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Background & Aims: EDP-305 is an oral farnesoid X receptor (FXR) agonist under development for the treatment of non-alcoholic steatohepatitis (NASH). Herein, we aimed to assess the efficacy, safety and tolerability of EDP-305 in patients with fibrotic NASH., Methods: In this double-blind phase II study, patients with fibrotic NASH (without cirrhosis), diagnosed by historical biopsy or phenotypically, were randomized to EDP-305 1 mg, EDP-305 2.5 mg, or placebo, for 12 weeks. The primary endpoint was mean change in alanine aminotransferase (ALT) from baseline to Week 12, and the key secondary endpoint was mean change in liver fat content from baseline to Week 12., Results: Between January 2018 and July 2019, 134 patients were randomized and 132 were evaluated. At Week 12, the least squares mean reductions from baseline in ALT for patients receiving 2.5 mg EDP-305 and 1 mg EDP-305 were -27.9 U/L (95% CI 0.03 to 24.9; p = 0.049) and -21.7 U/L (-5.8 to 18.3: p = 0.304), respectively, compared to -15.4 U/L for those receiving placebo. Absolute liver fat reduction was -7.1% (2.0-7.5; p = 0.0009) with 2.5 mg EDP-305, -3.3% with EDP-305 1 mg, and -2.4% with placebo. The most common (≥5%) adverse events were pruritus, nausea, vomiting, diarrhea, headache, and dizziness. Pruritus occurred in 50.9%, 9.1%, and 4.2% of patients in the 2.5 mg, 1 mg, and placebo groups, respectively, and led to study drug discontinuation in 20.8% of patients in the 2.5 mg group and 1.8% in the 1 mg group., Conclusions: EDP-305 reduced ALT levels and liver fat content, providing support for a longer-term trial assessing histological endpoints in patients with NASH. CLINICALTRIALS., Gov Number: NCT03421431 LAY SUMMARY: Non-alcoholic fatty liver disease is a chronic hepatic disease that can progress to non-alcoholic steatohepatitis (NASH), which is associated with an increased risk of cirrhosis and liver cancer. Results from this phase II study support continued development of EDP-305, an oral farnesoid X receptor agonist, for the treatment of patients with NASH., Competing Interests: Conflict of interest KK received support from Enanta paid to his institution; grants or contracts from Intercept, Gilead, NGM, Madrigal, Pfizer, Enanta, Viking, Celgene, Terns, Corcept paid to his institution; speaker’s and teaching honoraria or consulting fees from Intercept, Gilead, and Inipharm; Stock or stock options from Inipharm. EL received research grants from 89Bio, Allergan Inc, Akero Therapeutics, Alnylam Pharmaceuticals, Astrazeneca, Axcella Health, Bristol-Myers Squibb, Boeringer Ingelheim, Celgene, Durect Corporation, Eli Lilly and Company, Enanta Pharmaceuticals, Enyo, Galmed Pharmaceuticals, Genfit, Gilead Sciences, Hanmi Pharmaceuticals, Intercept Pharmaceuticals, Laboratory for Advanced Medicine, Madrigal Pharmaceuticals, Merck, Metacrine, Novartis, Novo Nordisk, Poxel, Roche Pharmaceuticals, Terns Pharmaceuticals, Viking Therapeutics, Zydus. AS reports research grants from Enanta Pharmaceuticals, Genentech, Madrigal, Viking Therapeutics, NovoNordisk, Bristol-Myers Squibb, NorthSea Therapeutics, Galectin, NGM Therapeutics, Intercept, Hepion, Allergan, Ionis, and Boehringer Ingelheim, and stock options from Gilead. B N-T received grants or contracts from Allergan, BMS, Cirius, Enanta, Genfit, Gilead, HighTide, Intercept, Madrigal, NGM payed to Saint Louis University. Payments for DSMB or Advisory Board participation by Akero, Alimentiv, Allergan, Allysta, Alnylam, Amgen, Arrowhead, Axcella, Boehringer Ingelheim, BMS, Coherus, Cymabay, Durect, Enanta, Fortress, Genfit, Gilead, High Tide, HistoIndex, Innovo, Intercept, Ionis, LG Chem, Lipocine, Madrigal, Medimmune, Merck, Mirum, NGM, NovoNordisk, Novus Therapeutics, pH-Pharma, Sagimet, Target RWE, Theratechnologies, 89Bio. Stock or stock options in HepGene; Honoraria from American Diabetes Association, American Gastroenterological Associations, Canadian Association for the Study of the Liver, Clinical Care Options, Houston Methodist Hospital, NASH Summit, NASH-TAG. ME received support from Enanta Pharmaceuticals for this study; grants or contracts from AbbVie, Gilead, Genfit, Intercept, Assembly, Madrigal, and Novartis; consulting fees from AbbVie, Gilead, and Intercept; and honoraria from AbbVie. JD received support from Enanta Pharmaceuticals for this study. DD, TK, MR, and TD have nothing to disclose. BG, AA, and NA are employees and may be stockholders of Enanta Pharmaceuticals, Inc. VR has received consulting fees from Boehringer-Ingelheim, Novo-Nordisk, Galmed, Terns, Theratechnologies, Bristol-Myers-Squibb, Genfit, Madrigal, and NGM Bio. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)