Research ArticleEmricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis
Graphical abstract
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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