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).

Figure 1

Proportions of patients with improved, unchanged, or worse fibrosis from baseline to week 24. Fibrosis improvement is defined as a decrease of at least one stage in fibrosis according to the NASH CRN Histologic Scoring System. Data are shown for the 67 patients with liver biopsies evaluable for fibrosis at baseline and week 24.

Figure 2

Factors associated with fibrosis improvement. Changes in body weight, MRI‐PDFF, and grades of steatosis and ballooning were not associated with fibrosis improvement. *All odds ratios were adjusted for baseline values. Abbreviations: CK18, cytokeratin‐18; GGT, gamma‐glutamyltransferase.

Figure 3

Change from baseline in MRE and MRI‐PDFF from baseline to week 24. Central line represents median value, box represents interquartile range, and whiskers show range not including outliers, which are represented by dots. (A) Change in MRE stiffness from baseline to week 24 in fibrosis responders and nonresponders. Fibrosis response was defined as a reduction of one or more stage in fibrosis. (B) Change in MRI‐PDFF from baseline to week 24 in steatosis responders and nonresponders. Steatosis response was defined as a reduction of one or more grade in steatosis.