C. Frenette, G. Morelli, M. Shiffman
Mar 1, 2019
Citations
2
Influential Citations
70
Citations
Quality indicators
Journal
Clinical Gastroenterology & Hepatology
Abstract
Background & Aims: Caspase‐mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan‐caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non‐alcoholic steatohepatitis (NASH). Methods: We performed a multicenter study of 86 patients with cirrhosis (Child‐Pugh class A or B; mean score, 6.9; 38% with alcohol‐associated cirrhosis, 29% with HCV‐associated cirrhosis, and 23% with NASH) and model for end‐stage liver disease (MELD) scores of 11–18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open‐label Emricasan (25 mg) twice‐daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK‐18) at month 3. Results: Seventy‐four patients completed the 3‐month study period (40 given Emricasan and 34 given placebo); 69 patients received open‐label Emricasan for 3 months afterward. At the 3‐month timepoint, Emricasan significantly reduced mean MELD (P = .003) and Child‐Pugh (P = .003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, –0.2882 to –0.0866) and total bilirubin (95% CI, –1.5069 to –0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P = .466) or Child‐Pugh (P = .124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full‐length CK‐18 (P = .02) and caspase 3/7 (P < .001), but not cleaved CK‐18 (P = .092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. Conclusions: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child‐Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.