1 National Institute for Health Research, Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. Electronic address: firstname.lastname@example.org.
2 Shire Plc, a Takeda company, Lexington, MA, USA.
3 Kansas City Research Institute, Kansas City, MO, USA.
4 Fresno Clinical Research Center, Fresno, CA, USA.
5 GI Specialists of Georgia, Marietta, GA, USA.
6 DHAT Research Institute, Garland, TX, USA.
7 Quality Medical Research, PLLC, Nashville, TN, USA.
8 Methodist Health System Clinical Research Institute, Dallas, TX, USA.
9 Inland Empire Liver Foundation, Rialto, CA, USA.
10 Southern California Research Center, Coronado, CA, USA.
11 National Institute for Health Research, Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
BACKGROUND & 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 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).