Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non‐alcoholic fatty liver disease

• Published in: Alimentary pharmacology & therapeutics Vol. 49; no. 1; pp. 64 - 73
• Main Authors: Shiffman, Mitchell, Freilich, Bradley, Vuppalanchi, Raj, Watt, Kymberly, Chan, Jean L., Spada, Al, Hagerty, David T., Schiff, Eugene
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2019; John Wiley and Sons Inc
• Subjects: Adult; Aged; Alanine Transaminase - blood; Apoptosis; Caspase 3 - metabolism; Caspase inhibitors; Caspase-3; Cirrhosis; Clinical trials; Cytokeratin; Double-Blind Method; Fatty liver; Female; Hepatitis; Humans; Inflammation; Keratin-18 - metabolism; Liver - pathology; Liver cirrhosis; Liver Cirrhosis - drug therapy; Liver Cirrhosis - pathology; Liver diseases; Male; Middle Aged; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - pathology; Pentanoic Acids - administration & dosage; Pentanoic Acids - pharmacology; Randomised Clinical Trial
• ISSN: 0269-2813; 1365-2036; 1365-2036
• DOI: 10.1111/apt.15030

Summary Background Lipotoxicity leading to excessive caspase‐mediated apoptosis and inflammation is believed to drive liver damage in NAFLD. Emricasan is a pan‐caspase inhibitor that decreased serum ALT and apoptotic and inflammatory markers in subjects with chronic hepatitis. Aims To assess whether 28 days of emricasan would reduce elevated levels of serum ALT, AST, cleaved cytokeratin‐18, full‐length cytokeratin‐18, and caspase 3/7 in subjects with NAFLD and raised aminotransferases. Methods Double‐blind, placebo‐controlled, office‐practice study assessed the efficacy, safety, and tolerability of emricasan in subjects with NAFLD and ALT levels ≥1.5 x ULN during screening. Subjects were randomised to emricasan 25 mg twice daily or matching placebo. Subjects with cirrhosis and other causes for raised aminotransferases were excluded. The primary endpoint was the change in ALT at day 28 in the emricasan group vs placebo. Results 38 subjects were randomised, 19 each to emricasan or placebo. Baseline disease factors were well balanced except for lower median ALT values in emricasan subjects. Three subjects randomised to placebo discontinued prior to day 28. ALT values decreased significantly in emricasan‐treated subjects vs placebo at days 7 (P < 0.0001) and 28 (P = 0.02). cCK18 (day 7), flCK18 (days 7 and 28), and caspase 3/7 (day 7) were also significantly decreased in emricasan‐treated subjects vs placebo. Emricasan treatment was generally safe and well tolerated. Conclusions Emricasan decreased ALT and biomarkers in subjects with NAFLD and raised aminotransferases after 28 days. These results support the further development of emricasan in patients with NAFLD. Trial registration: ClinicalTrials.gov, Identifier: NCT02077374.