Emricasan misses study endpoint for improving portal hypertension in people with NASH

The experimental caspase inhibitor emricasan did not meet the statistical threshold for improvement of portal hypertension in people with non-alcoholic steatohepatitis (NASH), but it did appear to have some benefit for those at high risk for decompensated liver disease, according to a report at the EASL International Liver Congress this month in Vienna.

"Although the primary endpoint was not met in this study, the reductions in HVPG [hepatic venous pressure gradient] observed in patients with compensated NASH cirrhosis and very severe portal hypertension are encouraging and support additional exploration in these patients. This group of patients is at greatest risk of progressing to decompensation and there are currently no approved treatments available to them," said presenter Prof. Guadalupe Garcia-Tsao of Yale University.

Non-alcoholic fatty liver disease (NAFLD) and its more severe form, NASH, are responsible for a growing proportion of advanced liver disease. The build-up of fat in the liver triggers inflammation, which over time can lead to the development of fibrosis, cirrhosis and liver cancer. In people with advanced cirrhosis, scar tissue replaces functional liver cells and can block the flow of blood through the liver, causing high blood pressure in the portal vein coming from the gastrointestinal tract. This can cause ascites (abdominal fluid accumulation) and bleeding varicose veins in the oesophagus and stomach – signs of liver decompensation.

The phase IIb ENCORE-PH trial evaluated whether emricasan would decrease portal pressure in people with cirrhosis related to NASH. Emricasan is a first-in-class pan-caspase inhibitor that was shown to improve biomarkers of liver health and decrease portal vein pressure in earlier studies. Caspases are protease enzymes that play a role in cell suicide and inflammation.

This interim analysis included 263 people from more than 50 sites in Europe and the US. More than half (57%) were women and the mean age was approximately 61 years. Many were obese and more than 80% had diabetes.

At baseline, the participants had an HVPG of 12 mmHg or higher (median 17). An HVPG above 10 to 12 mmHg is considered severe portal hypertension, and above 16 indicates a high risk for decompensation. Most were classified as Child-Pugh A, meaning not at high risk for death due to liver disease. About a quarter already had early decompensated cirrhosis, but they'd had only one prior event and were stable at study entry.

Participants were randomly assigned to receive various doses of oral emricasan (5, 25 or 50mg) or placebo twice daily for 48 weeks. HVPG was measured at study entry and again at 24 weeks, which was the study's primary endpoint.

HVPG declined by -0.5, -0.8 and -0.7 mmHg, respectively, in the emricasan 5, 25 and 50mg arms, compared with -0.2 mmHg in the placebo group. Overall, the decreases in HVPG in all three emricasan dose arms did differ enough from the placebo arm to reach the threshold for statistical significance, meaning the changes could have been due to chance.

However, a post hoc analysis showed that HVPG was significantly reduced in the subset of participants with compensated cirrhosis and worse portal hypertension at baseline (≥16 mmHg), with declines of around -1.5 mmHg in all emricasan dose arms. This much improvement is considered "clinically meaningful," according to Prof. Garcia-Tsao.

In addition, emricasan recipients showed significantly more improvement in biomarkers of liver health including ALT and AST liver enzyme levels.

Treatment was generally safe and well tolerated. Adverse events were common, but occurred with similar frequency in the emricasan and placebo groups (both 82%). Fewer than 5% stopped taking emricasan due to side-effects.

The study is ongoing and HVPG will be assessed again at the end of treatment at 48 weeks, Prof. Garcia-Tsao said.