Interim data from emricasan phase III trial for NASH cirrhosis and portal hypertension

There was no significant difference in severe portal hypertension for patients with non-alcoholic steatohepatitis (NASH) cirrhosis treated with emricasan from Conatus/Novartis versus placebo, according data presented at the European Association for the Study of the Liver (EASL) annual meeting.

No significant change in hepatic venous pressure gradient (HVPG), a key driver of cirrhosis, was observed at week 24, with either a 5-mg, 25-mg, or 50-mg dose of emricasan versus placebo, reported Guadalupe Garcia-Tsao, MD, of Yale University in New Haven, Connecticut, in a late-breaking abstract. While the primary endpoint was not met at the 24-week mark, the trial was a 48-week trial.

A year ago, emricasan, an oral pan-caspase inhibitor, failed to meet its primary endpoint in a phase IIb trial among liver transplant patients with hepatitis C, where the virus had cleared, but who still had fibrosis or cirrhosis.

Researchers performed the multi-center randomized trial at 59 sites in the U.S. and the EU. There were 263 patients with NASH cirrhosis and a baseline HVPG greater than 12 mmHg. They were a mean age of about 61, 57% were women, a large majority were Caucasian; around 85% had type 2 diabetes. About three-quarters of patients had compensated cirrhosis. Patients were randomized 1:1:1:1 to 5-mg, 25-mg, 50-mg of oral emricasan, or a placebo. Overall, there was no significant change in mean HVPG from baseline to week 24 with emricasan versus placebo: 5 mg emricasan: -0.48 mmHg 25 mg: -0.84 mmHg 50 mg: -0.70 mmHg Placebo: -0.18 mmHg . A planned subgroup analysis of patients with compensated cirrhosis also found no significant difference. However, a post-hoc analysis of patients with compensated cirrhosis and HVPG geater than 16 mmHg found what the authors described as a “clinically meaningful reduction” in HVPG with emricasan versus placebo, though not a dose-related effect. They also found that biomarkers cleaved cytokeratin-18 (cCK-18), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and caspase 3/7 were reduced with emricasan compared to placebo.

Treatment-related adverse events were similar for all emricasan groups (81.6% combined emricasan vs 82.1% placebo), although serious treatment-related adverse events were “numerically higher” for the emricasan groups (17.9% vs 11.9%, respectively). There were also 2% to 5% of patients in the emricasan groups with treatment-related adverse events who discontinued therapy versus 0% in the placebo.

Comment: The plan is to wait for the completion of the 48-week study.