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.
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.
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.
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.
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.