Investigators enrolled 227 such patients in a 52-week phase 2b trial, which was randomized, double-blind, and placebo-controlled. All patients were receiving standard of care prior to randomization. Their mean estimated glomerular filtration rate (eGFR) at study entry was 32 mL/min/1.73 m2. About 40% of patients had stage 4 CKD and 34% had macroalbuminuria. Researchers released 24-week data at the American Society of Nephrology’s 43rd Annual Meeting and Scientific Exposition (Renal Week).
At 24 weeks, 60% of patients who received the drug had a decrease in the classification of the severity of their CKD compared with only 17% of patients who received placebo, said lead researcher Pablo Pergola, MD, PhD, Research Director for Renal Associates PA and Clinical Associate Professor of Medicine at the University of Texas Health Science Center at San Antonio.
Bardoxolone methyl is an antioxidant inflammation modifier that activates Nrf2, a master regulator of the antioxidant response, thereby inducing transcription of genes that decrease the level of oxidative stress and suppress important inflammatory mediators.
Patients who received bardoxolone experienced an increase in eGFR beginning as early as four weeks after the start of treatment. Their eGFR continued increasing through week 12 and was sustained through week 24, with a mean increase in eGFR of 10 mL/min/1.73 m2 compared with no change in the placebo arm. Some three quarters of the bardoxolone methyl group had an improvement in eGFR of 10% or more. One quarter had an improvement of 50% or more compared with less than 2% for placebo-treated patients.
The patients with stage 4 CKD had a mean increase in eGFR of 8 mL/min/1.73 m2 at 24 weeks. Those with macroalbuminuria had a mean increase in eGFR of 5.4 mL/min/1.73 m2 compared with a decline of 1.9 mL/min/1.73 m2 among macroalbuminuric patients in the placebo group. These findings showed that treatment was effective in patients with advanced disease and those more likely to progress. The most common adverse events (occurring in more than 10% of patients) believed to be drug related was muscle spasms and nausea, all mild to moderate in intensity.
The increases in eGFR in the treatment group were accompanied by decreases in blood urea nitrogen, serum phosphorus, and uric acid, Dr. Pergola reported.
“These encouraging results suggest that bardoxolone methyl has the potential to change the treatment landscape of chronic kidney disease and offer new hope to these patients and their families,” Dr. Pergola said.
The drug may make it possible to delay onset of end-stage renal disease and to enable patients to discontinue dialysis, he said. Moreover, it is plausible that bardoxolone methyl, via its anti-inflammatory effects, could enable damaged nephrons to heal and thus make improvements in renal function permanent.
He said he expects 52-week data to be presented early this year and a phase 3 study to begin in the first half of 2011.