Back Other Health News Other Liver Disease EASL 2016: Emricasan May Improve Inflammation and Liver Function in People with Cirrhosis

Other Infections

EASL 2016: Emricasan May Improve Inflammation and Liver Function in People with Cirrhosis

alt

The novel caspase inhibitor emricasan (IDN-6556) led to improvements in various biomarkers and decreases in MELD scores in patients with liver cirrhosis due to hepatitis C, heavy alcohol use, or other causes, which significant declines among those who started with worse liver dysfunction, according to a late-breaking presentation at the European Association for the Study of the Liver's International Liver Congress (EASL 2016) last week in Barcelona.

Caspases are protease enzymes that play a role in apoptosis (programmed cell death) and inflammation, contributing to progression of chronic liver disease. Emricasan is a first-in-class pan-caspase inhibitor that has been shown to decrease biomarkers of apoptosis and inflammation in people with liver disease.

Catherine Frenette from the Scripps Clinic in San Diego and colleagues evaluated the effects of emricasan in people with cirrhosis who had MELD scores between 11 and 18. The MELD score is an indicator of liver disease severity calculated using bilirubin and creatinine levels and blood clotting capacity (INR), used to predict how urgently a patient needs a liver transplant. Scores of 10-19 predicted 3-month mortality of 6%, rising to more than 70% with a score above 40.

This multicenter Phase 2 study enrolled 86 participants with liver cirrhosis. Nearly two-thirds were men, most were white, and the mean age was 58 years. The main causes of liver disease were heavy alcohol use (38%), hepatitis C (29%), and non-alcoholic steatohepatitis (23%).

The mean MELD score at study entry was 12.8, though 22% had MELD >15. The mean Child- Pugh score was 6.9, with 56% classified as Child-Pugh class B, indicating significant functional impairment but not yet decompensation. Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were 30.9 and 52.2 U/L, respectively.

Hepatitis C patients receiving or planning antiviral treatment, hepatitis B patients on therapy for less than 3 months, and HIV-positive people were excluded, as were those with very advanced liver disease (e.g., recent bleeding varices, uncontrolled ascites, serious encephalopathy, or Child-Pugh class C.)

Participants were randomly assigned to receive 25 mg oral emricasan or placebo twice-daily for 3 months, followed by a second 3-month open-label phase in which everyone received emricasan.

Results

  • 74 participants completed the 3-month randomized treatment phase, while 12 discontinued early (4 on emricasan, 8 on placebo).
  • After 3 months of therapy, emricasan was associated with significant decreases in the serum apoptosis and inflammation markers caspase 3/7 and cCK18, with the former change being significant overall and the latter for people with high baseline MELD scores.
  • MELD scores decreased overall in the emricasan group while rising slightly in the placebo group (-0.1 vs +0.1), but the difference did not reach statistical significance (p=0.50).
  • Child-Pugh scores also fell overall in the emricasan group and rose in the placebo group (-0.2 vs +0.1), but again this was not significant (p=0.1).
  • However, in a pre-specified analysis looking at patients with more advanced disease who had baseline MELD scores of 15 or higher, those who received emricasan did show significant improvement compared to placebo in MELD scores, Child-Pugh scores, bilirubin levels, and blood clotting capacity.
  • A similar proportion of patients experienced clinical worsening events in the emricasan and placebo groups (both 14%), including development or worsening of ascites or encephalopathy.
  • Treatment was generally safe and well-tolerated, with similar adverse events, serious events, laboratory abnormalities, vital signs, and incidence of cancer and infections in the emricasan and placebo groups.
  • The most common adverse events in the emricasan group were headache, (16%), nausea (14%), and fatigue (9%).

These findings confirmed the mechanism of action and showed that emricasan "improved measures of liver function in patients with baseline MELD >15" and had a "reassuring safety profile," the researchers concluded. "These results support further study of emricasan in patients with cirrhosis and liver impairment."

Asked about evidence from other diseases suggesting that caspase inhibitors are associated with increased risk for infections, Frenette noted that emricasan is a liver-specific drug and in this study infections did not occur more often in the emricasan compared to the placebo group.

4/22/16

Reference

C Frenette, G Morelli, M Shiffman, et al. Emricasan(IDN-6556) orally for three months in patients with cirrhosis and MELD scores 11-18 improves clinical parameters of cirrhosis in patients with baseline MELD score >15. EASL International Liver Congress 2016. Barcelona, April 13-17, 2016. Abstract LB05.