NASH UPDATE ON DIAGNOSTICS AND THERAPY. Arun J Sanyal MBBS, MD Virginia Commonwealth University School of Medicine

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1 NASH UPDATE ON DIAGNOSTICS AND THERAPY Arun J Sanyal MBBS, MD Virginia Commonwealth University School of Medicine Conflicts of interest Salaried employee: of VCU Member of Board: McGuire VA Research Institute, unpaid member Ad hoc consultant: Salix: < $ 5K Ikaria: < $ 5K Abbott: $5-10K Bristol-Myers: < $ 5K Genfit: $ 5-10 K Genentech: < $ 5K Bristol Myers: < $ 5K Echosens: unpaid consultant Gilead: unpaid consultant Novartis: unpaid consultant Takeda: unpaid consultant Royalties: Elsevier- Boyers Textbook of Hepatology: < $ 5K Uptodate:<$5K Uptodate: < $ 5K Grants (awarded to university): NIH: $ 1.5 million annual direct costs Roche, Gilead, Astellas: $ 25-50K total Salix, Ikaria: $ each Gilead: $ 150 K annual direct costs based on recruitment Genfit: US PI for GFT505 trial Galectin: $ 30000

2 NASH and associated morbidity Risk factors for progression Age Obesity DM CVD Risk HCC Risk Hepatic Decompensation Progression Abbreviations: CVD, cardiovascular disease; DM, diabetes mellitus; HCC, hepatocellular carcinoma. Managing NAFLD in 3 simple steps IS NAFLD PRESENT? IS INTERVENTION NEEDED? WHAT INTERVENTION?

3 When to suspect NAFLD is present? Presence of risk factors: overweight-obesity it features of metabolic syndrome- especially T2DM Presence of liver injury without other causes: abnormal AST, ALT (invariably below 250 IU/l) negative HCV, HBV, hemochromatosis, Wilson disease, alpha1 antitrypsin i and high-titer h i ANA Direct evidence of increased hepatic fat: imaging (US, CT scan, MRI) MR-based proton density fat fraction estimation of steatosis CAP for fibroscan: - Point of care - AUC 0.85 with steatosis t grade (AASLD 2015) - CAP > 250 = steatosis Liver Fat index: based on clinical parameters An Tang et al, radiology, Epub 2014)

4 Managing NAFLD in 3 simple steps IS NAFLD PRESENT? IS INTERVENTION NEEDED? WHAT INTERVENTION? Presence of steatohepatitis and severity of fibrosis relate to outcomes Angulo et al, Gastroenterology, Gastroenterology Aug;149(2):

5 Time to First Liver-Related Event Low APRI and FIB-4 Event Free A FIB4 > 3 in someone over Age 40 yrs is associated with 20% risk of a liver event within 5 yrs APRI >1.50 or FIB-4 > Time (days) # at risk: Low # at risk: High Nguyen et al, Publication under review 2015 Fibroscan for NASH fibrosis Inter-observer concordance 0.96 For NASH (n > 500) Yoneda et al, Digestive and Liver Disease, 2007; Epub

6 Magnetic resonance elastography is superior to clinical prediction models for determination of advanced fibrosis in patients with non-alcoholic fatty liver disease: A prospective study Primary outcome: 2D-MRE vs. FIB-4 ROC curve of 2D-MRE AUROC 1.0 p= AUROC: p< D-MRE FIB-4 p-value: AUROC of 2D-MRE vs. FIB-4 DeLong Test Misclassifications: ifi 2D-MRE: 10 patients FIB-4: 5 patients (combination of upper and lower cutoffs) 33 patients in FIB-4 indeterminate range 25/33 correctly identified by 2D-MRE Cui JY, et al. EASL 2015, Vienna. #O020 One could use FIB-4 upper cut-point to rule in, and lower cut-point to rule out, and those in the intermediate range may be candidates for MRE assessment, to avoid a liver biopsy for detection of advanced fibrosis These strategies could be considered for inclusion into clinical trials for assessing efficacy of anti-fibrotic therapies in NASH Work up of NAFLD: who to biopsy? Suspected NAFLD Features of Met S FIB4, NAFLD fibrosis score Age Age < 40 FIB4 < 2 No Features of MetS except obesity Multiple features of MetS Fibroscan > 6 kp MRE > 2.9 kp Age > 50 FIB4 > 3, APRI > 1.5 Multiple features of MetS Fibroscan or MRE Life style intervention Monitor Consider rpt fibroscan x yearly Liver Bx indeterminate Confirm advanced disease > 12 Kp on FS

7 MELD less than 10 is associated with low short-term mortality MELD > 10 MELD < 10 Ripoll et al, GASTROENTEROLOGY 2007;133:4 Risk stratification of NASH Evaluate alcohol consumption Suspected NAFLD (steatosis on imaging +/- elevated ALT) Confirmed NAFLD Exclude alternate causes of ALT e.g. HCV Non-invasive risk stratification (use biopsy when non-invasive tests are indeterminate) Low risk profile - Steatosis alone on LBx - Normal lalt - Age < 40 yrs - Absence of T2DM, HTN - Low FIB4/APRI - Fibroscan < 5 kps Intermediate risk - Steatohepatitis^ - BMI > Stage Multiple features MetS - Increasing age - Elevated ALT - Fibroscan > 6 < 12 kps High risk profile - Steatohepatitis stage 4^ - Type 2 DM - FIB4 > 3, APRI > Fibroscan > 12 kps - MELD > 10* - HVPG > 10 mm Hg* Rinella and Sanyal, Nature Reviews Gastroenterology, 2015 in press

8 Managing NAFLD in 3 simple steps IS NAFLD PRESENT? IS INTERVENTION NEEDED? WHAT INTERVENTION? A variety of dietary approaches can produce weight loss in overweight and obese adults if reduction in dietary energy intake is achieved 1,200-1,500 kcal/d for women, or energy deficit 500 kcal/d gy 1,500-1,800 kcal/d for men, or energy deficit 750 kcal/d 30% energy deficit Strength of Evidence: High

9 ) Weight loss (%) Weight loss intensity is strongly associated to improvement of histological parameters in patients with nonalcoholic steatohepatitis after 52 weeks of lifestyle modification Correlations* between WL and steatohepatitis resolution 20 Rho=0.55, p< No Yes Resolution of steatohepatitis Weight loss (% %) Correlations between WL and fibrosis status at the end of intervention 20 Rho=0.13, p= Fibrosis Worsened Stabilized Fibrosis status Regressed No significant correlation was found with changes in the physical activity score at the end of the intervention Everyone who resolved steatohepatitis had weight loss Everybody with weight loss did not resolve hepatitis The data for fibrosis are inconclusive Vilar-Gomez E, et al. EASL 2015, Vienna. #O042 Is a little bit of alcohol safe or even beneficial in subjects with NAFLD?? Decreased liver disease? Increased HCC

10 What are the potential targets for therapeutics for NASH Insulin sensitizers Insulin resistance FFA + insulin+ cytokines Steatosis + metabolic dysregulation ER stress Oxidative stress Mitochondrial injury Anti oxidants Inflammatory Apoptosis signaling Cell death Stellate cell activation Multiple sources fibrosis Efficacy of anti-nash therapies (only drugs that have undergone phase 2B trials shown) Table 1. Effects of four anti-nash treatments on decrease in NAFLD activity scores Histologic Improvement Group % x/n OR 95% CI P Vitamin E 45% 70/ , 4.7 < No Vitamin E (Placebo) 22% 42/ Pioglitazone 56% 39/ , Placebo 24% 17/ Metformin 48% 24/ , Placebo 26% 12/ Obeticholic acid 49% 50/ , Placebo 23% 23/ Kowdley et al for NASH CRN, EASL 2015

11 Vitamin E and Pioglitazone resolve NASH Table 2. Effects of four anti-nash treatments on resolution of NASH Resolution of NASH Group % x/n OR 95% CI P Vitamin E 38% 56/ , 3.9 <0.001 No Vitamin E (Placebo) 20% 37/ Pioglitazone 47% 33/ , Placebo 21% 15/ Metformin 41% 16/ , Placebo 28% 11/ Obeticholic acid 22% 22/ , Placebo 13% 13/ Kowdley et al for NASH CRN, EASL 2015 What s beyond vitamin E and glitazones?

12 Therapeutic landscape for NASH (phase 2-3 trials) October 22, 2014, Clinicaltrials.gov Obeticholic Acid -6α-Ethyl Chenodeoxycholic Acid - INT-747 CDCA chenodeoxycholic acid Semi-Synthetic Synthetic Derivative of Chenodeoxycholic Acid INT-747 6α-ethyl chenodeoxycholic acid FXR EC 50 (agonism) 8.66 μm ~ 100x FXR agonism μm Pelliciari R. J.Med.Chem 2002

13 FLINT: Primary and Secondary Histological Endpoints 70% 60% 50% % of Patients w/ Improvement OCA Pbo P= P=0.001 P=0.006 P=0.03 P=0.004 P=0.08 P= % 53% 45% 46% 40% 30% 20% 10% 21% 38% 35% 31% 35% 19% 22% 13% 12% 13% 0% Primary Endpoint Steatosis Lobular Inflammation Ballooning Fibrosis NASH resolution Portal Inflammation 1: Data from Tetri et al. The Lancet. Published online November 7, : All p-values compared to placebo. P-value calculated with the Cochran-Mantel-Haenszel test, stratified by clinic and diabetes status. 45% 40% 35% FLINT: Fibrosis Improvement Across Baseline Fibrosis Scores P=0.004 % of Patients w/ 1-stage Improvement not sig. 35% 35% P= % OCA Pbo 30% 25% 20% 15% 19% 14% 25% 10% 5% 0% N=102 N=98 N=31 N=21 N=60 N=61 Total Group F1 F2 & F3 1: Data from Tetri et al. The Lancet and Supplementary Appendix. Published online November 7, : All p-values compared to placebo. P-values for Intercept analyses estimated by Intercept using Fisher s Exact test on published data in Supplementary Appendix, but not stratified.

14 Obeticholic acid for NASH: Benefits in a high risk subgroup and the effects of concomitant statin use No statin Baseline statin New statin OCA-no statin Placebo-no statin ti OCA-baseline statin Placebo-baseline b li Statinti OCA-new statin Placebo-new Statinti Mean LDL-C (mg/dl) LS mean (SE) 16.0 (3.5) *** LS mean (SE) 8.7 (4.6) LS mean (SE) (5.9) ** Visit week EOT Visit week EOT Visit week EOT No statin ***p<0.0001, baseline statin p=0.0597, new statin **p= Sensitivity analysis of FLINT trial subsets of patients demonstrates efficacy of OCA for histologic improvement of NASH OCA induces an increase in LDL cholesterol; in statin naive patients, this can be reduced by statins Sanyal A, et al. EASL 2015, Vienna. #LP18 Liraglutide improved NASH in a multicenter, doubleblinded, randomised, placebo-controlled phase II trial Patients, % Primary endpoint: NASH resolution with no worsening of fibrosis 60 p< Liraglutide (n=23) Placebo (n=22) Secondary endpoints Liraglutide (n=23) Placebo (n=22) Kleiner fibrosis -0.2 (0.8) 0.2 (1.0) Improvement, n (%) 6 (26.1) 3 (13.6) Worsening, n (%) 2 (8.7)* 8 (36.4) *p<0.05 vs placebo More diarrhea with liraglutide Liraglutide, a long-acting GLP-1 agonist dosed once daily SC, with overall benefits in T2DM Results replicated here; patients showed significant histological resolution of NASH Long-term and larger studies with liraglutide or other GLP-1 agonists in NASH are warranted Armstrong MJ, et al. EASL 2015, Vienna. #G01

15 Improvement of NASH by PPARα/δ activation Metabolic Syndrome Macrophages Visceral and liver fat & inflammation Hepatocytes PPARδ PPARα Inflammatory Cytokines Metabolic Control FA and lipoprotein metabolism Tailleux, Wouters & Staels BBA 2012 ;1821: Results: Evolution of Fibrosis after surgery Fibrosis improves after bariatric surgery 100% 3.75% 7.5% 7.5% 90% 13.75% 80% 21.25% 70% 60% 32.5% 2.5% Metavir scale % 40% 40% 2 30% 20% 10% 27.5% 43.75% 1 0 0% Before After p<0.003 Histologic feature Improvement p Value Fibrosis (Kleiner score) 33.8% p<0.003 Mathurin et al, AASLD 2014

16 Outcomes in subjects with cirrhosis undergoing a variety of bariatric procedures Parameter Nor% Total # of subjects 122 (60% female) # Child Pugh A 96.5% Complications 21.3% Decompensation 6.55% Early mortality 1.6% Late mortality 25% 2.5% Jan et al, Obes Surg 2015, epub May 16 Management of NAFLD by disease stage Low risk Intermediate risk High risk Lifestyle intervention Pharmaco ological therapy Bariatric Surge ery HCC and EV screening

17 Thank You Courtesy- Dr. David Kleiner