A Placebo-Controlled, Multicenter, Double-Blind, Phase 2 Randomized Trial of the Pan-Caspase Inhibitor Emricasan in Patients with Acutely Decompensated Cirrhosis

Background: Cirrhosis and acute-on-chronic liver failure (ACLF) are associated with systemic inflammation, and caspase-mediated hepatocyte cell death. Emricasan is a novel, pan-caspase inhibitor. Aims of this study were to assess the pharmacokinetics, pharmacodynamics, safety and clinical outcomes of emricasan in acute decompensation (AD) of cirrhosis. Methods: This was a phase 2, multicentre, double-blind, randomized trial. The primary objective was to evaluate the pharmacokinetics, pharmacodynamics and safety of emricasan in patients with cirrhosis presenting with AD and organ failure. AD was defined as an acute decompensating event <= 6 weeks' duration. Patients were randomized proportionately to emricasan 5 mg bid, emricasan 25 mg bid, emricasan 50 mg bid or placebo. Treatment was continued to 28 days, or voluntary discontinuation. Results: Twenty-three subjects were randomized, of whom 21 were dosed (placebo n = 4; 5 mg n = 5; 25 mg n = 7; 50 mg n = 5). Pharmacokinetic data showed 5 mg dose was associated with low plasma levels (< 50 ng/ml), and 25 mg and 50 mg doses showed comparable pharmacokinetic profiles. Therefore, for analysis of secondary endpoints, placebo and 5 mg groups were merged into a 'placebo/low-dose' group, and 25 mg and 50 mg groups were merged into a 'high-dose' group. Five deaths occurred amongst the 21 patients, all due to progression of liver disease (2 in placebo/low-dose, 3 in high-dose). No statistically significant changes from baseline MELD score or CLIF-C ACLF score were noted between placebo/low-dose and high-dose groups at day 7 (MELD -1 vs -1, CLIF-C ACLF 0.7 vs 0.8). An initial reduction in cleaved keratin M30 fragment was noted between placebo/low-dose and high-dose groups (percent relative change: day 2: -11.6 vs -42.6, P = 0.017, day 4: -3.5 vs -38.9 P = 0.017) although this did not persist to day 7 (-3.1 vs -20.8, P = 0.342). Conclusion: This study demonstrates that emricasan is safe and well tolerated in advanced liver disease. However, this study fails to provide proof-of-concept support for caspase inhibition as a treatment strategy for ACLF.