Non-alcoholic fatty liver disease: time to take note and manage. Philip Newsome Professor of Hepatology & Director of Centre for Liver Research

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1 Non-alcoholic fatty liver disease: time to take note and manage Philip Newsome Professor of Hepatology & Director of Centre for Liver Research

2 Disclosures Consultancy, Co-ordinating Investigator roles and Grant funding AbbVie, Boehringer Ingelheim, DS Biopharma, Echosens, E3Bio, Gilead, Novo Nordisk, Pfizer, Pharmaxis, Shire

3 NAFLD the entire spectrum Normal Steatosis Inflammation +/- Fibrosis Cirrhosis NAFL NASH NASH cirrhosis

4 Annual Prevalent Number of Cases of NAFLD 1% of UK population has NASH and significant fibrosis Younossi, et al. Hepatology 2016.

5 Causes of death in patients with NASH 619 patients with bx-confirmed NAFLD US, Europe & Thailand 12.6 years f/u (range ) Angulo et al, Gastro 2015

6 Liver not just a bystander Targher, Day, 2010 NEJM

7 What are the challenges in 2017? 1. Which patient should I worry about and how do I find them? 2. When I ve found them what should I do?

8 Fibrosis predicts Mortality in patients with NAFLD All Cause Mortality Liver Related Mortality Dulai et al. Hepatology 2017

9 IMAGING BLOOD Identifying patients with fibrosis AST/ALT ratio AST to platelet ratio index BARD FIB-4 NAFLD fibrosis score Pro-C3 Fibrosis Classification : (equivalence in fibrosis stage) LSM: 1 (F0/1) 2 (F1±1) 3 (F1/2) 4 (F2/3) (F3±1) 6 (F3/4) kpa Image: Boursier et al, J Hepatol, (F4) Acoustic Radio-Frequency Imaging

10 Magnetic Resonance: FAT and FIBROSIS Loomba et al, Hepatology, 2014

11 Work-up Confirmed NAFLD Negative liver screen, evidence of steatosis, alcohol consumption within recommended limit Diagnosis unclear / indeterminate fibrosis score / Fibroscan inconsistent / staging required Evidence of fibrosis? Algorithm Fibroscan/ARFI/ELF test Discharge to primary care. Recommend optimisation of cardiovascular risk factors and review liver status in 3-5 yrs Liver biopsy Townsend & Newsome; Dig Dis 2017

12 What are the challenges in 2017? 1. Which patient should I worry about and how do I find them? 2. When I ve found them what should I do?

13 Treatment for NASH Managing complications of cirrhosis Liver-directed pharmacotherapy Targeting components of metabolic syndrome Lifestyle modification There are no treatments currently licensed for the treatment of NASH Dyson et al. Frontline Gastroenterology 2015

14 Effect of weight loss on NASH/fibrosis Prospective study of 293 patients with bx-proven NASH in Cuba Lifestyle changes to wt over 52 weeks: cal/d 2. Walk 200 mins/wk 3. Behavioural (/8wk) Overall n=293 <5 n=205 % Weight Loss Achieved n= n=25 10 n=29 NASH FIBROSIS Vilar-Gomez et al, Gastro, 2015

15 Musso et al, Diabetologia, Pioglitazone for NASH (non-diabetics)

16 Thiazolidinediones (TZD) in NASH patients with Diabetes Fibrosis 1-point improvement n (%) Mean change in score (SD) PBO (n=51) 13 (25) 0 (1.2) Pio (n=50) 20 (39) -0.5 (1.0) Treatment Difference (95% CI) 14 (-6 to 34) -0.5 (-0.9 to 0) p value Table: Cusi et al, Ann Int Med, 2016.; PBO, placebo; Pio, pioglitazone.; CI, confidence interval

17 Regulatory land-scape for NASH Reduction in fibrosis w/o worsening in NASH Reduction in NASH w/o worsening in fibrosis STEP 1 accelerated approval due to lack of therapies and clinical need As prelude to licensing end-points such as: Death (all cause) MELD score 15 Other clinical events STEP 2

18 Clinical Trials. Gov 4 th July Clinical trials in NASH

19 Potential mechanisms of farnesoid X receptor agonists in NASH Pacana et al, F1000Prime Rep. 2015

20 Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial Neuschwander-Tetri, Lancet 2014

21 DPPIV Inhibitors/Glucagon-like Peptide-1 Receptor Agonists

22 Liraglutide Safety & Efficacy In Patients With Non-alcoholic Steatohepatitis (LEAN) Key inclusion criteria Patients with diagnosis of definite NASH on liver biopsy Adults years with BMI 25 kg/m 2 Normal glucose tolerance or T2D with HbA 1c <9% Chief Investigator Newsome Trial information Phase 2 Multicentre Double-blind Randomised Placebocontrolled 52 patients Screening 2 Liraglutide 1.8 mg Placebo 0 Duration 48 (weeks) Randomisation (1:1) End of treatment Follow-up 60 End of study Armstrong et al Lancet 2016.

23 Resolution of NASH NAFLD Fibrosis Kleiner Fibrosis Mean score (SD) n (%) improvement n (%) worsening Lira -0.2 (0.8) 6 (26.1%) 2 (8.7%)* Placebo 0.2 (1.0) 3 (13.6%) 8 (36.4%) Newsome (Chief Investigator) Lancet 2016

24 GLP-1 reduce cardiovascular events LEADER trial Kang et al, EnM, 2016 Met primary endpoint of showing non-inferiority as well as demonstrating superiority, with a statistically significant reduction in cardiovascular risk. SUSTAIN 6 trial Semaglutide

25 25 SUSTAIN 6 - Time to first occurrence of CV death or non-fatal MI or non-fatal stroke Marso et al. NEJM 2016

26 Apoptosis signal-regulating kinase 1 (ASK1) Inhibition in NASH Oxidative stress Hepatocyte dysfunction p38 ASK1 ASK1 P JNK Fibrogenesis Macrophage activation/recruitment 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 nm), small molecule inhibitor of ASK1a Courtesy R Loomba; AASLD late-breaker 2016

27 Aim: To evaluate the safety and efficacy of GS in subjects with NASH and F2-F3 fibrosis. Study Design Week N=20 N=22 N=10 N=10 N=10 GS mg PO QD GS mg PO QD GS mg PO QD + SIM 125 mg SQ qwk GS mg PO QD + SIM 125 mg SQ qwk SIM 125 mg SC qwk MRI-PDFF, MRE Liver Biopsy Key inclusion criteria Biopsy-proven NASH with NAS 5 ( 1 point for steatosis, lobular inflammation, hepatocellular ballooning) F2-3 fibrosis 2:2:1:1:1 randomization (stratified by diabetes) Courtesy R Loomba; AASLD late-breaker 2016

28 Results: Fibrosis Responses 18 mg ± SIM 6 mg ± SIM SIM 80 Fibrosis Improvement Fibrosis Improvement without NASH Worsening* Progression to Cirrhosis 60 Patients, % n= 13/30 8/27 2/10 11/30 8/27 2/10 1/30 2/27 2/10 Data for patients with liver biopsies evaluable for fibrosis at baseline and week 24 (N=67). * Defined as any increase in NAS (NAS increased from 5 to 6 in 2 patients).

29 Histological improvement with Selonsertib is Associated with Improvement of PROMs Patients blinded to most recent lab results 4 validated PRO questionnaires: Short Form-36 (SF-36), Chronic Liver Disease Questionnaire (CLDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Work Productivity and Activity Index (WPAI:SHP) Improved fibrosis (N=23) Fibrosis not changed or worsened (N=44) General Health Social Functioning Role Emotional Mental Health Mental Summary Worry (CDLQ) Courtesy Z Younossi; ILC 2017

30 Bariatric surgery Greater weight loss than other Rx Results are maintained for up to eight years Improvement in comorbidities Overall mortality rate <1% Adverse events occur in about 20% of cases.

31 Bariatric surgery in the UK

32 O p e r a t i o n s / y e a r Bariatric surgery with liver disease B P D D S & S l e e v e D S B a l lo o n S l e e v e R o u x B a n d F i n a n c i a l y e a r e n d i n g Data courtesy of UK bariatric database Rachel Batterham

33 Meta-analysis of bariatric surgery for NASH Improvement in steatohepatitis Improvement in fibrosis Mummadi et al, CGH, 2008

34 Conclusions Clinical Background Fibrosis is key determinant Cardiovascular AND liver deaths Identification Algorithms Non-invasive tests - Imaging and Serum MRI PDFF and MRE Therapies & Mechanisms No licensed therapies Outcomes in clinical trials awaited FXR agonists/glp-1 analogues/ask-1 inhibitors Combinations likely