Kidney Week

Abstract: FR-OR110

AYAME Study: Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Bardoxolone Methyl in Diabetic Kidney Disease (DKD) Patients

Session Information

• High-Impact Clinical Trials
  November 03, 2023 | Location: Hall A, Pennsylvania Convention Center
  Abstract Time: 11:00 AM - 11:15 AM

Category: Diabetic Kidney Disease

• 702 Diabetic Kidney Disease: Clinical

Authors

• Akizawa, Tadao, Showa University School of Medicine, Tokyo, Japan

Tadao Akizawa,

• Yamawaki, Kengo, Kyowa Kirin Co., Ltd., Tokyo, Japan

Kengo Yamawaki,

• Ichikawa, Tomohiro, Kyowa Kirin Co., Ltd., Tokyo, Japan

Tomohiro Ichikawa,

• Mukai, Kazuya, Kyowa Kirin Co., Ltd., Tokyo, Japan

Kazuya Mukai,

• Nangaku, Masaomi, The University of Tokyo Graduate School of Medicine, Tokyo, Japan

Masaomi Nangaku,

Background

Bardoxolone methyl (BARD) is an activator of the Keap1-Nrf2 pathway. Previous study demonstrated that BARD improves the estimated glomerular filtration rate (eGFR). However, the phase 3 study was terminated prematurely because of an imbalance in heart failure (HF) between BARD and placebo groups. The subsequent phase 2 TSUBAKI study demonstrated no incidence of HF and an improved GFR as determined by inulin clearance in diabetic kidney disease (DKD) patients without the risk factors of HF. We conducted an event-driven study to evaluate the efficacy and safety of BARD in more than 1,000 patients.

Methods

A phase3 (AYAME) study was conducted in DKD patients and comprises a screening period, a treatment period of 3-4 years, and a post-treatment observation period of 16 weeks. Eligible patients had eGFR ≥15.0 - <60 ml/min/1.73m² and urinary albumin creatinine ratio (UACR) ≤3500 mg/g without the risk factors of HF. The primary and the key secondary endpoints were the time to onset of a ≥30% decrease in the eGFR or end-stage kidney disease (ESKD: dialysis, kidney transplantation or eGFR ≤6) and a ≥40% decrease in the eGFR or ESKD, respectively. Other secondary endpoints included the time to onset of ESKD. The safety endpoints were adverse events and time to onset of cardiac events, including HF.

Results

1013 patients were randomized (1:1) to receive BARD or placebo. The mean eGFR (standard deviation, ［SD］) and UACR (SD) at baseline were 37.84 (12.64) ml/min/1.73 m² and 712.39 (834.22) mg/g, and were generally comparable among the groups. The primary outcome occurred in 153 of 507 patients in the BARD group and 229 of 506 patients in the placebo group (hazard ratio (HR), 0.56; 95% CI, 0.45 to 0.69; P<0.001). A key secondary outcome occurred in 122 patients in the BARD group and 172 patients in the placebo group (HR, 0.69; 95% CI, 0.55 to 0.87; P=0.0018). ESKD occurred 69 patients in the BARD group and 62 patients in the placebo group without significant differences (HR, 1.21; 95% CI, 0.86 to 1.71; P=0.2706). Cardiac events occurred 24 events in the BARD group and 26 events in the placebo group, and there were no other safety concerns.

Conclusion

AYAME study achieved its primary and key secondary endpoint without major safety concern, while BARD did not decrease the occurrence of ESKD.

Funding

• Commercial Support – Kyowa Kirin Co.,Ltd.