Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis.

Abstract Background and aims Nonalcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity result in chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation, and decreased portal pressures and improved synthetic function in mice with CCl4-induced cirrhosis. Methods This double-blind, placebo-controlled study randomized 217 subjects with decompensated NASH cirrhosis 1:1:1 to emricasan (5 or 25 mg) or placebo. Patients were stratified by decompensation status and baseline MELD-Na score. The primary endpoint was comprised of any subject who died, had a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥ grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. Results There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (5 mg; 95% confidence interval 0.59, 1.77; p=0.94) and 1.28 (25 mg; 95% confidence interval 0.75, 2.21; p=0.37). MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, INR, total serum bilirubin albumin level or Child-Turcotte-Pugh score. Emricasan was generally safe and well-tolerated. Conclusions Emricasan was safe but ineffective in treatment of decompensated NASH cirrhosis with regard to MELD-Na score improvement, reducing new decompensation events, improving liver function or mortality. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis.