The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.

Abstract

Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2018;67:549-559).

• Authors: Rohit Loomba, Eric Lawitz, Parvez S Mantry, Saumya Jayakumar, Stephen H Caldwell, Hays Arnold, Anna Mae Diehl, C Stephen Djedjos, Ling Han, Robert P Myers, G Mani Subramanian, John G McHutchison, Zachary D Goodman, Nezam H Afdhal, Michael R Charlton, GS-US-384-1497 Investigators
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 67 Issue 2 Pg. 549-559 (02 2018) ISSN: 1527-3350 [Electronic] United States
• PMID: 28892558 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

Chemical References

• Antibodies, Monoclonal, Humanized
• Benzamides
• Imidazoles
• Protein Kinase Inhibitors
• Pyridines
• simtuzumab
• MAP Kinase Kinase Kinase 5
• selonsertib

Topics

• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• Benzamides (pharmacology, therapeutic use)
• Elasticity Imaging Techniques
• Female
• Humans
• Imidazoles (pharmacology, therapeutic use)
• Liver Cirrhosis (diagnostic imaging, drug therapy, pathology)
• MAP Kinase Kinase Kinase 5 (antagonists & inhibitors)
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease (diagnostic imaging, drug therapy, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)