Stephen A Harrison1, Zachary Goodman2, Abdul Jabbar3, Ravi Vemulapalli4, Ziad H Younes5, Bradley Freilich6, Muhammad Y Sheikh7, Jörn M Schattenberg8, Zeid Kayali9, Adam Zivony10, Aasim Sheikh11, Javier Garcia-Samaniego12, Sanjaya K Satapathy13, George Therapondos14, Edward Mena15, Detlef Schuppan16, James Robinson17, Jean L Chan17, David T Hagerty18, Arun J Sanyal19. 1. Pinnacle Clinical Research, San Antonio, TX, United States. 2. Inova Fairfax Hospital, Falls Church, VA, United States. 3. Gastroenterology of Southern Indiana, New Albany, IN, United States. 4. Iowa Digestive Disease Center' Clive, IA, United States. 5. Gastro One, Germantown, TN, United States. 6. Kansas City Research Institute, Kansas City, MO, United States. 7. Fresno Clinical Research Center, Fresno, CA, United States. 8. Department of Medicine, University Medical Center, Mainz, Germany. 9. Inland Empire Liver Foundation, Rialto, CA, United States. 10. Asheville Gastroenterology Associates, Asheville, NC, United States. 11. Gastrointestinal Specialists of Georgia, Marietta, GA, United States. 12. Hospital Universitario La Paz, CIBERehd, IdiPAZ, Madrid, Spain. 13. Methodist University Hospital, University of Tennessee Health Sciences Center, Memphis, TN, United States. 14. Ochsner Medical Center, New Orleans, LA, United States. 15. California Liver Research Institute, Pasadena, CA, United States. 16. Department of Medicine, University Medical Center, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA, United States. 17. Conatus Pharmaceuticals, Inc., San Diego, CA, United States. 18. Conatus Pharmaceuticals, Inc., San Diego, CA, United States. Electronic address: dthagerty@aol.com. 19. Virginia Commonwealth University, Richmond, VA.
Abstract
BACKGROUND & 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 patients with NASH. This study postulated that 72 weeks of emricasan treatment would improve liver fibrosis without worsening of NASH. METHODS: In this double-blind, placebo-controlled study 318 patients were randomized 1:1:1 to twice-daily treatment with emricasan (5 mg or 50 mg) or matching placebo for 72 weeks. Patients 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 patients with consistent normalization of serum alanine aminotransferase over 72 weeks, emricasan may have improved histologic outcomes. CONCLUSIONS: Emricasan treatment did not improve liver histology in patients with NASH fibrosis despite target engagement and may have worsened fibrosis and ballooning. Caspase inhibition lowered serum alanine aminotransferase in the short-term but may have directed cells to alternative mechanisms of cell death, resulting in more liver fibrosis and hepatocyte ballooning. CLINICAL TRIAL NUMBER: Clinical Trials.gov #NCT02686762. 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.
RCT Entities:
BACKGROUND & 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 patients with NASH. This study postulated that 72 weeks of emricasan treatment would improve liver fibrosis without worsening of NASH. METHODS: In this double-blind, placebo-controlled study 318 patients were randomized 1:1:1 to twice-daily treatment with emricasan (5 mg or 50 mg) or matching placebo for 72 weeks. Patients 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 patients with consistent normalization of serum alanine aminotransferase over 72 weeks, emricasan may have improved histologic outcomes. CONCLUSIONS: Emricasan treatment did not improve liver histology in patients with NASHfibrosis despite target engagement and may have worsened fibrosis and ballooning. Caspase inhibition lowered serum alanine aminotransferase in the short-term but may have directed cells to alternative mechanisms of cell death, resulting in more liver fibrosis and hepatocyte ballooning. CLINICAL TRIAL NUMBER: Clinical Trials.gov #NCT02686762. 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.
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