Emricasan May Lower Hepatic Venous Pressure Gradient in Patients With Nonalcoholic Steatohepatitis Cirrhosis and Severe Portal Hypertension: Presented at EASL

By Walter Alexander

VIENNA, Austria -- April 17, 2019 -- Several trends favour emricasan treatment for patients with nonalcoholic steatohepatitis cirrhosis and severe portal hypertension (hepatic venous pressure gradient [HVPG], ≥12 mm Hg) and support its further study in this population, according to a study presented here at The International Liver Meeting, the 54th Annual Meeting of the European Association for the Study of the Liver (EASL).

Emricasan is an oral pan-caspase inhibitor that has been shown to lower portal pressure in animal models and humans with compensated cirrhosis (HVPG, ≥12 mm Hg), said Guadalupe Garcia-Tsao, MD, Yale University, New Haven, Connecticut, on April 13. She noted that caspases play a central role in apoptosis and inflammation, both of which are pathogenic mechanisms in nonalcoholic steatohepatitis.

Severe portal hypertension, defined as HVPG of >10 to 12 mm Hg, is a key driver of cirrhosis decompensation. HPVG measurement is the best available method to evaluate the presence and severity of portal hypertension and is a robust surrogate marker for diagnosis and risk stratification. Decreases in HVPG as small as 1 mm Hg have been associated with a reduction in the risk of decompensation.

This interim analysis of a 48-week trial of HVPG decreases with emricasan versus placebo in a population with severe portal hypertension also looked at mechanistic biomarkers and safety/tolerability. Patients (n = 263; mean age, 60.8 years; 57% women) with nonalcoholic steatohepatitis cirrhosis and baseline HVPG of ≥12 mm Hg were randomised 1:1:1:1 to
emricasan 5, 25, or 50 mg or placebo orally twice daily for 48 weeks. HVPG assessment at the 24-week follow-up was the primary endpoint. Patients were stratified according to compensated (76%) or early decompensated (24%) status.

Mean HVPG was ~17.0 mm Hg at baseline and 16.5, 16.6, 15.8, and 16.6 mm Hg at week 24 in the emricasan 5-, 25-, and 50-mg and placebo groups, respectively. A post hoc analysis of subjects with baseline HVPG of ≥16 mm Hg, however, revealed clinically meaningful changes favouring emricasan over placebo at all doses. Biomarker (caspase, cCK18, alanine aminotransferase, and aspartate transaminase) reductions with emricasan were also generally significant.

Treatment-emergent adverse event rates were found to be similar (81.6% for combined emricasan doses vs 82.1% for placebo), with serious adverse events reported among 17.9% for emricasan treatment and 11.9% for placebo. Adverse events were distributed widely across various organ system classes.

“These results support additional exploration of emricasan in patients with severe portal hypertension,” said Dr. Garcia-Tsao.

“Although the primary endpoint was not met, these data suggest that caspase inhibition with emricasan for 24 weeks reduced portal pressure in compensated nonalcoholic steatohepatitis cirrhosis patients with severe portal hypertension, especially those with higher baseline HVPG,” concluded Dr. Garcia-Tsao, adding that decreases in transaminases suggest an intrahepatic effect with reduction of liver injury.

A full analysis will be conducted at 48 weeks.

[Presentation title: Multicenter, Double-Blind, Placebo-Controlled, Randomized Trial of Emricasan in Subjects With NASH Cirrhosis and Severe Portal Hypertension. Abstract LB-01]

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