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Review

An update on drug development for the treatment of nonalcoholic fatty liver disease – from ongoing clinical trials to future therapy

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Pages 333-340 | Received 30 Nov 2020, Accepted 28 Jan 2021, Published online: 13 Feb 2021

References

  • 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 Jul;64(1):73–84. (Baltimore, Md)
  • Eslam M, Newsome PN, Anstee QM, et al. A new definition for metabolic associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020 Jul;73(1):2020-209.
  • 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 Oct;69(4):896–904.
  • 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 Nov;64(5):1577–1586. (Baltimore, Md)
  • US Food and Drug Administration. Noncirrhotic Non-Alcoholic Steatohepatitis with Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry. [cited 2021 Jan 23]. https://wwwfdagov/media/119044/download.
  • EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016 Jun;64(6):1388–1402.
  • 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 Jan;67(1):328–357. (Baltimore, Md)
  • Roeb E, Steffen HM, Bantel H, et al. [S2k Guideline non-alcoholic fatty liver disease]. Z Gastroenterol. 2015 Jul;53(7):668–723.
  • Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313–1321. (Baltimore, Md)
  • Bedossa P, Poitou C, Veyrie N, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012 Nov;56(5):1751–1759. (Baltimore, Md)
  • 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 Aug;149(2):389–97.e10.
  • 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 May;65(5):1557–1565. (Baltimore, Md)
  • 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 May;61(5):1547–1554. (Baltimore, Md)
  • 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 Dec;67(6):1265–1273.
  • Hagström H, Nasr P, Ekstedt M, et al. SAF score and mortality in NAFLD after up to 41 years of follow-up. Scand J Gastroenterol. 2017 Jan;52(1):87–91.
  • Harrison SA, Ratziu V, Boursier J, et al. A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study. Lancet Gastroenterol Hepatol. 2020 Nov 5;5(11):970–985.
  • Geier A, Boursier J. Non-invasive diagnosis of patients with ‘at-risk’ NAFLD : only fibrosis counts? Gut. 2020 Jul;69(7):1164–1165.
  • Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015 Aug;149(2):367–78.e5. quiz e14-5
  • Geier A, Rau M. Emerging therapies for NASH - the future is now. Expert Rev Clin Pharmacol. 2017 May;10(5):467–469.
  • Dufour JF, Caussy C, Loomba R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges. Gut. 2020 May 7;69(10):1877–1884.
  • Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013 Sep;145(3):574–82e1.
  • Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.. Lancet. 2015 Nov 7;385(9972):956–965.
  • 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 Dec 14;394(10215):2184–2196.
  • Halegoua-De Marzio D, Thuluvath PJ, Abdelmalek MF, Van Biene C, et al. Obeticholic acid was safe and well tolerated in patients with nonalcoholic steatohepatitis and compensated cirrhosis: a secondary analysis of the control study. HEPATOLOGY. 2018;68(NUMBER 1 (SUPPL)):45A.
  • Lucas JK, Lawitz EJ et al. Tropifexor, a highly potent fxr agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransgerase in patients with fibrotic NASH after 12 weeks of Therapy: FLIGHT-FXR Part C interim results. L04;AASLD Liver Meeting 2019.
  • Sanyal A, Lawitz E et al. Tropifexor, a FXR agonist for the treatment of nonalcoholic steatohepatitis - Interim results based on baseline body mass index from first two parts of Phase 2b study FLIGHT-FXR. SAT-357; ILC 2019.
  • Patel K, Harrison SA, Elkhashab M, et al. Cilofexor, a nonsteroidal fxr agonist, in patients with noncirrhotic nash: a phase 2 randomized controlled trial. Hepatology. 2020 Jul;72(1):58–71. (Baltimore, Md)
  • Press Release Albireo: Topline Results from Phase 2 Trial of Elobixibat in NAFLD/NASH. August 18, 2020.
  • Charles ED, Hompesch M, Luo Y, et al. A phase 1 study of BMS-986036 (Pegylated FGF21) in healthy obese subjects. AASLD liver meeting; Boston. 2016;Abstract 1082.
  • Sanyal A, Charles ED, Neuschwander-Tetri BA, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet. 2018 Dec 22;392(10165):2705–2717.
  • Harrison SA, Ruane PJ, Freilich BL, Neff G, et al. EFRUXIFERMIN (EFX), A LONG-ACTING FC-FGF21 FUSION PROTEIN, ADMINISTERED FOR 16 WEEKS TO PATIENTS WITH NASH SUBSTANTIALLY REDUCES LIVER FAT AND ALT, AND IMPROVES LIVER HISTOLOGY: ANALYSIS OF A RANDOMIZED, PLACEBO-CONTROLLED, PHASE 2a STUDY (BALANCED). HEPATOLOGY. 2020;72(NUMBER 1 (SUPPL)):6A.
  • Harrison SA, Rinella ME, Abdelmalek MF, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2018 Mar 24;391(10126):1174–1185.
  • Harrison SA, Rossi SJ, Paredes AH, et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology. 2020 Apr;71(4):1198–1212. (Baltimore, Md)
  • Harrison SA, Neff G, Guy CD, Bashir MR, et al. FINAL ANALYSIS OF A 24-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY OF ALDAFERMIN (NGM282) IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS. HEPATOLOGY. 2020;72(NUMBER 1 (SUPPL)):55A.
  • 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 Feb 13;387(10019):679–690.
  • Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2020 Nov 13; DOI:10.1056/NEJMoa2028395
  • Harrison SA, Bashir MR, Guy CD, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019 Nov 30;394(10213):2012–2024.
  • 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 May;150(5):1147–1159.e5.
  • Press Release GENFIT: Announces Results from Interim Analysis of RESOLVE-IT Phase 3 Trial of Elafibranor in Adults with NASH and Fibrosis. May 11, 2020.
  • Press Release GENFIT: Provides Initial Update on Corporate Strategy. July 22, 2020.
  • Abitbol JL, Junien JL Metabolic effects and good tolerance of IVA337 a Pan-PPAR agonist in diabetic patients warrant further investigation in NASH. ILC. 2016;Abstract PS105.
  • Franque S, Bedossa P, Ratziu V, Anstee Q, et al. THE PANPPAR AGONIST LANIFIBRANOR INDUCES BOTH RESOLUTION OF NASH AND REGRESSION OF FIBROSIS AFTER 24 WEEKS OF TREATMENT IN NON-CIRRHOTIC NASH: RESULTS OF THE NATIVE PHASE 2b TRIAL. HEPATOLOGY. 2020;72(NUMBER 1 (SUPPL)):9A.
  • Gawrieh S. A phase 2, prospective, multicenter, double-blind, randomized study of saroglitazar magnesium 1 mg, 2 mg or 4 mg versus placebo in patients with NAFLD and/or NASH (evidence IV). Hepatology. 2019;70.
  • Sanyal A, Ratziu V, Harrison S, Abdelmalek MF, et al., Lefebvre E cenicriviroc versus placebo for the treatment of nonalcoholic steatohepatitis with liver fibrosis: results from the year 1 primary analysis of the phase 2b CENTAUR study. AASLD liver meeting; Boston. 2016;Abstract LB-1.
  • 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 Jan 13;72(3):892–905. (Baltimore, Md)
  • https://www.clinicaltrials.gov/ct2/show/NCT03028740?term=cenicriviroc&cond=NAFLD+NASH&draw=2&rank=5. access date: 2021 Jan 23.
  • Ratziu V, de Geuvara L, Safadid R, et al. One-year results of the globalphase 2b randomized placebo-controlled arrest trial of aramchol, a stearyl CoA desaturase modulator in 247 NASH patients. Hepatology. 2018;68.
  • Loomba R, Rinella ME, Harrison SA, Wong V, et al. FIRST-IN-CLASS, FATTY ACID SYNTHASE (FASN) INHIBITOR, TVB-2640 DEMONSTRATES CLINICALLY SIGNIFICANT REDUCTION IN LIVER FAT BY MRI-PDFF, AND ALT IN NASH: a PHASE 2 RANDOMIZED PLACEBOCONTROLLED TRIAL (FASCINATE-1). HEPATOLOGY. 2020;72(NUMBER 1 (SUPPL)):50A.
  • Harrison SA, Wong VW, Okanoue T, et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials. J Hepatol. 2020 Jul;73(1):26–39.
  • Loomba R, Noureddin M, Kowdley K, Kohli A, et al. Safety and efficacy of combination therapies including cilofexor/firsocostat in patients with bridging fibrosis and cirrhosis due toNASH: results of the phase 2b ATLAS trial. LBO04 Digital ILC 2020.
  • Alkhouri N, Herring R, Kabler H, Kayali Z, et al. Safety and efficacy of combination therapies including semegalutide, cilofexor, and firsocostat in patients with NASH. The Liver Meeting Digital Experience 2020, Abstract LO2. ;
  • Kaufmann B, Reca A, Wang B, et al. Mechanisms of nonalcoholic fatty liver disease and implications for surgery. Langenbecks Arch Surg. 2020 Aug 24;
  • Tarantino G, Citro V, Capone D. Nonalcoholic fatty liver disease: a challenge from mechanisms to therapy. J Clin Med. 2019 Dec 19;9(1):15.
  • Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek atorvastatin and coronary heart disease evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010 Dec 4;376(9756):1916–1922.
  • Press Release Gilead: Gilead Announces Topline Data From Phase 3 STELLAR-3 Study of Selonsertib in Bridging Fibrosis (F3) Due to Nonalcoholic Steatohepatitis (NASH) April 25, 2019.
  • Press Release Gilead: Gilead Announces Topline Data From Phase 3 STELLAR-4 Study of Selonsertib in Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH). February 11, 2019.
  • Press Release Intercept: Intercept Receives Complete Response Letter from FDA for Obeticholic Acid for the Treatment of Fibrosis Due to NASH. Jun 29, 2020.

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