Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis

Background & Aims: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18 -month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years.Methods: Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) >= 1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events.Results: Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a >= 1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More partic-ipants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 par-ticipants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups.Conclusions: These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.(c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).