Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study

Abstract

Background & aims: Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH.

Methods: In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48.

Results: Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (-14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (-16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation.

Conclusions: Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH.

Lay summary: A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease.

Clinical trial identifier: NCT02787304.

Keywords: ASBT inhibitor; Alanine aminotransferase; Humans; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Phase II; Steatosis.

Conflict of interest statement

Conflict of interest PNN reports grants from Boehringer Ingelheim and Novo Nordisk and consultancy work (for the University of Birmingham) for Boehringer Ingelheim, Gilead Sciences Inc., Intercept Pharmaceuticals, Novo Nordisk, Pfizer, Poxel SA and Shire International. MP was an employee of Shire International (a Takeda company) during the conduct of the study. BF reports support from Shire International (a Takeda company). AS reports advisory board fees from Novartis and grants from Allergan, Cirius Therapeutics, Conatus Pharmaceuticals Inc., GENFIT, Gilead Sciences Inc., Intercept Pharmaceuticals, Madrigal Pharmaceuticals, Novartis, Novo Nordisk and Zydus Cadila. TH reports grants from Shire International (a Takeda company). H-ML was an employee of Shire International (a Takeda company) during the conduct of the study. MYS, HS, RH, PM, ZK and GPA have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.

Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.