TY - JOUR
T1 - The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis
T2 - A randomized, phase 2 trial
AU - for the GS-US-384-1497 Investigators
AU - Loomba, Rohit
AU - Lawitz, Eric
AU - Mantry, Parvez S.
AU - Jayakumar, Saumya
AU - Caldwell, Stephen H.
AU - Arnold, Hays
AU - Diehl, Anna Mae
AU - Djedjos, C. Stephen
AU - Han, Ling
AU - Myers, Robert P.
AU - Subramanian, G. Mani
AU - McHutchison, John G.
AU - Goodman, Zachary D.
AU - Afdhal, Nezam H.
AU - Charlton, Michael R.
N1 - Funding Information:
Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.29514/suppinfo. Supported by Gilead Sciences. Presented in part at the annual meeting of the American Association for the Study of Liver Diseases held in Boston on November 11-15, 2016. Copyright VC 2017 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
Funding Information:
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.29514 Potential conflict of interest: Dr. Caldwell received grants from Gilead, Genfit, Galmed, NGM, Conatus, Immuron, VitalTherapy, and Intercept. Dr. Lawitz received grants from Bristol-Myers Squibb, Conatus, Exalenz, Galectin, Galmed, Genfit, Gilead, Intercept, Madrigal, Novartis, Octeta, and Zydus. Dr. Mantry consults, advises, is on the speakers’ bureau, and received grants from AbbVie, Gilead, Bristol-Myers Squibb, Genfit, Intercept, Salix, Tobira, Merck, and Conatus. Dr. Jayakumar is on the speakers’ bureau for Gilead and Astellas. She received grants from Bristol-Myers Squibb. Dr. Loomba consults and received grants from Gilead. Dr. Charlton consults and received grants from Gilead, Intercept, NGM, Genfit, and Novartis. He received grants from Conatus. Dr. Diehl consults, advises, and received grants from Cellgene and Immuron. She consults and advises Taiwan Pharmaceuticals and Novartis. She received grants from Metabolomics, Gilead, Galmed, NGM, Bristol-Myers Squibb, Madrigal, and Galactin.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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).
AB - 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).
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U2 - 10.1002/hep.29514
DO - 10.1002/hep.29514
M3 - Article
C2 - 28892558
AN - SCOPUS:85037641328
VL - 67
SP - 549
EP - 559
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 2
ER -