1 Pinnacle Clinical Research, San Antonio, TX.
2 Inova Fairfax Hospital, Falls Church, VA.
3 Gastroenterology of Southern Indiana, New Albany, IN.
4 Iowa Digestive Disease Center' Clive, IA.
5 Gastro One, Germantown, TN.
6 Kansas City Research Institute, Kansas City, MO.
7 Fresno Clinical Research Center, Fresno, CA.
8 Department of Medicine, University Medical Center, Mainz, Germany.
9 Inland Empire Liver Foundation, Rialto, CA.
10 Asheville Gastroenterology Associates, Asheville, NC.
11 Gastrointestinal Specialists of Georgia, Marietta, GA.
12 Hospital Universitario La Paz, CIBERehd, IdiPAZ, Madrid, Spain.
13 Methodist University Hospital, University of Tennessee Health Sciences Center, Memphis, TN.
14 Ochsner Medical Center, New Orleans, LA.
15 California Liver Research Institute, Pasadena, CA.
16 Department of Medicine, University Medical Center, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA.
17 Conatus Pharmaceuticals, Inc., San Diego, CA.
18 Conatus Pharmaceuticals, Inc., San Diego, CA. Electronic address: email@example.com.
19 Virginia Commonwealth University, Richmond, VA.
BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by hepatocyte steatosis, ballooning, and lobular inflammation which may lead to fibrosis. Lipotoxicity activates caspases, which cause apoptosis and inflammatory cytokine (IL-1β and IL-18) production. Emricasan is a pan-caspase inhibitor that decreases serum aminotransferases and caspase activation in NASH patients. This study postulated that 72 weeks of emricasan treatment would improve liver fibrosis without worsening of NASH.
METHODS: This double-blind, placebo-controlled study randomized 318 subjects 1:1:1 to twice-daily treatment with emricasan (5 or 50 mg) or matching placebo for 72 weeks. Subjects had definite NASH and NASH CRN fibrosis stage F1-F3, as determined by a central reader, on a liver biopsy obtained within 6 months of randomization.
RESULTS: Emricasan treatment did not achieve the primary objective of fibrosis improvement without worsening of NASH(emricasan 5 mg: 11.2%; emricasan 50 mg: 12.3%; placebo: 19.0%; odds ratios vs. placebo 0.530 and 0.588, with p=0.972 and 0.972, respectively) or the secondary objective of NASH resolution without worsening of fibrosis (emricasan 5 mg: 3.7%; emricasan 50 mg: 6.6%; placebo: 10.5%; odds ratios vs. placebo 0.334 and 0.613, with p=0.070 and 0.335, respectively). In the small subset of subjects with consistent normalization of serum ALT over 72 weeks, emricasan may have improved histologic outcomes.
CONCLUSIONS: Emricasan treatment did not improve liver histology in subjects with NASH fibrosis despite target engagement and may have worsened fibrosis and ballooning. Caspase inhibition lowered serum ALT in the short-term but may have directed cells to alternative mechanisms of cell death, resulting in more liver fibrosis and hepatocyte ballooning.
LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is characterized by fat accumulation in liver cells, which leads to inflammation and fibrosis. Emricasan was previously shown to inhibit some of the liver enzymes which lead to liver inflammation and fibrosis. In this study, emricasan did not improve liver inflammation or fibrosis in patients with NASH and pre-existing liver fibrosis.