Drug development of nonalcoholic fatty liver disease: challenges in research, regulatory pathways, and study endpoints

References

• Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148:547–555.
   PubMed Web of Science ®Google Scholar
• Estes C, Razavi H, Loomba R, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67:123–133.
   PubMed Web of Science ®Google Scholar
• Younossi ZM, Stepanova M, Younossi Y, et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2020;69:564-568.
   Google Scholar
• Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.
   PubMed Web of Science ®Google Scholar
• Collaborators GO. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377:13–27.
   PubMed Web of Science ®Google Scholar
• Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. 2019;15:288.
   PubMed Web of Science ®Google Scholar
• Mantovani A, Byrne CD, Bonora E, et al. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care. 2018;41:372–382.
   PubMed Web of Science ®Google Scholar
• Ballestri S, Zona S, Targher G, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta‐analysis. J Gastroenterol Hepatol. 2016;31:936–944.
   PubMed Web of Science ®Google Scholar
• Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in china, france, germany, italy, japan, spain, united kingdom, and united states for the period 2016–2030. J Hepatol. 2018;69:896–904.
   PubMed Web of Science ®Google Scholar
• White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10:1342–1359 e1342.
   PubMed Web of Science ®Google Scholar
• Younossi ZM, Otgonsuren M, Henry L, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62:1723–1730.
   PubMed Web of Science ®Google Scholar
• Söderberg C, Stål P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28‐year follow‐up. Hepatology. 2010;51:595–602.
   PubMed Web of Science ®Google Scholar
• Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30:1212–1218.
   PubMed Web of Science ®Google Scholar
• Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Clin Pract Gastroenterol Hepatol. 2013;10:330.
   Google Scholar
• Friedman SL, Neuschwander-Tetri BA, Rinella M, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–922.
   PubMed Web of Science ®Google Scholar
• Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. 2016;150:1769–1777.
   PubMed Web of Science ®Google Scholar
• Ekstedt M, Hagstrom H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–1554.
   PubMed Web of Science ®Google Scholar
• Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67:1265–1273.
   PubMed Web of Science ®Google Scholar
• Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–397 e310.
   PubMed Web of Science ®Google Scholar
• Schuppan D, Surabattula R, Wang XY. Determinants of fibrosis progression and regression in NASH. J Hepatol. 2018;68:238–250.
   PubMed Web of Science ®Google Scholar
• Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53:1874–1882.
   PubMed Web of Science ®Google Scholar
• Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol. 2003;98:2042–2047.
   PubMed Web of Science ®Google Scholar
• Singh S, Allen AM, Wang Z, et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(643–654):e649.
   Google Scholar
• Sanyal AJ, Harrison SA, Ratziu V, et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology. 2019;70:1913–1927.
   Google Scholar
• Lomonaco R, Ortiz‐Lopez C, Orsak B, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:1389–1397.
   PubMed Web of Science ®Google Scholar
• Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver disease. Hepatology. 2013;57:2525–2531.
   PubMed Web of Science ®Google Scholar
• St. George A, Bauman A, Johnston A, et al. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2009;50:68–76.
   PubMed Web of Science ®Google Scholar
• Kim Y, Chang Y, Cho YK, et al. Obesity and weight gain are associated with progression of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2019;17(543–550):e542.
   Google Scholar
• Mitchell T, Jeffrey GP, de Boer B, et al. Type and pattern of alcohol consumption is associated with liver fibrosis in patients with non-alcoholic fatty liver disease. Am J Gastroenterol. 2018;113:1484–1493.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Campbell–Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–1192.
   PubMed Web of Science ®Google Scholar
• Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest. 2007;117:539–548.
   PubMed Web of Science ®Google Scholar
• Liver EAftSot, Diabetes EAftSo. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Obes Facts. 2016;9:65–90.
   PubMed Web of Science ®Google Scholar
• Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the study of liver diseases. Hepatology. 2018;67:328–357.
   PubMed Web of Science ®Google Scholar
• Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367–378e365; quiz e314–365.
   Web of Science ®Google Scholar
• Mummadi RR, Kasturi KS, Chennareddygari S, et al. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008;6:1396–1402.
   PubMed Web of Science ®Google Scholar
• Lassailly G, Caiazzo R, Ntandja-Wandji L-C, et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology. 2020. DOI:https://doi.org/10.1053/j.gastro.2020.06.006.
   Google Scholar
• Petit J-M, Vergès B. GLP-1 receptor agonists in NAFLD. Diabetes Metab. 2017;43:2S28–22S33.
   PubMed Web of Science ®Google Scholar
• Younossi ZM, Stepanova M, Ong J, et al. Effects of alcohol consumption and metabolic syndrome on mortality in patients with non-alcoholic and alcohol-related fatty liver disease. Clin Gastroenterol Hepatol. 2019;17:1625-1633. e1621.
   Google Scholar
• Aberg F, Helenius-Hietala J, Puukka P, et al. Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population. Hepatology. 2018;67:2141–2149.
   PubMed Web of Science ®Google Scholar
• Anstee QM, Seth D, Day CP. Genetic factors that affect risk of alcoholic and nonalcoholic fatty liver disease. Gastroenterology. 2016;150:1728–1744 e1727.
   PubMed Web of Science ®Google Scholar
• Eslam M, Sanyal AJ, George J. Toward more accurate nomenclature for fatty liver diseases. Gastroenterology. 2019;157:590–593.
   PubMed Web of Science ®Google Scholar
• Simonetto DA, Shah VH, Kamath PS. Outpatient management of alcohol-related liver disease. Lancet Gastroenterol Hepatol. 2020;5:485–493.
   PubMed Web of Science ®Google Scholar
• Bush K, Kivlahan DR, McDonell MB, et al. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Arch Internal Med. 1998;158:1789–1795.
   PubMed Web of Science ®Google Scholar
• Cabezas J, Lucey MR, Bataller R. Biomarkers for monitoring alcohol use. Clin Liver Dis. 2016;8:59.
   Google Scholar
• Younossi ZM, Ratziu V, Loomba R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394:2184–2196.
   PubMed Web of Science ®Google Scholar
• Golabi P, Otgonsuren M, de Avila L, et al. Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD). Medicine (Baltimore). 2018;97:e0214.
   Web of Science ®Google Scholar
• Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med. 2005;143:722–728.
   PubMed Web of Science ®Google Scholar
• Ekstedt M, Franzén LE, Mathiesen UL, et al. Long‐term follow‐up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Banas C, Sargeant C, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43:682–689.
   PubMed Web of Science ®Google Scholar
• Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med. 2017;377:2063–2072.
   PubMed Web of Science ®Google Scholar
• Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461.
   PubMed Web of Science ®Google Scholar
• Shen J, Wong GH, Chan HY, et al. PNPLA 3 gene polymorphism accounts for fatty liver in community subjects without metabolic syndrome. Aliment Pharmacol Ther. 2014;39:532–539.
   PubMed Web of Science ®Google Scholar
• Trépo E, Valenti L. Update on NAFLD genetics: from new variants to the clinic. J Hepatol. 2020;72:1196–1209.
   Google Scholar
• Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018;68:268–279.
   PubMed Web of Science ®Google Scholar
• Skoien R, Richardson MM, Jonsson JR, et al. Heterogeneity of fibrosis patterns in non‐alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways. Liver Int. 2013;33:624–632.
   PubMed Web of Science ®Google Scholar
• Siddiqui MS, Harrison SA, Abdelmalek MF, et al. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science. Hepatology. 2018;67:2001–2012.
   PubMed Web of Science ®Google Scholar
• Eslam M, Sanyal AJ, George J, et al. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158:1999–2014.e1991.
   PubMed Web of Science ®Google Scholar
• Alexander M, Loomis AK, Fairburn-Beech J, et al. Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med. 2018;16:1–11.
   Web of Science ®Google Scholar
• Arab JP, Barrera F, Gallego C, et al. High prevalence of undiagnosed liver cirrhosis and advanced fibrosis in type 2 diabetic patients. Ann Hepatol. 2017;15:721–728.
   Web of Science ®Google Scholar
• Sumida Y, Okanoue T, Nakajima A, et al. Phase 3 drug pipelines in the treatment of non‐alcoholic steatohepatitis. Hepatol Res. 2019;49:1256–1262.
   PubMed Web of Science ®Google Scholar
• Chow S, Lin M. Analysis of two-stage adaptive seamless trial design. Pharm Anal Acta. 2015;6:2.
   Google Scholar
• Bhatt DL, Mehta C. Adaptive designs for clinical trials. N Engl J Med. 2016;375:65–74.
   PubMed Web of Science ®Google Scholar
• Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377:62–70.
   PubMed Web of Science ®Google Scholar
• Filozof C, Chow SC, Dimick‐Santos L, et al. Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: facilitating development approaches for an emerging epidemic. Hepatol Commun. 2017;1:577–585.
   PubMed Web of Science ®Google Scholar
• Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129.
   PubMed Web of Science ®Google Scholar
• Petersen KF, Dufour S, Befroy D, et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54:603–608.
   PubMed Web of Science ®Google Scholar
• Hickman I, Jonsson J, Prins J, et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut. 2004;53:413–419.
   PubMed Web of Science ®Google Scholar
• Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–690.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Sanyal A, Harrison SA, et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study. Hepatology. 2020. DOI:https://doi.org/10.1002/hep.31108.
   Web of Science ®Google Scholar
• Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–1685.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator− activated receptor− α and− δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(1147–1159):e1145.
   Google Scholar
• Han MAT, Altayar O, Hamdeh S, et al. Rates of and factors associated with placebo response in trials of pharmacotherapies for nonalcoholic steatohepatitis: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019;17(616–629):e626.
   Google Scholar
• McCarney R, Warner J, Iliffe S, et al. The hawthorne effect: a randomised, controlled trial. BMC Med Res Methodol. 2007;7:30.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration (FDA). Surrogate endpoint resources for drug and biologic development. [Internet]. 2019. [cited 2020 Jul 1]. Available from:  https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development
   Google Scholar
• Rinella ME, Tacke F, Sanyal AJ, et al. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD. J Hepatol. 2019;71:823-833.
   Web of Science ®Google Scholar
• Vilar-Gomez E, Calzadilla-Bertot L, Wong VW-S, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology. 2018;155(443–457):e417.
   Google Scholar
• Nasr P, Ignatova S, Kechagias S, et al. Natural history of nonalcoholic fatty liver disease: a prospective follow‐up study with serial biopsies. Hepatol Commun. 2018;2:199–210.
   PubMed Web of Science ®Google Scholar
• Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38:420–427.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the study of liver diseases–US Food and Drug Administration joint workshop. Hepatology. 2015;61:1392–1405.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency (EMA). Human regulatory: conditional marketing authorisation. [Internet]. 2019. [cited 2020 Jul 1]. Available from:  https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/conditional-marketing-authorisation
   Google Scholar
• US Food and Drug Administration (FDA). Nonalcoholic steatohepatitis with compensated cirrhosis: developing drugs for treatment guidance for industry. [internet]. 2019. [cited 2020 Jul 1]. Available from: https://www.fda.gov/media/127738/download
   Google Scholar
• US Food and Drug Administration (FDA). Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment guidance for industry. 2019. [cited 2020 Jul 1]. Available from: https://www.fda.gov/media/119044/download
   Google Scholar
• Wree A, Broderick L, Canbay A, et al. From NAFLD to NASH to cirrhosis—new insights into disease mechanisms. Nat Clin Pract Gastroenterol Hepatol. 2013;10:627–636.
   Google Scholar
• Schuster S, Cabrera D, Arrese M, et al. Triggering and resolution of inflammation in NASH. Nat Clin Pract Gastroenterol Hepatol. 2018;15:349–364.
   Google Scholar
• Brunt EM, Kleiner DE, Wilson LA, et al. Improvements in histologic features and diagnosis associated with improvement in fibrosis in nonalcoholic steatohepatitis: results from the nonalcoholic steatohepatitis clinical research network treatment trials. Hepatology. 2019;70:522–531.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration (FDA). Table of surrogate endpoints that were the basis of drug approval or licensure [Internet]. 2019. [cited 2020 Jul 1]. Available from:  https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure
   Google Scholar
• Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341–1350.
   PubMed Web of Science ®Google Scholar
• Vilaseca M, García‐Calderó H, Lafoz E, et al. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology. 2017;65:2031–2044.
   PubMed Web of Science ®Google Scholar
• Brunt EM, Kleiner DE, Wilson LA, et al. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53:810–820.
   PubMed Web of Science ®Google Scholar
• Nascimbeni F, Bedossa P, Fedchuk L, et al. Clinical validation of the FLIP algorithm and the SAF score in patients with non-alcoholic fatty liver disease. J Hepatol. 2020;72:828–838.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–1906.
   PubMed Web of Science ®Google Scholar
• Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta‐analysis. Hepatology. 2017;65:1557–1565.
   PubMed Web of Science ®Google Scholar
• Cheung A, Neuschwander‐Tetri BA, Kleiner DE, et al. Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the liver forum. Hepatology. 2019;70:1841–1855.
   PubMed Web of Science ®Google Scholar
• Younossi ZM. Patient-reported outcomes for patients with chronic liver disease. Clin Gastroenterol Hepatol. 2018;16:793–799.
   PubMed Web of Science ®Google Scholar
• Younossi ZM, Stepanova M, Lawitz EJ, et al. Patients with nonalcoholic steatohepatitis experience severe impairment of health-related quality of life. Am J Gastroenterol. 2019;114:1636–1641.
   PubMed Web of Science ®Google Scholar
• Golabi P, Otgonsuren M, Cable R, et al. Non-alcoholic fatty liver disease (NAFLD) is associated with impairment of health related quality of life (HRQOL). Health Qual Life Outcomes. 2016;14:18.
   PubMed Web of Science ®Google Scholar
• Younossi ZM. Patient‐reported outcomes and the economic effects of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: the value proposition. Hepatology. 2018;68:2405–2412.
   PubMedGoogle Scholar
• Younossi ZM, Blissett D, Blissett R, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64:1577–1586.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration (FDA). Drug development tools | DDTs. [Internet]. 2019. [cited 2020 Jul 1]. Available from: https://www.fda.gov/drugs/development-approval-process-drugs/drug-development-tools-ddts
   Google Scholar