Effects of Selonsertib in Patients with Diabetic Kidney Disease

Significance Statement Findings in animal models of diabetic kidney disease identified selonsertib, a selective inhibitor of apoptosis signal–regulating kinase 1 (ASK1), as a potential therapeutic agent. In a randomized, dose-ranging, placebo-controlled phase 2 trial evaluating selonsertib’s safety and efficacy in patients with moderate-to-advanced diabetic kidney disease, the authors found that selonsertib appeared safe, with no dose-dependent adverse effects over 48 weeks, including for the 18-mg daily dose thought to maximally inhibit ASK1. Although the trial did not meet its primary efficacy end point of change in eGFR from baseline to week 48, acute effects related to inhibition of creatinine secretion by selonsertib confounded differences in eGFR. Exploratory post hoc analyses accounting for these effects suggest that selonsertib resulted in a dose-dependent reduction in kidney function decline and merits further study. Background Apoptosis signal-regulating kinase 1 (ASK1) activation in glomerular and tubular cells resulting from oxidative stress may drive kidney disease progression. Findings in animal models identified selonsertib, a selective ASK1 inhibitor, as a potential therapeutic agent. Methods In a phase 2 trial evaluating selonsertib’s safety and efficacy in adults with type 2 diabetes and treatment-refractory moderate-to-advanced diabetic kidney disease, we randomly assigned 333 adults in a 1:1:1:1 allocation to selonsertib (oral daily doses of 2, 6, or 18 mg) or placebo. Primary outcome was change from baseline eGFR at 48 weeks. Results Selonsertib appeared safe, with no dose-dependent adverse effects over 48 weeks. Although mean eGFR for selonsertib and placebo groups did not differ significantly at 48 weeks, acute effects related to inhibition of creatinine secretion by selonsertib confounded eGFR differences at 48 weeks. Because of this unanticipated effect, we used piecewise linear regression, finding two dose-dependent effects: an acute and more pronounced eGFR decline from 0 to 4 weeks (creatinine secretion effect) and an attenuated eGFR decline between 4 and 48 weeks (therapeutic effect) with higher doses of selonsertib. A post hoc analysis (excluding data for 20 patients from two sites with Good Clinical Practice compliance–related issues) found that between 4 and 48 weeks, rate of eGFR decline was reduced 71% for the 18-mg group relative to placebo (difference 3.11±1.53 ml/min per 1.73 m 2 annualized over 1 year; 95% confidence interval, 0.10–6.13; nominal P =0.043). Effects on urine albumin-to-creatinine ratio did not differ between selonsertib and placebo. Conclusions Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression.