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

JOURNAL OF HEPATOLOGY

卷:73

Article

Newsome, Philip N.^1,2  Palmer, Melissa³  Freilich, Bradley⁴  Sheikh, Muhammad Y.⁵  Sheikh, Aasim⁶  Sarles, Harry⁷  Herring, Robert⁸  Mantry, Parvez⁹  Kayali, Zeid¹⁰  Hassanein, Tarek¹¹  Lee, Hak-Myung³  Aithal, Guruprasad P.^12,13,14 

[1] Univ Hosp Birmingham NHS Fdn Trust, Natl Inst Hlth Res, Birmingham Biomed Res Ctr, Birmingham, W Midlands, England

[2] Univ Birmingham, Ctr Liver & Gastrointestinal Res, Inst Immunol & Immunotherapy, Birmingham, W Midlands, England

[3] Shire Plc, Lexington, MA USA

[4] Kansas City Res Inst, Kansas City, MO USA

[5] Fresno Clin Res Ctr, Fresno, CA USA

[6] GI Specialists Georgia, Marietta, GA USA

[7] DHAT Res Inst, Garland, TX USA

[8] Qual Med Res PLLC, Nashville, TN USA

[9] Methodist Hlth Syst Clin Res Inst, Dallas, TX USA

[10] Inland Empire Liver Fdn, Rialto, CA USA

[11] Southern Calif Res Ctr, Coronado, CA USA

[12] Nottingham Univ Hosp NHS Trust, Nottingham Biomed Res Ctr, Natl Inst Hlth Res, Nottingham, England

[13] Univ Nottingham, Nottingham, England

[14] Univ Nottingham, Nottingham Digest Dis Ctr, Sch Med, Nottingham, England

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

DOI  :  10.1016/j.jhep.2020.03.024

来源: Elsevier

【 摘 要 】

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 pre-defined 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. (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

【 授权许可】

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