Effects of NRF2 polymorphisms on safety and efficacy of bardoxolone methyl: subanalysis of TSUBAKI study

Background In the TSUBAKI study, bardoxolone methyl significantly increased measured and estimated glomerular filtration rates (GFR) in patients with multiple forms of chronic kidney disease (CKD), including Japanese patients with type 2 diabetes and stage 3–4 CKD. Since bardoxolone methyl targets the nuclear factor erythroid 2–related factor 2 pathway, this exploratory analysis of the TSUBAKI study investigated the impact of the regulatory single nucleotide polymorphism, rs6721961, on the effects of bardoxolone methyl. Methods Japanese patients aged 20–79 years with type 2 diabetes and stage 3–4 CKD were randomized to bardoxolone methyl 5–15 mg/day (titrated as tolerated) or placebo for 16 weeks. Genotype frequency, clinical characteristics, renal function, and adverse events were primarily assessed. Results Of 104 patients (bardoxolone methyl n = 55, placebo n = 49); 57% were genotype C/C, 32% C/A and 12% A/A. The frequency of the A/A genotype was higher among patients with diabetic kidney disease than in the general Japanese population (~ 5%). Measured and estimated GFRs increased from baseline in all genotypes receiving bardoxolone methyl. There were no significant differences between genotypes for safety parameters, including blood pressure, bodyweight, and levels of B-type natriuretic peptide, or in the type and frequency of adverse events, suggesting that the efficacy and safety of bardoxolone methyl are unaffected by the rs6721961 polymorphism-617 (C→A) genotype. Conclusions Our approach of combining genome analysis with clinical trials for an investigational drug provides important and useful clues for exploring the efficacy and safety of the drug. Trial registration ClinicalTrials.gov; NCT02316821.