Bardoxolone Methyl Improves Kidney Function in Patients with Chronic Kidney Disease Stage 4 and Type 2 Diabetes: Post-Hoc Analyses from Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Study

Abstract

Background: Increases in measured inulin clearance, measured creatinine clearance, and estimated glomerular filtration rate (eGFR) have been observed with bardoxolone methyl in 7 studies enrolling approximately 2,600 patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The largest of these studies was Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), a multinational, randomized, double-blind, placebo-controlled phase 3 trial which enrolled patients with T2D and CKD stage 4. The BEACON trial was terminated after preliminary analyses showed that patients randomized to bardoxolone methyl experienced significantly higher rates of heart failure events. We performed post-hoc analyses to characterize changes in kidney function induced by bardoxolone methyl.

Methods: Patients in -BEACON (n = 2,185) were randomized 1: 1 to receive once-daily bardoxolone methyl (20 mg) or placebo. We compared the effects of bardoxolone methyl and placebo on a post-hoc composite renal endpoint consisting of ≥30% decline from baseline in eGFR, eGFR <15 mL/min/1.73 m2, and end-stage renal disease (ESRD) events (provision of dialysis or kidney transplantation).

Results: Consistent with prior studies, patients randomized to bardoxolone methyl experienced mean increases in eGFR that were sustained through study week 48. Moreover, increases in eGFR from baseline were sustained 4 weeks after cessation of treatment. Patients randomized to bardoxolone methyl were significantly less likely to experience the composite renal endpoint (hazards ratio 0.48 [95% CI 0.36-0.64]; p < 0.0001).

Conclusions: Bardoxolone methyl preserves kidney function and may delay the onset of ESRD in patients with T2D and stage 4 CKD.

Keywords: Bardoxolone methyl; eGFR.

Fig. 1.

Early increases in eGFR with bardoxolone methyl correlate with durable response through 1 year and sustained eGFR benefit in BEACON. Scatter plots of (left) week 12 vs. 48 changes from baseline in eGFR and (right) changes from baseline in eGFR at week 12 vs. 4 weeks after last dose in bardoxolone methyl-treated patients. Data only include bardoxolone methyl patients treated for at least 48 weeks with eGFR data at week 12 and 48 (n = 236) or week 12 and 4 weeks post treatment (n = 221). Pearson correlations were calculated using change from baseline in eGFR at week 12 with changes at week 48 or post treatment.

Fig. 2.

Distribution of changes from baseline in eGFR at week 48 in bardoxolone methyl-treated and placebo patients in BEACON. Bars represent eGFR changes from baseline at week 48 for individual patients. Data only include patients with week 48 data.

Fig. 3.

Time-to-event analysis for kidney failure composite outcomes in BEACON. Kaplan-Meier plots of the time-to-first-event for composites consisting of: (top) ≥30% decline from baseline in eGFR, eGFR <15 mL/min/1.73 m², and adjudicated ESRD events; (bottom) ≥30% decline from baseline in eGFR and eGFR <15 mL/min/1.73 m². Hazards ratios and 95% CI were computed using Cox proportional hazards regression models. Median duration of exposure to the study drug was 7 months for patients randomized to bardoxolone methyl and 8 months for patients randomized to placebo.