Efficacy of bardoxolone methyl for DKD, without increased cardiac risk

Bardoxolone methyl slowed the decline of the estimated glomerular flow rate (eGFR) in patients with diabetic kidney disease (DKD). It did not increase the risk of severe cardiac events, which had been observed in previous trials.

“Bardoxolone methyl is an activator of NRF2 [nuclear factor erythroid-2-related factor 2] and has been shown to continuously increase eGFR calculated by serum creatinine in previous trials, in patients with DKD,” said Dr Tadao Akizawa (Showa University School of Medicine, Japan) [1]. While the phase 2 TSUBAKI trial (NCT02316821) indeed showed increased eGFR, the phase 3 BEACON trial (NCT01351675) was terminated early because of severe cardiac events [2,3].

The current AYAME study was a phase 3, double-blind, placebo-controlled trial that again assessed bardoxolone methyl for DKD. Participants were randomised 1:1 to bardoxolone methyl (n=507) or placebo (n=506). The primary endpoint was time to onset of a ≥30% decline in eGFR from baseline or progression to end-stage kidney disease (ESKD). The key secondary endpoint was time to onset of a ≥40% decline in eGFR or progression to ESKD.

The primary endpoint was met: fewer participants receiving bardoxolone methyl reached a 30% decrease in eGFR or ESKD compared with placebo, and this was statistically significant (30.2% vs 45.3%; HR 0.56; 95% CI 0.45–0.69; P<0.0001). The secondary endpoint was also met: compared with 34.0% of the placebo arm, only 24.1% of bardoxolone methyl-treated participants had either >40% decrease in eGFR or ESKD (HR 0.69; 95% CI 0.55–0.87; P=0.0018).

Severe adverse effects were similar between the bardoxolone methyl and placebo-treated groups. Importantly, no increase was observed in the incidence of cardiac events in the bardoxolone methyl treatment group.

1. Akizawa T, et al. AYAME Study: Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Bardoxolone Methyl in Diabetic Kidney Disease (DKD) Patients. FR-OR110, ASN Kidney Week 2023, 2–5 November, Philadelphia, PA, USA.
2. Nangaku M, et al. Kidney Int Rep. 2020;5(6):879-890.
3. de Zeeuw D, et al. N Engl J Med 2013;369(26):2492-503.

 

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Posted on 28 November, 202328 November, 2023