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.

Effect of bardoxolone methyl on the urine albumin-to-creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease

“…21 Finally, in the BEACON trial, bardoxolone methyl significantly reduced the likelihood of CKD progression, defined as the composite endpoint of end-stage renal disease (dialysis or transplantation) or a 30% or more decline in eGFR. 41 In conclusion, the increase in urinary albumin excretion with bardoxolone methyl treatment was not associated with signs of disease progression or kidney injury, and was likely the result of a pharmacologic effect of improved glomerular filtration and decreased albumin reabsorption. Notably, these effects may preserve kidney function by reducing interstitial inflammation and fibrosis associated with excessive albumin uptake in proximal tubule cells.…”

Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases

“…Nonetheless, Reata Pharmaceuticals reported that post-hoc analysis of the trial data demonstrated preservation of kidney function (55). In addition, preliminary data from the follow-up TSUBAKI study showed improved renal function as assessed by inulin clearance (56).…”

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

“…We followed up on our observations by using the NRF2 agonist Bardoxolone methyl, which is currently in phase 3 clinical trials for treating chronic kidney disease [62,63]. Interestingly, Bardoxolone methyl impaired the infection.…”