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.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Nonalcoholic fatty liver disease: epidemiology, liver transplantation trends and outcomes, and risk of recurrent disease in the graft.J Clin Transl Hepatol. 2018; 6: 420-424
- Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.Gastroenterology. 2015; 148: 547-555
- Lipotoxicity and the gut-liver axis in NASH pathogenesis.J Hepatol. 2018; 68: 280-295
- Proteolytic processing of interleukin-1 family cytokines: variations on a common theme.Immunity. 2015; 42: 991-1004
- Elevated serum levels of caspase-cleaved cytokeratin 18 (CK18-Asp396) in patients with nonalcoholic steatohepatitis and chronic hepatitis C.Med Sci Monit. 2009; 15: 189-193
- Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.Gastroenterology. 2003; 125: 437-443
- The pan-caspase inhibitor emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis.Liver Int. 2015; 35: 953-966
- Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation.J Mol Med (Berl). 2018; 96: 575-583
- Emricasan ameliorates portal hypertension and liver fibrosis in cirrhotic rats through a hepatocyte-mediated paracrine mechanism.Hepatol Commun. 2019; 3: 987-1000
- Emricasan improves liver function in patients with cirrhosis and high model for end-stage liver disease scores compared with placebo.Clin Gastroenterol Hepatol. 2019; 17: 774-783
- Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the Liver Forum.Hepatology. 2019; 70: 1841-1855
- Randomized placebo-controlled trial of emricasan in non-alcoholic steatohepatitis (NASH) cirrhosis with severe portal hypertension.J Hepatol. 2020; 72: 885-895
- Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.J Hepatol. 2006; 44: 217-231
- Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.Aliment Pharmacol Ther. 2014; 39: 1180-1193
- Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD.Hepatology. 2019; 70: 1424-1436
- The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.Hepatology. 2019; 70: 1913-1927
- Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397
- The 20% rule of NASH progression: the natural history of advanced fibrosis and cirrhosis caused by NASH.Hepatology. 2019; 70: 1885-1888
- Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.J Hepatol. 2015; 63: 743-752
Article info
Publication history
Published online: October 07, 2020
Accepted:
September 22,
2020
Received in revised form:
September 6,
2020
Received:
February 20,
2020
Identification
Copyright
© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
