Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo

• Published in: Clinical gastroenterology and hepatology Vol. 17; no. 4; pp. 774 - 783.e4
• Main Authors: Frenette, Catherine T., Morelli, Giuseppe, Shiffman, Mitchell L., Frederick, R. Todd, Rubin, Raymond A., Fallon, Michael B., Cheng, Jason T., Cave, Matt, Khaderi, Saira A., Massoud, Omar, Pyrsopoulos, Nikolaos, Park, James S., Robinson, James M., Yamashita, Mason, Spada, Alfred P., Chan, Jean L., Hagerty, David T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019
• Subjects: Biomarker; CASP3; CASP7; Cell Death; CK-18; IDN-6556; Biomarker; AE; LSM; ALT; cCK-18; INR; NASH; IDN-6556; CASP7; MELD; CASP3; Cell Death; HCV; CK-18; flCK-18
• ISSN: 1542-3565; 1542-7714
• DOI: 10.1016/j.cgh.2018.06.012

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). 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. 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. 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.