Emricasan (IDN-6556) Lowers Portal Pressure in Patients With Compensated Cirrhosis and Severe Portal Hypertension

Caspases are pivotal in regulating apoptosis, inflammation, and fibrosis. They generate hemodynamically active, pro-inflammatory microparticles that contribute to intrahepatic inflammation, vasoconstriction, and extrahepatic splanchnic vasodilation. Emricasan, a pan-caspase inhibitor, has been shown to reduce portal hypertension (PH) and improve survival in murine models of cirrhosis. This exploratory study aimed to evaluate whether emricasan can lower PH in patients with compensated cirrhosis.

In this multicenter, open-label study, 23 participants with compensated cirrhosis and PH (hepatic vein pressure gradient [HVPG] >5 mm Hg) were enrolled. Participants received 25 mg of emricasan twice daily for 28 days. HVPG measurements were standardized and taken before and after treatment, with all tracings assessed by a single expert. The median age of participants was 59 years (range 49-80), with 70% being male. The primary causes of cirrhosis included nonalcoholic steatohepatitis and hepatitis C virus. Most subjects were classified as Child class A (87%), with a median Model for End-Stage Liver Disease (MELD) score of 8 (range 6-15). Twelve participants had severe PH (HVPG ≥12 mm Hg).

Overall, there was no significant change in HVPG after emricasan treatment (mean [standard deviation, SD] -1.1 [4.57] mm Hg). However, in patients with severe PH, HVPG decreased significantly (mean [SD] -3.7 [4.05] mm Hg; P = 0.003): 4 out of 12 showed a ≥20% decrease, 8 out of 12 had a ≥10% decrease, and 2 out of 12 had HVPG drop below 12 mm Hg. There were no significant changes in blood pressure or heart rate. Additionally, levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased significantly in both the overall group and those with severe PH. Serum levels of cleaved cytokeratin 18 and caspase-3/7 also showed significant reductions. Emricasan was well tolerated, with only one participant discontinuing due to non-serious adverse events.

In conclusion, emricasan administration for 28 days significantly reduced HVPG in patients with compensated cirrhosis and severe PH, likely affecting portal venous inflow, while concomitant decreases in AST and ALT suggest an anti-inflammatory effect within the liver.