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Randomized Controlled Trial
. 2024 Mar;28(3):225-234.
doi: 10.1007/s10157-023-02427-w. Epub 2023 Nov 14.

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

Kazuaki Ikejiri  1 , Takafumi Suzuki  2   3 , Satsuki Muto  1 , Hirotaka Takama  1 , Kengo Yamawaki  1 , Tatsuya Miyazawa  1 , Itaru Urakawa  1 , Yuichi Aoki  3 , Akihito Otsuki  3 , Fumiki Katsuoka  3   4 , Kengo Kinoshita  3   4 , Masaomi Nangaku  5 , Tadao Akizawa  6 , Masayuki Yamamoto  7   8   9
Affiliations
Randomized Controlled Trial

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

Kazuaki Ikejiri et al. Clin Exp Nephrol. 2024 Mar.

Abstract

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.

Keywords: Bardoxolone methyl; Chronic kidney disease; Diabetic kidney disease; Glomerular filtration rate; Nuclear factor erythroid 2-related factor; Single nucleotide polymorphisms.

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Conflict of interest statement

K. Ikejiri, S. Muto, H. Takama, K. Yamawaki, T. Miyazawa and I. Urakawa are employees of Kyowa Kirin. M. Nangaku has received research grants, consulting fees, and lecture fees from Kyowa Kirin and is vice president of the Japanese Society of Internal Medicine, president of the Asian Pacific Society of Nephrology, and president-elect of the International Society of Nephrology. T. Akizawa has received consulting fee and honoraria from Kyowa Kirin. T. Suzuki, Y. Aoki, A. Otsuki, F. Katsuoka, K. Kinoshita and M. Yamamoto declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Patient disposition of all analysis sets included in the study. FAS full analysis set of the TSUBAKI study, FASs full analysis set of the genotype substudy, PPS per-protocol set of the TSUBAKI study, PPSs per-protocol set of the genotype substudy
Fig. 2
Fig. 2
Change from baseline in estimated glomerular filtration rate (eGFR) at week 16 in FASs. FASs full analysis set of the genotype substudy
Fig. 3
Fig. 3
The time course of changes in (a, b) albumin: creatinine ratio (ACR), (c, d) systolic blood pressure (SBP), (e, f) diastolic blood pressure (DBP), and levels of (g, h) B-natriuretic peptide (BNP), and (i, j) troponin (T), in the two treatment groups of the FASs, stratified by genotype. FASs full analysis set of the genotype substudy
Fig. 3
Fig. 3
The time course of changes in (a, b) albumin: creatinine ratio (ACR), (c, d) systolic blood pressure (SBP), (e, f) diastolic blood pressure (DBP), and levels of (g, h) B-natriuretic peptide (BNP), and (i, j) troponin (T), in the two treatment groups of the FASs, stratified by genotype. FASs full analysis set of the genotype substudy
Fig. 4
Fig. 4
The change from baseline in (a, b) bodyweight, and (c, d) creatine kinase (CK) levels in the two treatment groups of the FASs, stratified by genotype. FASs full analysis set of the genotype substudy
See this image and copyright information in PMC

References

    1. Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997;236:313–322. doi: 10.1006/bbrc.1997.6943. - DOI - PubMed
    1. Itoh K, Wakabayashi N, Katoh Y, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13:76–86. doi: 10.1101/gad.13.1.76. - DOI - PMC - PubMed
    1. Suzuki T, Shibata T, Takaya K, et al. Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels. Mol Cell Biol. 2013;33:2402–2412. doi: 10.1128/MCB.00065-13. - DOI - PMC - PubMed
    1. Shimoyama Y, Mitsuda Y, Hamajima N, Niwa T. Polymorphisms of Nrf2, an antioxidative gene, are associated with blood pressure in Japanese. Nagoya J Med Sci. 2014;76:113–120. - PMC - PubMed
    1. Marzec JM, Christie JD, Reddy SP, et al. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J. 2007;21:2237–2246. doi: 10.1096/fj.06-7759com. - DOI - PubMed

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