First European NAFLD-NASH Summit European Parliament, Brussels, May 31 st NAFLD/NASH : an expanding burden on liver health

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1 First European NAFLD-NASH Summit European Parliament, Brussels, May 31 st 2017 NAFLD/NASH : an expanding burden on liver health Vlad Ratziu, Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France

2 Diet Lifestyle Heritability/ genetic Comorbid conditions (metab sd, diabetes, OSA) Non-Alcoholic Fatty Liver Disease (NAFLD) Steatosis in >5% of hepatocytes Microbiota Non-Alcoholic Steatohepatitis (NASH) Steatosis Lobular Inflammation Hepatocellular ballooning Non-Alcoholic Fatty Liver (NAFL) Steatosis in >5% of hepatocytes No or minimal inflammation FIBROSIS early (F0, F1) advanced (F2, F3) cirrhosis (F4) cirrhosis decompensation encephalopathy ESLD (OLT) HCC neurocognitive disorders - QOL

3 Portal fibrosis peri sinusoidal fibrosis Bridging fibrosis cirrhosis

4 Obesity : magnitude of the problem 2 Billion adults overweight (39%) 600 Million adults obese (13%) USA: 2/3 overweight or obese

5 Global prevalence of NAFLD : 25% Trends : 20%; : 24%; : 27%

6 NAFLD Secondary Alcohol Drugs (amiodarone, metothrexate, tamoxifen, corticosteroids) A/hypo betalipoprotéinémia Chronic HCV (genotype 3) Wilson disease Industrial toxins Lipodystrophies Cholesteryl ester storage disease Microvesicular steatosis PRIMARY Metabolic Risk Factors

7 Causes of Cirrhosis (US) Multiethnic Cohort, Medical Claims, Medicare claims % NAFLD 29% NAFLD ALD HCV Crypto HBV Other Setiawan, Hepatology 2016

8 NASH as an indication for liver Data from UNOS Registry transplantation NASH : second cause of LT waitlist registrants NASH : less likely to undergo LT NASH : less likely to survive for 90 days on the waiting list Wong, Gastroenterology 2015

9 Prevalence of NAFLD and NAFLD fibrosis in the general Dutch population (>45 yrs) N= 3041 indiv, general pop, >45 yrs 35.5 % NAFLD 27 % Alcohol, drugs, viruses 2.3 % NAFLD fibrosis Koehler, Hepatology 2016

10 Factors associated with Fibrosis in the general Dutch population older than 45 yrs Age Diabetes 34%-10% Male sex 62%-44% Steatosis 59%-34% Smoking 78%-64% LSM >8 kpa Metab Sd Alcohol NO! Koehler, Hepatology 2016

11 NAFLD is an increasing cause of HCC in Northern England Over the past decade 35% ALD: 28% NAFLD: 22% No CLD: 20% Dyson, J Hepatol 2013

12 NAFLD : an underrecognized disease % 39.4% recognition of ALT increase 21.5% diagnosis of NAFLD/NASH 15% lifestyle modifications 10.5% referral specialist evaluation NO NAFLD CARE Only the magnitude and proportion of ALT elevation were predictive of receiving NAFLD care Blais, Am J Gastroenterol 2014

13 Routine, non-invasive assessment of hepatic fibrosis SERUM MARKERS TRANSIENT ELASTOMETRY Fibrometer biopredictive.com Biols.fr

14 MRE elastography Loomba, Hepatology 2014

15 NASH : reduced survival Survival vs. the general population Liver-related mortality STEATOSIS NASH Cardiovascular mortality Same survival as the general population Cirrhosis : an independent risk factor of death Hepatocellular carcinoma Matteoni, Gastro 1999, Adams, Gastro 2005, Ekstedt, Hepatol 2006, Ong, J Hepatol 2008, Dunn AJG 2008, Sorderberg, Hepatology 2010, Dyson J Hepatol 2014

16 NAFLD Both consequence and catalyzer of the metabolic syndrome? Hypertension Cardiovascular Prevalence essential HTN Incident diabetes Insulin requirements NAFLD Diabetes Endothelial & coronary dysfunction Carotid plaques Impaired ventricular fct and metabolism CV events

17 Work-up in patients with NAFLD: a multiorgan approach NAFLD Extrahepatic comorbidities? Liver condition Type 2 diabetes Sleep apnea Hypertension, arterial Dyslipidemia Cofactors of fibrosis Pathological form Stage Prognosis

18 First records of CLDs in Scotland by diabetes status Retrospective population-based cohort Scottish Diabetes Register & National hospital cancer and death records ; years; 26 M Pt/years of F/u 97% mono diagnosis of CLD #2 #1 #1 #2 Wild, J Hepatol 2016

19 Impact of NAFLD on health-care utilization and cost in a general population Cohort Study of Health in Pomerania, patients at baseline 5 year follow-up examination in 3300 subjects 4 categories : US +/-, ALT N/abN 14% US-, ALT N 16% 10% 60% US-, ALT abn US+, ALT N US+, ALT abn Baumeister, Gastroenterology 2010

20 40 Levels of health-care utilization and costs US +, ALT abn vs. US neg, ALT N % higher cost US +, ALT abn 5 0 Adjusted on sex, age, income, education, smoking, physical activity, BMI, waist circumf Baumeister, Gastroenterology 2010

21 Diet Exercise

22 Weight loss pyramid Weight Loss 10% 1 Fibrosis (45%) Patients achieving: <10% in 1 year 1 Weight Loss 7% 1 NASH Resolution (64 90%) * 18% in 1 year 1 Weight Loss 5% 1-3 Ballooning / inflammation (41 100%) * 30% in 1 year 1 Weight Loss 3% 1-4 Steatosis (35 100%) * *Depending on degree of weight loss 1 Vilar-Gomez E, et al. Gastroenterology. 2015;149: Promrat K, et al. Hepatology. 2010;51: Harrison SA, et al. Hepatology. 2009;49: Wong VW, et al. J Hepatol. 2013;59: Slide courtesy of S. Harrison 22

23 Exercise Diet Drugs

24 Late phase RCTs in NASH Completed Phase 2b trials: FLINT: obeticholic acid vs. Placebo (Lancet 2015) GOLDEN: elafibranor vs placebo (Gastroenterology 2016) CENTAUR (Year 1): cenicriviroc vs placebo (submitted) Current Phase 3 trials (registrational): REGENERATE (obeticholic acid) RESOLVE-IT (elafibranor) STELLAR 1 and 2 (selonsertib) STELLARIS (cenicriviroc)

25 EASL EASD - EASO V Ratziu May31st 2017

26 Fatty Liver: Inhibition of Progression HEALTH-F Subprogram Area: Prevention and treatment of non-alcoholic fatty liver disease (NAFLD) Contract type: Small or medium-scale focused research project

27 EPoS The EPoS project has received funding from the European Union s Horizon 2020 research and innovation programme under grant agreement No nd SC Meeting, 26-27/1/16 27

28 Investigative Medicines Initiative 2: Call 9 (2016) LITMUS Liver Investigation: Testing Marker Utility in Steatohepatitis 2 nd SC Meeting, 26-27/1/16