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Abstract Details
Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis
J Hepatol. 2020 Oct 7;S0168-8278(20)33673-4. doi: 10.1016/j.jhep.2020.09.029.Online ahead of print.
Catherine Frenette1, Zeid Kayali2, Edward Mena3, Parvez S Mantry4, Kathryn J Lucas5, Guy Neff6, Miguel Rodriguez7, Paul J Thuluvath8, Ethan Weinberg9, Bal R Bhandari10, James Robinson11, Nicole Wedick12, Jean L Chan11, David T Hagerty11, Kris V Kowdley13, IDN-6556-17 Study Investigators
Author information
1Department of Organ Transplant, Scripps Clinic, La Jolla, CA.
2Inland Empire Liver Foundation, Rialto, CA.
3California Liver Research Institute, Pasadena, CA.
4Methodist Health System Clinical Research Institute, Dallas, TX.
5Diabetes & Endocrinology Consultants, PC, Moorhead City, NC.
6Covenant Research, Lakewood Ranch, FL.
7IMIC Inc, Palmetto Bay, FL.
8Mercy Medical Center, Baltimore, MD.
9University of Pennsylvania Medical Center, Philadelphia, PA.
10Delta Research Partners, Bastrop, LA.
11Conatus Pharmaceuticals, Inc., San Diego, CA.
12SimulStat, Inc., Solana Beach, CA.
13Liver Institute Northwest, Seattle, WA. Electronic address: kkowdley@liverinstitutenw.org.
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.