NKF 2009: Bardoxolone May Improve Renal Function Through Inflammatory Pathways

Bob Roehr

April 06, 2009

April 6, 2009 (Nashville, Tennessee) — Bardoxolone methyl, the first drug in a new class of antioxidant inflammation modulators (AIMs) designed to improve renal function, caught the eye of many attending the National Kidney Foundation 2009 Spring Clinical Meetings. Two posters on the drug were presented here: 1 a study in patients with cancer, and 1 an ongoing study in patients with type 2 diabetes.

Bardoxolone has the potential for application to many diseases characterized by inflammation. But the data are preliminary, the number of patients limited, and it will take years to turn that potential into clinical practice.

The orally available small molecule "mimics endogenous antioxidant systems" in inducing Nrf2, a major regulator of at least 250 antioxidant and detoxification genes at the cellular level, Colin Meyer, MD, explained to Medscape Nephrology. Existing anti-inflammatory agents "limit the initiation of inflammation, but bardoxolone induces the resolution of inflammation."

Dr. Meyer is vice president of product development at Reata Pharmaceuticals, a company created to commercially develop research discoveries made in the University of Texas system.

The compound initially was identified at the National Cancer Institute. A 21-day phase 1 trial in 60 oncology patients showed a favorable response in 49 patients (82%). Serum creatinine levels decreased a mean of 19.3%, and estimated glomerular filtration rate (eGFR) increased a mean of 20.9%. The effect appeared to be greater in patients with established chronic kidney disease (CKD; 13 of 60 patients); in these patients, eGFR increased a mean of 27.6%.

"We noticed that the majority of our patients had improvements in renal function. It turns out that the inflammatory status of the kidney is very underappreciated; the function is highly correlated to the inflammatory status," Dr. Meyer said.

"Surprisingly, in our oncology patients, those with the greater severity baseline disease experienced a more pronounced effect. It is likely because the level of the inflammatory status in the kidneys was higher," he added.

About 20% of patients did not respond to bardoxolone. "We don't know why," Dr. Meyer said. "Perhaps they were noncompliant, or perhaps the inflammatory component was much less involved" with their disease.

Dr. Meyer chose to focus the next trial "on patients who do the worst — patients with type 2 diabetes and kidney disease." The phase 2a dose-ranging study looks at 60 stage 3 and 4 CKD patients with type 2 diabetes. They were randomly assigned to receive 25, 75, or 150 mg/day of bardoxolone in addition to standard therapy for 28 days. The primary end point was the change in eGFR from baseline to the end of the trial.

Interim analysis of 25 patients has shown an overall mean increase in eGFR of 20.5%; the subset of patients with stage 4 CKD experienced a mean increase in eGFR of 36%. Other markers of renal function, such as serum creatinine levels, cystatin C levels, creatinine clearance, blood urea nitrogen scores, phosphorus levels, and uric acid levels, also showed improvement.

The complete analysis will be presented in an oral session at the American Diabetes Association meeting in June.

Dr. Meyer said toxicity has so far not proven to be an issue. Safety studies have dosed cancer patients with up to 1300 mg/day (and twice that dose in monkey studies) without seeing toxicities or adverse effects. The doses in the diabetes/CKD studies are an order of magnitude lower than that.

"The posters are very fascinating, but we have a long way to go," Harold M. Szerlip, MD, a nephrologist at the Medical College of Georgia, in Augusta, told Medscape Nephrology. "Diabetes is the leading cause of end-stage renal disease, and even though we have improved our ability to slow progression, we have a long way to go before we prevent the progression. Any new drug that will help us do that will be positive."

Reata Pharmaceuticals, a start-up biotech company, funded the studies. Dr. Meyer is employed by the company. Dr. Szerlip has disclosed no relevant financial relationships.

National Kidney Foundation 2009 Spring Clinical Meetings: Abstracts 43 and 66.

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