Randomized Placebo-Controlled Trial of Emricasan in Non-alcoholic Steatohepatitis (NASH) Cirrhosis with Severe Portal Hypertension.

Abstract

BACKGROUND AND AIM

Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in patients with cirrhosis and portal pressure (assessed by the hepatic venous pressure gradient [HVPG]) ≥12 mmHg. We aimed to confirm these results in a randomized, placebo-controlled, double blind study.

METHODS

Multicenter study including 263 patients with cirrhosis due to non-alcoholic steatohepatitis (NASH) and baseline HVPG ≥12 mmHg randomized 1:1:1:1 to emricasan 5 (n=65), 25 (n=65), 50 (n=66) mg or placebo (n=67) orally twice daily for up to 48 weeks. Primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes.

RESULTS

There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21, -0.45, -0.58 mmHg, respectively) adjusted by baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated subjects (n=201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p=0.06), the decrease being greater in those with higher baseline HVPG (p=0.018), with a significant interaction between baseline HVPG (continuous, p=0.024; dichotomous at 16 mmHg [median], p=0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in MELD and Child Pugh scores, and treatment-emergent adverse events were similar among treatment groups.

CONCLUSIONS

Despite reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH cirrhosis and severe portal hypertension. Compensated subjects with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated.