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

Newsome, Philip N and Palmer, Melissa and Freilich, Bradley and Sheikh, Muhammad Y and Sheikh, Aasim and Sarles, Harry and Herring, Robert and Mantry, Parvez and Kayali, Zeid and Hassanein, Tarek and Lee, Hak-Myung and Aithal, Guruprasad P (2020) Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study. Journal of hepatology. ISSN 1600-0641. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Official URL: https://www.journal-of-hepatology.eu/article/S0168...

Abstract

BCKGROUND & AIMS

Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT), hypothesized to treat non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic<i> </i>bile acid production.

METHODS

Adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive double-blind volixibat 5, 10 or 20 mg or placebo once daily for 48 weeks. A predefined interim analysis (n = 80) at week 24 had endpoints of ≥5% reduction in magnetic resonance imaging-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was ≥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 [standard deviation (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. In the liver histology 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, there was no therapeutic benefit of ASBT inhibition with volixibat on the liver in adults with NASH (ClinicalTrials.gov identifier: NCT02787304).

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: QV Pharmacology
WI Digestive system. Gastroenterology
Divisions: Clinical Support > Immunology
Planned IP Care > Gastroentrology
Related URLs:
Depositing User: Mrs Yolande Brookes
Date Deposited: 08 Apr 2020 15:37
Last Modified: 08 Apr 2020 15:37
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2976

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