Multi-Omics Reveal Antioxidant Effects of Bardoxolone Methyl in the Phase 2 Study of Bardoxolone Methyl in Patients with CKD and Type 2 Diabetes Study
Year: 2025
Type: article
Abstract: Key Points The study aims to clarify the effects of bardoxolone methyl using proteomics and metabolomics analyses of plasma and urine from The Phase 2 Study of Bardoxolone Methyl in Patients with CKD and Type 2 Diabetes. This study demonstrated the first evidence in humans that bardoxolone methyl activates an antioxidant response. Background NF erythroid 2-related factor 2 (NRF2) is crucial for defense against oxidative stress. In The Phase 2 Study of Bardoxolone Methyl in Patients with CKD and Type 2 Diabetes, bardoxolone methyl, an NRF2 activator, was shown to increase the GFR in patients with diabetic kidney disease. Although nonclinical reports suggest that bardoxolone methyl acts mainly through NRF2-mediated antioxidant response activation, this has not been proven in clinical settings. This study assessed its effects using plasma and urine from The Phase 2 Study of Bardoxolone Methyl in Patients with CKD and Type 2 Diabetes. Methods Patients received either bardoxolone methyl or placebo daily for 16 weeks. Urine and plasma samples were collected at baseline, after 16 weeks of dosing, and 4 weeks postdosing and were cryopreserved for an analysis. A total of 45 patients in the bardoxolone methyl group and 52 in the placebo group were subjected to proteomic and metabolic analyses. Proteomic profiling was conducted using the SOMAscan assay, whereas metabolomics analyses were performed by Human Metabolome Technologies, Inc. Results Plasma proteomics revealed that two oxidative stress–related pathways have been significantly changed by bardoxolone methyl treatment. Among these two pathways, antioxidative proteins and proteins that enhance the antioxidative process were significantly increased. Some of these increased proteins were known to be NRF2 target proteins. Similarly, urine proteomics revealed that four pathways were changed, and antioxidative proteins that are the target proteins of NRF2 were increased. Furthermore, seven metabolites that potentiate the antioxidative effect were significantly increased in urine. Conclusions This study demonstrated the first evidence in humans that bardoxolone methyl activates an antioxidant response.
Source: Kidney360
Authors: Kentaro Yoshioka, Hiroto Kaneko, Waka Haruyama, Tetsuro Tomiyama, Atsuko Takami, Tetsuya Kitayama, Kohei Yamasaki
Institution: Kyowa Kirin (Japan)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W4411207435