Bardoxolone methyl: drug development for diabetic kidney disease

Abstract

Bardoxolone methyl activates the Keap1/Nrf2 system that plays an important role in defense responses against oxidative stress. Importantly, bardoxolone methyl has demonstrated increases in estimated glomerular filtration rate (eGFR) in patients with diabetic kidney disease (DKD) in clinical studies. However, an overseas Phase 3 study of bardoxolone methyl in patients with stage G4 DKD was prematurely terminated due to an increased risk for heart failure, which was considered to have been caused by early-onset fluid overload. Subsequently, a Japanese Phase 2 study demonstrated, for the first time, that bardoxolone methyl directly improves GFR, which is a true indicator of kidney function, using the inulin clearance method. In Japan, bardoxolone methyl was designated for the treatment of DKD under the Priority Review and Designation (SAKIGAKE Designation) System established by the Ministry of Health, Labour and Welfare. A Japanese Phase 3 study, with endpoints such as a ≥ 30% decrease in eGFR, is currently ongoing to assess the efficacy and safety of bardoxolone methyl in more than 1,000 patients with stages G3 and G4 DKD who have no identified risk factors.

Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling

“…Natural bioactive compounds and their sources have been demonstrated to have kidney protective potential by activating Nrf2 in experimental CKD models [23,24]. In a recent review on clinical studies, bardoxolone methyl (CDDO-me), a semi-synthetic triterpenoid activating the Nrf2 pathway, has been reported as an effective therapeutic for diabetic kidney disease (DKD), although it has limitations in that it increases the risk of heart failure [25]. Heme oxygenase-1 (HO-1), one of the target molecules of Nrf2, attenuates the overall production of ROS through its ability to degrade heme and to produce carbon monoxide (CO), biliverdin/bilirubin, and the release of free iron.…”

Eat Your Broccoli: Oxidative Stress, NRF2, and Sulforaphane in Chronic Kidney Disease

“…In humans, the most well-studied pharmacologic agent activating the NRF2 system is the drug bardoxolone methyl, which covalently binds to cysteine residues of KEAP1, allowing NRF2 to escape ubiquitination and degradation and translocate to the nucleus to induce the myriad antioxidant genes [ 53 ]. The potential beneficial effect of bardoxolone methyl on kidney function was first observed in a phase I cancer trial, where it was found to result in a statistically significant increase in estimated glomerular filtration rate (eGFR) of 26% [ 54 ].…”

Chronic kidney disease in patients with diabetes mellitus

“…Sulodexide, a glycosaminoglycan described as being able to prevent structural changes in the glomerular basement membrane, has shown positive effects on proteinuria in two small studies (60,61). Bardoxolone mathyl is demonstrated to improve inulin GFR in a Japanese phase two study, the phase 3 study results are expected early in 2022 (62). Lowering of the serum urate level with allopurinol, was however, not shown to slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic nephropathy (63).…”