Novel Anti-Inflammatory Bardoxolone Improves GFR in CKD

Nancy A. Melville

November 24, 2010

November 24, 2010 (Denver, Colorado) — A novel anti-inflammatory drug bardoxolone methyl (Reata Pharmaceuticals) shows efficacy in the treatment of patients with chronic kidney disease (CKD) and may even have the potential to reverse disease progression, according to findings presented here at Renal Week 2010: American Society of Nephrology 43rd Annual Meeting.

Results from week 24 of an ongoing 52-week multicenter placebo-controlled study of 227 patients with either type 2 diabetes or moderate to severe CKD showed a rapid increase in glomerular filtration rate (GFR) in the treatment group; there were no improvements in the placebo group at week 24.

"Bardoxolone treatment was associated with a fairly rapid increase in GFR that was seen as early as 4 weeks, with a continuous increase to up to week 12," Pablo E. Pergola, MD, PhD, lead author of the study, told meeting attendees. "The increase was sustained [and continued to] increase through week 24, where the average increase in GFR was 10.1 mL/min per 1.73 m2, compared with no change in the placebo group."

"We believe these results are very clinically significant," said Dr. Pergola, who is from the University of Texas Health Science Center at San Antonio.

The study also showed that 59% of patients in the bardoxolone group had an improvement in CKD status of at least 1 stage, compared with only 16% of patients in the placebo group.

CKD status dropped at least 1 stage in 14% of patients in the placebo group, but in only 4% of patients in the bardoxolone group. In addition, bardoxolone reduced the number of patients with stage 4 CKD by 50%; there was no change in the placebo group.

Dr. Pergola said that patients in the study had baseline characteristics typical of CKD, including a mean age of 67 years and long-term diabetes; 75% of subjects were obese. Patients had moderate to severe disease, with a mean estimated GFR of 32 mL/min per 1.73 m2.

Thirty-eight percent of subjects had stage 4 CKD, and 62% had stage 3b. Nearly all patients were receiving the standard of care, with 98% taking an angiotensin-converting enzyme (ACE) inhibitor or and angiotensin II receptor blocker. Mean blood pressure was 130/69 mm Hg.

The most common adverse effect was muscle spasms, reported by 49% of patients in the bardoxolone group and 12% in the placebo group; however, Dr. Pergola said, the spasms were transitory.

"The spasms were typically transient and, importantly, there were no markers of muscle damage or increase in pain," Dr. Pergola said. "In general, patients tolerated the drug very well."

Bardoxolone works by targeting Nrf2, a novel anti-inflammatory pathway. The drug has been shown in shorter studies to increase estimated GFR, to decrease blood urea nitrogen, serum phosphorus, and serum uric acid, and to increase creatinine clearance. Dr. Pergola said that 52-week data from the study will be analyzed in January, but added that the 24-week results merit initiation of a phase 3 study.

Session comoderator Rajiv Agarwal, MD, professor of medicine at Indiana University and VA Medical Center in Indianapolis, called the findings encouraging. However, he said, more data, such as the drug's role in end-stage renal disease (ESRD), are needed before the true value of bardoxolone can be determined.

"The finding that this drug can increase GFR is exciting; however, the data are preliminary," cautioned Dr. Agarwal.

"Whether this drug will save kidneys or hurt kidneys in the long term is unknown at present, [and] we will need longer-term studies evaluating the rate of decline in kidney function. Preferably, the more meaningful end point of time to ESRD will be measured."

Dr. Agarwal added that more rigorous testing is needed to determine the risks of the drug's adverse events.

"Cramps and hypomagnesemia were frequent adverse events; their mechanisms are not clear and should be evaluated," he said. "Given that low magnesium concentrations are associated with cardiac arrhythmias and sudden death is common in CKD, it is not a trivial side effect."

The study received support from Reata Pharmaceuticals and Abbott. Dr. Pergola reports a relationship with Reata Pharmaceuticals. Dr. Agarwal has disclosed no relevant financial relationships.

Renal Week 2010: American Society of Nephrology 43rd Annual Meeting: Abstract LB-FC2. Presented November 20, 2010.