Selonsertib in Patients with Diabetic Kidney Disease: A Phase 2b Randomized Active Run-In Clinical Trial.

Abstract

In a randomized, placebo-controlled, phase 2b study, we compared the effects of selonsertib with placebo on eGFR decline in people with type 2 diabetes and CKD. Patients taking selonsertib had slower eGFR decline but were more likely to reach a composite kidney outcome and report AKI. A larger trial with longer-term follow-up would more precisely assess the relative benefits and risks of selonsertib in this setting. Selonsertib is an apoptosis signal–regulating kinase 1 inhibitor that reduces inflammation, fibrosis, and apoptosis. The MOSAIC study evaluated whether selonsertib attenuated kidney function decline in patients with diabetic kidney disease. We conducted a phase 2b study in adults with type 2 diabetes and eGFR 20 to <60 ml/min per 1.73 m² with urine albumin-creatinine ratio 150–5000 mg/g on maximum tolerated dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. To account for an acute selonsertib-related decrease in serum creatinine–based eGFR (eGFR_cr), patients entered a 4-week selonsertib run-in period to establish treatment-specific baseline eGFR_cr. Patients were randomized 1:1 to selonsertib 18 mg or matching placebo once daily. We followed all participants up until the last randomized participant completed 48 weeks of follow-up. The primary efficacy outcome was the difference in eGFR_cr slopes from treatment-specific baselines to week 84, evaluated at a prespecified two-sided <i>P</i> = 0.30. We also evaluated kidney clinical events (eGFR_cr ≥40% decline from pre–run-in baseline, kidney failure, or death due to kidney disease) and adverse events. In total, 310 patients were randomized (selonsertib <i>n</i>=154, placebo <i>n</i>=156; 68% male, mean age 65 years, mean baseline eGFR_cr 35 ml/min per 1.73 m²). Mean difference between selonsertib and placebo eGFR_cr slopes at week 84 was 1.20 ml/min per 1.73 m² per year (95% confidence interval, −0.41 to 2.81; <i>P</i> = 0.14). Kidney clinical events occurred in 17% (26/154) of patients randomized to selonsertib and 12% (19/156) of those randomized to placebo (difference 4.7%; 95% confidence interval, −6.3% to 15.9%). The most common investigator-reported adverse event was AKI (selonsertib 11.0/100 and placebo 5.9/100 patient-years). Selonsertib attenuated the decline in eGFR_cr over up to 84 weeks; however, it resulted in a numerically higher number of patients reaching a kidney clinical event and a numerically higher rate of investigator-reported AKI. Study to Evaluate the Efficacy and Safety of Selonsertib in Participants With Moderate to Advanced Diabetic Kidney Disease (MOSAIC), NCT04026165.