Multi-Omics Reveal Antioxidant Effects of Bardoxolone Methyl in the TSUBAKI Study.

Abstract

Background: Nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial for defense against oxidative stress. In the Phase 2 TSUBAKI study, bardoxolone methyl, an Nrf2 activator, was shown to increase the glomerular filtration rate (GFR) in patients with diabetic kidney disease (DKD). Though non-clinical reports suggest that bardoxolone methyl acts mainly through Nrf2-mediated antioxidant response activation, this has not been proven in clinical settings. The present study assessed its effects using plasma and urine from the TSUBAKI study.

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 post-dosing 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, while 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.