New Findings Confirm Bardoxolone's Efficacy
PRAGUE—Therapy with bardoxolone, an oral antioxidant inflammation modulator, is associated with improved kidney function out to one year in patients with advanced chronic kidney disease (CKD) and type 2 diabetes, according to investigators.
David Warnock, MD, Professor of Medicine at the University of Alabama in Birmingham, reported the results of the phase 2b, double-blind, placebo-controlled Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM) trial at the 48th Congress of the European Renal Association-European Dialysis and Transplant Association.
Improvements in estimated glomerular filtration rate (eGFR) at 52 weeks in the BEAM trial were consistent with six-month data presented last year at the American Society of Nephrology annual meeting. The latest results, published today online by the New England Journal of Medicine (www.nejm.org), suggest that the drug may be useful for the treatment of CKD.
The trial randomly assigned 227 adults with type 2 diabetes and an eGFR of 20-45 mL/min/1.73 m2 equally to placebo or to one of three doses of bardoxolone: 25, 75, or 150 mg once daily. All patients also received standard of care, an ACE inhibitor or angiotensin-receptor blocker unless they could not tolerate them. The trial's primary endpoint was the change in eGFR from baseline with bardoxolone compared with placebo at 24 weeks. The change at 52 weeks was a secondary endpoint.
The treatment groups were well matched at baseline and had a mean age of 67 years, a mean eGFR of 32.4 mL/min/1.73 m2, diabetes duration of approximately 18 years, and a body mass index of about 35.0 kg/m2. Blood glucose levels and blood pressure were generally well controlled.
Superior eGFR at 52 weeks
Patients' eGFR increased within one month of starting the drug, peaked at 12 weeks, and was relatively stable through 52 weeks, Dr. Warnock reported. At 24 weeks, all doses of bardoxolone were associated with a statistically significant increase in eGFR compared with placebo. The 75 mg dose produced significantly greater improvement in eGFR compared with the 25 mg dose, but there was no significant difference between the groups on 75 or 150 mg of bardoxolone.
At 52 weeks, every dose of bardoxolone was associated with more improvement in eGFR compared with placebo, which produced no significant improvements at 24 or 52 weeks compared with baseline. At 52 weeks, the 25, 75, and 150 mg doses were associated with increases in eGFR of 5.8, 10.5, and 9.3 mL/min/1.73 m2, respectively. Earlier in the study, at 24 weeks, fewer patients (2%) in the combined bardoxolone groups showed a significant eGFR reduction of 25% or more compared with the placebo group (13%).
Four weeks after the last administration of the drug (56 weeks), eGFR improvements persisted in the bardoxolone groups although at a lower level than during active treatment. Dr. Warnock pointed out that “the greater the beneficial effect on therapy, the greater the persisting effect four weeks after the drug was withdrawn.” He said this finding of a persistent effect, especially in patients with the greatest increases in eGFR, suggests that the drug probably did not just cause hyperfiltration and did not appear to cause any kidney injury. Measurements of markers of inflammation were not available at the time of the presentation. Laboratory parameters of blood urea nitrogen, serum phosphorus, uric acid, and magnesium, however, all decreased in the bardoxolone groups compared with placebo at both 24 and 52 weeks, and their levels inversely correlated with the increase in eGFR.
The most common adverse effect for the bardoxolone-treated patients was muscle spasms, which were generally mild and dose related. Hypomagnesemia, mild increases in aminotransferase levels, and gastrointestinal effects also were observed.
Reata Pharmaceuticals, the developer of bardoxolone, along with its partner, Abbott, today announced the start of a multinational pivotal phase 3 trial of bardoxolone with an aim of recruiting 1,600 patients. It will use a 20 mg reformulated version of the drug. The trial is expected to take two years to complete.