Elsevier

Journal of Hepatology

Volume 74, Issue 2, February 2021, Pages 274-282
Journal of Hepatology

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

https://doi.org/10.1016/j.jhep.2020.09.029Get rights and content

Highlights

  • Pan-caspase inhibition with emricasan did not decrease clinical events in patients with decompensated NASH-cirrhosis.

  • Caspase inhibition did not affect MELD-Na scores, INR, total serum bilirubin or Child-Pugh score.

  • Emricasan was generally well-tolerated over the duration of treatment.

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.

Introduction

Non-alcoholic steatohepatitis (NASH) is the most rapidly growing indication for liver transplantation1 and the second most common cause of chronic liver disease in patients listed for transplant in the United States.2 Excessive accumulation of lipids in the liver leads to lipotoxicity, chronic inflammation and hepatocellular damage through oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and activation of death receptors.3 Caspases are intracellular proteases that activate pro-inflammatory cytokines such as IL-1β and mediate apoptotic cell death by cleaving cytoskeletal proteins such as cytokeratin-18.4 Levels of cleaved cytokeratin-18 (cCK18) are elevated in patients with NASH5 and the degree of apoptosis correlated with fibrosis and inflammation,6 suggesting that excessive apoptosis may contribute to the development of NASH.

Emricasan is an oral pan-caspase inhibitor that inhibits excessive apoptosis and inflammation in NASH. In addition to decreasing liver injury and fibrosis in a mouse model of NASH,7 emricasan decreased portal pressure and/or improved survival in rodent models of cirrhosis.8 In rats with carbon tetrachloride-induced cirrhosis and ascites, emricasan improved liver and microcirculatory function (increase in bile production) and reduced hepatic inflammation with improvement in sinusoidal endothelial cell and hepatic stellate cell phenotypes.9 In an exploratory 3-month placebo-controlled study of 86 patients with Child-Pugh class A or B cirrhosis and an elevated model for end-stage liver disease-sodium (MELD-Na) score of 11 to 18, emricasan reduced MELD-Na and Child-Pugh scores, especially in those with MELD-Na ≥15 and NASH cirrhosis.10

We therefore conducted a randomized, double-blind, placebo-controlled multicenter trial of emricasan in patients with decompensated NASH cirrhosis who had ascites requiring diuretics and/or a history of variceal hemorrhage to determine if emricasan treatment could improve all-cause mortality, and reduce new decompensation events and MELD-Na progression.

Section snippets

Study design

The study was conducted in outpatients at 91 sites in the U.S. The first participant was enrolled on 13 April 2017 and the last visit was 23 July 2019. Eligible individuals were randomized 1:1:1 using a validated program to twice-daily emricasan (5 mg or 25 mg) or placebo, stratified by baseline decompensation status (variceal hemorrhage [VH] alone, ascites alone, or both VH and ascites) and MELD-Na category (<15 or ≥15). Treatment was intended to continue until the last participant in the

Disposition and participant flow diagram

Patient disposition is shown in Fig. 1. A total of 399 individuals were screened, 217 randomized and 214 treated. Forty-eight individuals (22.1%) discontinued the study at the time of the primary efficacy analysis, although 23/48 had experienced a primary endpoint event before discontinuation, thus limiting the missing data for the primary analysis to 25/214 individuals (11.7%). Eight individuals were transplanted during the study (n = 4 in placebo, n = 2 in emricasan 5 mg [EMR5], n = 2 in

Discussion

This study of emricasan is the largest trial of its sort in decompensated NASH cirrhosis. To our knowledge, it is also the only phase II or III study specifically designed to evaluate liver-related outcomes, such as decompensation events and MELD-Na score progression in patients with decompensated NASH cirrhosis.11 This study enrolled individuals with decompensated NASH cirrhosis in order to evaluate whether emricasan could potentially decrease new decompensation events. A previous 3-month

Financial support

The study was funded by Conatus Pharmaceuticals, Inc and Novartis.

Authors' contributions

Kris Kowdley, Catherine Frenette, James Robinson, Jean L. Chan, and David T. Hagerty designed the study, analyzed the results and participated in writing the manuscript. Kris Kowdley and Catherine Frenette were the lead study investigators and participated in the analysis and writing of the manuscript. Nicole Wedick analyzed the results and participated in writing the manuscript. Zachary Goodman read all study liver biopsies and participated in writing the manuscript. Zeid Kayali, Edward Mena,

Data availability statement

Data were collected by investigators and analyzed by the Sponsor. Authors had access to the data after unblinding, participated in data analysis and interpretation, and vouch for the accuracy of the results.

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 Pharmaceuticals, Inc., and reports personal fees from SimulStat, Inc., during the conduct of the study. Catherine Frenette reports research funding from Conatus Pharmaceuticals, Inc., during the conduct of this study and personal fees from Conatus Pharmaceuticals, Inc., outside of the submitted work. Kris Kowdley

Acknowledgements

The authors would like to acknowledge the expert assistance of Dr. Paul Kwo in the design of the study and the help of Dr. Joanne Imperial in helping to provide medical oversight for the conduct of the study.

We would also like to thank the patients and investigators who participated in our study: Kathleen Corey, David Bernstein, Mazen Noureddin, Nyingi Kemmer, Andrew DeLemos, Nikolaos Pyrsopoulos, William Lee, Marwan Ghabril, Andrew Scanga, Mark McKenzie, Eric Lawitz, Viviana Figueroa-Diaz,

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