Philip N Newsome1, Melissa Palmer2, Bradley Freilich3, Muhammad Y Sheikh4, Aasim Sheikh5, Harry Sarles6, Robert Herring7, Parvez Mantry8, Zeid Kayali9, Tarek Hassanein10, Hak-Myung Lee2, Guruprasad P Aithal11. 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: p.n.newsome@bham.ac.uk. 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.
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.
RCT Entities:
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.
Authors: Stephen J Keely; Andreacarola Urso; Alexandr V Ilyaskin; Christoph Korbmacher; Nigel W Bunnett; Daniel P Poole; Simona E Carbone Journal: Am J Physiol Gastrointest Liver Physiol Date: 2021-11-10 Impact factor: 4.052