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Frenette C, Kayali Z, Mena E, et al. Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. J Hepatol. 2020;74(2):274-282doi: 10.1016/j.jhep.2020.09.029.
Frenette, C., Kayali, Z., Mena, E., Mantry, P. S., Lucas, K. J., Neff, G., Rodriguez, M., Thuluvath, P. J., Weinberg, E., Bhandari, B. R., Robinson, J., Wedick, N., Chan, J. L., Hagerty, D. T., Kowdley, K. V. (2021). Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. Journal of hepatology, 74(2), 274-282. https://doi.org/10.1016/j.jhep.2020.09.029
Frenette, Catherine, et al. "Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis." Journal of hepatology vol. 74,2 (2021): 274-282. doi: https://doi.org/10.1016/j.jhep.2020.09.029
Frenette C, Kayali Z, Mena E, Mantry PS, Lucas KJ, Neff G, Rodriguez M, Thuluvath PJ, Weinberg E, Bhandari BR, Robinson J, Wedick N, Chan JL, Hagerty DT, Kowdley KV. Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. J Hepatol. 2021 Feb;74(2):274-282. doi: 10.1016/j.jhep.2020.09.029. Epub 2020 Oct 08. PMID: 33038432.
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J Hepatol. 2021 Feb;74(2):274-282. doi: 10.1016/j.jhep.2020.09.029. Epub 2020 Oct 08.

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

Journal of hepatology

Catherine Frenette, Zeid Kayali, Edward Mena, Parvez S Mantry, Kathryn J Lucas, Guy Neff, Miguel Rodriguez, Paul J Thuluvath, Ethan Weinberg, Bal R Bhandari, James Robinson, Nicole Wedick, Jean L Chan, David T Hagerty, Kris V Kowdley,

Affiliations

  1. Department of Organ Transplant, Scripps Clinic, La Jolla, CA.
  2. Inland Empire Liver Foundation, Rialto, CA.
  3. California Liver Research Institute, Pasadena, CA.
  4. Methodist Health System Clinical Research Institute, Dallas, TX.
  5. Diabetes & Endocrinology Consultants, PC, Moorhead City, NC.
  6. Covenant Research, Lakewood Ranch, FL.
  7. IMIC Inc, Palmetto Bay, FL.
  8. Mercy Medical Center, Baltimore, MD.
  9. University of Pennsylvania Medical Center, Philadelphia, PA.
  10. Delta Research Partners, Bastrop, LA.
  11. Conatus Pharmaceuticals, Inc., San Diego, CA.
  12. SimulStat, Inc., Solana Beach, CA.
  13. Liver Institute Northwest, Seattle, WA. Electronic address: [email protected].

PMID: 33038432 DOI: 10.1016/j.jhep.2020.09.029

Abstract

BACKGROUND & AIMS: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause 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; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis.

METHODS: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, 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 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated.

CONCLUSIONS: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis.

LAY SUMMARY: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS.

GOV IDENTIFIER: NCT03205345.

Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Keywords: Ascites; Hepatic encephalopathy; MELD-Na; NASH; Variceal hemorrhage

Conflict of interest statement

Conflict of interest James Robinson, Jean L. Chan and David Hagerty were employees of Conatus Pharmaceuticals, Inc., during the conduct of the study. Nicole Wedick was a consultant employed by Conatus

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