Newcastle NIHR BRC Liver Theme

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1 Newcastle NIHR BRC Liver Theme Professor Quentin M. Anstee PhD, FRCP Professor of Experimental Hepatology & Honorary Consultant Hepatologist, Institute of Cellular Medicine, Newcastle University, UK.

2 Why a Liver Theme? Liver disease is a major cause of morbidity and mortality in our population It robs people in the middle years and beyond of high quality life Unlike most other major chronic disease groups, its impact is growing A therapeutics revolution is underway with major industry interest and investment Williams et al, Lancet 2014

3 Why Newcastle? A world leading centre for both clinical practice and research in liver disease High liver disease clinical need in NE England Tertiary Liver Unit (1 of 7 Liver Transplant Units in the UK) Research excellence across the spectrum from basic research to therapeutics, quality of life and implementation. Strong links to allied disciplines (e.g. public health and behaviour change) that are critical for lifestyle related diseases such as ALD and NAFLD/NASH. Leadership in internationally unique research platforms. Outstanding environment to deliver Translational Research with Impact. Highest recruiting Trust nationally. NuTH tops national NIHR clinical research activity league table for 7 th consecutive year. Socioeconomic NAFLD Excess ALD Mortality Weight Deprivation Public Health England, 2014

4 Newcastle BRC Liver Theme Established Disease-Area Translational Programmes Rare Disease (linked to NIHR Rare Disease Bioresource) Autoimmune Hepatitis (UK-AIH) Primary Biliary Cholangitis (UK-PBC) High-Prevalence Disease (linked to NIHR NAFLD Bioresource) Non-Alcoholic Fatty Liver Disease (NAFLD) & Non-Alcoholic Steatohepatitis (NASH) Alcoholic Liver Disease Emerging opportunity areas Hepatocellular carcinoma (CRUK Accelerator Award) Liver Immunology (cross theme) Complex systemic symptoms Excellent Research Environment Strong Clinical Trials Portfolio Fatigue, Pruritus Cognitive symptoms (cross theme) Disease-specific PROM development in PBC and NAFLD/NASH Tertiary liver unit & liver transplant service Liver pathology resource All senior clinicians (Academic & NHS) are research active Track record of Leadership & Delivery of Investigator-led & Commercial clinical trials

5 Primary Biliary Cholangitis (UK-PBC) Impact Highlights Name change (from Primary Biliary Cirrhosis) supporting patient lobbying Worlds largest & best characterised cohort (7000 patients) Unique trials platform (pre-consent) supporting multiple trials of stratified therapy (NEJM, Lancet Gastroenterology & Hepatology, Hepatology etc) Stratified therapy approved and in practice (guideline supported) Disease predictive model (UK-PBC risk score) available as app and in guideline Additional key tools (baseline therapy response prediction, health economics etc) First new agent in 20 years for pruritus (Lancet) First ever trial of an agent for peripheral fatigue in liver disease (Hepatology) Translational data from preclinical models suggest that therapy for PBC may beneficially impact on associated cognitive decline (PoC trial planned). Emerging data on molecular risk prediction and treatment targeting towards curative therapy

6 Cognitive Dysfunction in Cholestasis: A Window into Dementia and its Treatment? Cognitive symptoms ( brain fog ) are a major problem in PBC They are associated with overt cognitive dysfunction, impaired executive function and pathway tract abnormality on MRI DTI (diffusion tensor imaging) in PBC patients. Degree of pathway abnormality correlates with degree of cognitive symptoms, suggesting potential as a clinical trial outcome measure In cholestatic BDL mice, cognitive dysfunction reverses completely with Obeticholic Acid (OCA), a licensed Farnesoid X Receptor Agonist (MRC funded work) Cognitive dysfunction in cholestatic mice is associated with dementia associated neuronal processed (taf expression). This is fully Reversed with OCA (MRC funded work) Substantial industry funding for PoC trial in PBC and Parkinsons Disease linking BRC themes. orange denotes pathways showing significant regression with cognitive dysfunction FA R² = COGFAIL

7 Autoimmune Hepatitis (UK-AIH) Impact Highlights Worlds largest and best characterised rare disease cohort (n=2000) Clear demonstration of the failure or current therapy (41% of patients not in remission, 33 treatment approaches in routine use) Demonstration that there is reliance on steroid use (54% of patients) despite proven major role in quality of life impairment (Hepatology) First ever trial of a biological agent (and first of any therapy in a generation) in collaboration with Novartis enabled by the UK-AIH pre-consent platform

8 Hepatocellular Carcinoma (CRUK Accelerator HUNTER ) Hepatology & Pathology WP2 Lead Llovet/Pinyol; IDIBAPS, Barcelona Decoding HCC immunology by largescale multi-omics integrative analysis WP1 Lead Reeves; NICR, Newcastle Project, patient, tissues and data management Sarah Greenhalgh Project Co-ordinator HUNTER CRUK FC AECC AIRC Network shared resources, platforms, knowledge, training Breaking immunosuppressive networks in HCC Immunophenotyping for HCC biomarker and therapeutic target development Developing platforms - HCC secretome WP3 Lead Bird/Sansom; Beatson, Glasgow Preclinical models platform development WP4 Lead Maini/Meyer; UCL, London Breaking immunosuppressive networks in HCC - Evaluating tumour immune escape mechanisms INDUSTRY

9 Non-Alcoholic Fatty Liver Disease (NAFLD) Normal Liver Steatosis NAFL NAFLD Steatohepatitis NASH Cirrhosis Risk factors for NASH include Metabolic Syndrome (Obesity, Hypertension, Dyslipdaemia & Type 2 Diabetes/Insulin resistance) Fat infiltration >5% with or without mild inflammation For NAFLD, alcohol consumption <20/30g per day Other causes for liver dysfunction/hepatotoxins excluded Steatosis + Necroinflammation Ballooning hepatocyte degeneration, Mallory bodies, megamitochondria Increasing fibrosis, leading to cirrhosis

10 Non-Alcoholic Fatty Liver Disease (NAFLD)

11 Non-Alcoholic Fatty Liver Disease (NAFLD) Impact Highlights Preeminent Two-Hit Hypothesis of NAFLD Pathogenesis (Day & James, 1998) Assembled both the largest single centre and international cohorts of histologically characterised NAFLD patients to support translational research. Leadership of major international research consortia: FLIP, EPoS, LITMUS. Longstanding interest in disease natural history and clinical risk stratification: Genetic & Epigenetic modifiers of risk & progression (PNPLA3, TM6SF2, etc.) Widely adopted clinical NAFLD Fibrosis Score (Angulo et al, 2007) Major contributions to the search for effective therapies: Scalable innovations in Lifestyle Modification (diet and exercise) Leadership of NICE NAFLD Guidelines panel. Expertise in clinical trial design and delivery across PoC, Phase 2b and Phase 3. International chief investigator/steering committee of multiple Ph2b/3 studies. Strong links with Regulators including MHRA, EMA and FDA.

12 NAFLD Fibrosis Score = x Age x BMI x IFG/diabetes x AST/ALT ratio x Platelets x Albumin. Low Cutoff (NPV) High Cutoff (PPV) Low Probability of F3/4 Indeterminate High Probability of F3/4 Existing Threshold for Age >65 New Threshold for Age >65 Threshold Se/Sp % H/L Risk % Correct Threshold Se/Sp % H/L Risk % Correct < %/20% 45% 76% < %/70% 80% 80%

13 The Imperative for Biomarkers in NAFLD An important paradox exists: a significant proportion of the population have NAFLD but only a minority progress to advanced liver disease or morbidity/mortality A lack of tractable non-invasive biomarkers has impeded the diagnosis, risk stratification and monitoring of patients and so many cases remain undiagnosed and present with advanced disease. The lack of biomarkers has also hampered drug development and the conduct of clinical trials, which still depend on histological effect as an endpoint.

14 IMI2-LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) 47 Partners* 29 Academic, 17 EFPIA/Industrial, 1 Professional body 14 Countries for Clinical Recruitment UK, France, Germany, Italy, Switzerland, Netherlands, Austria, Luxembourg, Sweden, Finland, Greece, Spain, Portugal, USA True Public-Private co-funding model Effective budget > 34 million (includes > 20 million cash from EU & Industry) Coordinator: Prof Quentin M. Anstee

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16 LITMUS: A Global Effort to Validate NAFLD/NASH Biomarkers The overarching objectives of LITMUS are to develop, robustly validate and advance towards regulatory qualification biomarkers that diagnose, risk stratify and/or monitor NAFLD/NASH progression and fibrosis stage.

17 LITMUS: A Global Effort to Validate NAFLD/NASH Biomarkers EU FP7 ( ) Discovery Science EU H2020 ( ) Expanded Partner Network Clinical Application EU IMI2 ( ) NIMBLE (KO?late 2018)

18 The European NAFLD Registry Recruitment active in 14 countries >4,000 histologically characterised NAFLD/NASH patients enrolled to date (+ approx. 6,000 Phase 2b/3 trial patients) Cross-sectional and Longitudinal follow-up data

19 BRC Liver Theme Selected Recent High Impact Publications McPherson S., Hardy T., Henderson E., Burt A.D., Day C.P. & Anstee Q.M. Evidence of NAFLD Progression from Steatosis to Fibrosing-Steatohepatitis using Paired Biopsies: Implications for Prognosis & Clinical Management Journal of Hepatology, 2015, May; 62(5): p McPherson S., Hardy T., Dufour J-F, Petta S., Romero-Gomez M., Allison M., Oliveira C.P., Francque S., Van Gaal L., Schattenberg J.M., Tiniakos D., Burt A., Bugianesi E., Ratziu V., Day C.P. & Anstee Q.M. Age as a Confounding Factor for the Accurate Non- Invasive Diagnosis of Advanced NAFLD-Fibrosis American Journal of Gastroenterology, 2017, 112(5): p Ogrodnik M., Miwa S., Tchkonia T., Tiniakos D., Wilson C.L., Lahat A., Day C., Burt A., Palmer A., Anstee Q.M., Grellscheid S., Hoeijmakers J.H.J., Barnhoorn S., Mann D., Bird T.G., Vermeij W.P., Kirkland J.L., Passos J.F., von Zglinicki T. & Jurk D. Cellular senescence drives age-dependent hepatic steatosis Nature Communications, 2017, 13; 8: Shalapour S., Lin X-J., Bastian I.N., Li W., Brain J., Burt A.D., Matsutani T., Aksenov A.A., Vrbanac A.F., Loomba R., Zhong Z., Perkins A., Dhar D., Navas-Molina J.A., Xu J., Downes M., Yu R.T., Dorrestein P.C., Knight R., Benner C., Anstee Q.M. & Karin M. Inflammation induced IgA + cells dismantle anti-liver cancer immunity Nature, 2017, 551(7680): p Hardy T., Zeybel M., Sharkey V., Day C.P., Dipper C., Masson S., McPherson S., Henderson E., Tiniakos D., White S., French J., Mann D.A., Anstee Q.M.* & Mann J.* Plasma DNA methylation: A potential biomarker for stratification of liver fibrosis in nonalcoholic fatty liver disease Gut, 2017, 66(7): p Hegade VS, Kendrick SF, Dobbins RL, Miller SR, Thompson D, Richards D, Storey J, Dukes GE, Corrigan M, Oude Elferink RP, Beuers U, Hirschfield GM, Jones DE. Effect of ileal bile acid transporter inhibitor GSK on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study Lancet. 2017;389(10074):

20 Acknowledgements Prof Chris Day, Prof David Jones, Prof Helen Reeves, Prof Mike Trennel, Dr Jess Dyson, Dr Mark Hudson, Dr Stuart McPherson, Dr Steve Masson. Prof Ann Daly, Prof Fiona Oakley, Prof Derek Mann, Prof Jelena Mann, Dr Dina Tiniakos, Dr Marie Boyle, Dr Jenny Gallacher, Dr Tim Hardy. Dr Olivier Govaere, Dr Katherine Johnson, Dr Kate Hallsworth, Ms Laura Haigh, Mrs Elsbeth Henderson, Mrs Lorna Brownlee, Ms Hannah Stevenson. FP7, Horizon 2020 & IMI2