The ASK1 Inhibitor Selonsertib in Patients with Nonalcoholic Steatohepatitis: A Randomized, Phase 2 Trial

ABSTRACT

Inhibition of apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis (NASH). We evaluated the safety and efficacy of selonsertib, a selective inhibitor of ASK1, alone or in combination with simtuzumab, in patients with NASH 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 pre- and post-treatment liver biopsies, magnetic resonance elastography (MRE), and 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 ≥1-stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% CI, 26-63), in 6-mg selonsertib group, 8 of 27 (30%; 95% CI, 14-50), and in the simtuzumab-alone group, 2 of 10 (20%; 95% CI, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on MRE, and 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.

Conclusions: These findings suggest that selonsertib may reduce liver fibrosis in patients with NASH and stage 2-3 fibrosis. (Funded by Gilead Sciences; ClinicalTrials.gov number NCT02466516) This article is protected by copyright. All rights reserved.

http://ift.tt/2xqMf6x