Bardoxolone methyl: drug development for diabetic kidney disease
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REVIEW ARTICLE
Bardoxolone methyl: drug development for diabetic kidney disease Hironori Kanda1 · Kengo Yamawaki1 Received: 11 August 2019 / Accepted: 11 June 2020 © The Author(s) 2020
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. Keywords Bardoxolone methyl · Keap1 · Nrf2 · GFR
Introduction The prevalence of chronic kidney disease (CKD) is increasing worldwide, with primarily diabetic kidney disease (DKD), being a major public health concern. In Japan, as of 2017, approximately 335,000 patients with CKD (i.e., one out of 380 Japanese people) were undergoing chronic dialysis, making Japan notable as the country with the second highest prevalence of chronic dialysis patients in the world [1]. Diabetic nephropathy was the most frequently noted underlying disease among patients who initiated chronic dialysis in 2017, and accounted for 42.5% of these patients [1]. The medical cost of dialysis in Japan is estimated to be as high as 1.6 trillion Japanese yen (approximately US$ 17 billion) per year, which imposes a substantial burden on the national health care system. In Japan, a limited number of drugs are approved for the treatment of CKD, including two renin-angiotensin system (RAS) inhibitors (Nu-Lotan® and T anatril®), which suppress * Hironori Kanda [email protected] 1
Nephrology R&D Unit, R&D Division, Kyowa Kirin Co., Ltd. Otemachi Financial City Grand Cube, 1‑9‑2 Otemachi, Chiyoda‑ku, Tokyo 100‑0004, Japan
urinary protein excretion, and one spherical carbon absorbent (Kremezin®), which lowers the level of uremic toxins. In addition, a selective vasopressin V2 receptor antagonist (Samsca®) was approved in Japan in 2014 as the first drug to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). In many cases, the therapeutic effectiveness of these drugs is limited, and they have been reported to primarily suppress kidney function decline [2–5]. Thu
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