Phase 2 clinical trial data published online in The New England Journal of Medicine show that patients with moderate to severe chronic kidney disease and type 2 diabetes receiving bardoxolone methyl for 52 weeks experienced a sustained improvement in kidney function throughout the treatment period, as measured by estimated glomerular filtration rate (eGFR). The data were also presented at the 2011 European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress in Prague, Czech Republic.
The Phase 2 dose-finding clinical trial, known as the BEAM study, showed that in patients with moderate to severe chronic kidney disease – defined by an eGFR of 20 to 45 mL/min/1.73m2 – and type 2 diabetes, eGFR at 52 weeks was significantly improved with bardoxolone methyl treatment by up to 10.5 mL/min/1.73m2 in patients receiving 75 mg (p<0.001).
“The published data for bardoxolone methyl suggest that it may have potential to delay kidney disease progression in patients with compromised kidney function,” said Dr. David Warnock of the University of Alabama at Birmingham, who presented the findings at the ERA-EDTA session and is the senior author of the article. “Further study to learn more about the clinical benefits of this drug candidate is warranted.”
The multi-center, double-blind, placebo-controlled trial enrolled 227 patients who were randomly assigned to receive placebo, 25, 75 or 150 mg of bardoxolone methyl orally, once daily for 52 weeks.
Specifically, the 52-week data showed:
• At 52 weeks, patients receiving each of the three tested doses of bardoxolone methyl experienced a statistically significant improvement in eGFR, an important measure of kidney function. Increases were 5.8, 10.5 and 9.3 mL/min/1.73m2 for the 25, 75 and 150 mg groups, respectively, relative to placebo (p=0.002, 25 mg; p<0.001, 75 mg and 150 mg). This is consistent with what was observed at week 24 (the primary endpoint), when all treatment groups showed statistically significant improvement in eGFR with increases of 8.2, 11.4, and 10.4 mL/min/1.73m2 at 25, 75 and 150 mg, respectively.
• The most common adverse event associated with the bardoxolone methyl-treated group was muscle spasm (with incidence rates of 42%, 61% and 59% in the 25, 75 and 150 mg dose groups vs. 18% in the placebo group). Other adverse events more common to bardoxolone methyl-treated patients were transient elevations in liver enzymes, nausea, decreased appetite and hypomagnesemia.
• Nineteen percent of patients treated with placebo experienced a decline in eGFR (loss in kidney function) of more than 25% over 52 weeks, compared to 9% of bardoxolone methyl-treated patients (p=0.058).
• A statistically significant reduction in uric acid was also observed (p=0.026, 25 mg; p<0.001, 75 mg and 150 mg). Improvement was also seen in another important measure of kidney function, reduction in blood urea nitrogen (BUN), though this reduction did not reach statistical significance.
• Four weeks after study drug withdrawal, eGFR remained above baseline in each bardoxolone methyl-treated group, although this did not meet statistical significance, while patients on placebo experienced a modest decline.
“Chronic kidney disease and dialysis place enormous financial and social burdens on our society,” said Paul Audhya, M.D., Chief Medical Officer at Reata. “If these study results are confirmed in a Phase 3 clinical outcome study, bardoxolone methyl may prove to have a positive impact on the health of patients suffering from a debilitating disease, while potentially reducing the costs associated with its progression.”
“The Phase 2 data we have seen showing sustained improvements in eGFR are very encouraging,” said Eugene Sun, M.D., Vice President, Global Pharmaceutical Research and Development, Abbott. “These results set the stage for our Phase 3 program for bardoxolone methyl, which will evaluate whether it is possible to delay or prevent progression to dialysis.”
Date: June 24, 2011
Filed Under: Drug Discovery