Elafibranor PPAR-alpha/delta agonist X ✓ Obeticholic acid FXR agonist ? ✓ Selonsertib ASK-1 inhibitor ? ✓ Cenicriviroc CCR2/5 antagonist X

Combination of ASK1 and acetyl-coA carboxylase inhibitors in animal models Bates et al. AASLD 2017 #425

Thank you very much! State Key Laboratory of Digestive Disease Department of Imaging and Interventional - Prof Henry Chan Radiology - Prof Grace Wong - Prof Winnie Chu - Angel Chim - Dr Jill Abrigo - Carmen Chan - Dr David Yeung - Sally Shu - Julie Leung Australian National University - Pete Tse - Prof Geoff Farrell - Katherine Kwan - Prof Shiv Chitturi - HY Li University of Sydney Department of Anatomical and Cellular - Prof Jacob George Pathology - Dr Paul Choi University of Malaya - Prof Anthony Chan - Prof K L Goh - Prof W K Chan University of Bordeaux - Prof Victor de Lédinghen Vincent Wong wongv@cuhk.edu.hk