ASN: Drug Improves Kidney Function in Diabetics

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ASN: Drug Improves Kidney Function in Diabetics
   
   By Charles Bankhead, Staff Writer, MedPage Today
November 21, 2010
   
   MedPage Today Action Points

    * Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


    * Discuss with patients that preliminary data from a recent multicenter placebo-controlled trial indicated that a novel anti-inflammatory drug significantly improved estimated glomerular filtration rate in patients with type 2 diabetes and chronic kidney disease.

   
   Review

DENVER -- A novel anti-inflammatory drug significantly improved estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes and chronic kidney disease (CKD), results of a multicenter placebo-controlled trial showed.

The phase II trial, involving more than 200 patients, found those treated with bardoxolone methyl had a mean improvement in eGFR of 10.1 mL/min/1.73 m2 after six months compared with 0.1 mL/min/1.732 m2 in the placebo group (P<0.0001), Pablo E. Pergola, MD, PhD, of the University of Texas Health Science Center at San Antonio, and colleagues, reported.

Almost four times as many bardoxolone-treated patients had an improvement in CKD stage compared with placebo.

"Bardoxolone was generally well tolerated," Pergola said during a news briefing here at the American Society of Nephrology meeting.

"The 52-week data will be analyzed in January, but these results merit initiation of a phase III study, and that has already begun. The trial will measure other important clinical outcomes in CKD in addition to those evaluated in this trial," Pergola added.

An estimated 26 million Americans have CKD, which confers a high risk of dialysis, cardiac events, and death, as GFR declines. Currently available therapies slow, but do not reverse disease progression, said Pergola.

Bardoxolone is a novel anti-inflammatory drug that targets the Nrf2 anti-inflammatory pathway. Preliminary clinical studies showed improvement in eGFR and creatinine clearance, and reductions in blood urea nitrogen, serum phosphorus, and serum uric acid in patients with diabetic kidney disease.

On the strength of the early results, investigators at 41 U.S. centers conducted a phase II, placebo-controlled study of bardoxolone in patients with type 2 diabetes and moderate to severe CKD (stage 3b to 4, eGFR 20 to 45 mL/min/1.73 m2).

The patients were randomized to placebo or to one of three doses of bardoxolone (25, 75, or 150 mg). The primary endpoint was change in eGFR at 24 weeks, which included a pooled analysis of the three bardoxolone groups.

Investigators randomized 227 patients, who typified individuals with diabetic kidney disease, said Pergola. The patients had a mean age of 67, a mean diabetes duration of 18 years, and 75% were obese. Baseline eGFR averaged 32 mL/min/1.73 m2.

All patients were on standard care for diabetes and CKD at baseline, including treatment with an ACE inhibitor or angiotensin receptor blocker, Pergola continued. Baseline hemoglobin A1c averaged 7.2%, and the mean blood pressure was 130/69 mm Hg.

In addition to meeting the primary endpoint, the trial results showed that 59% of bardoxolone patients had improvement in CKD stage compared with 16% of the placebo group (P<0.001).

Three-fourths of the bardoxolone patients had at least 10% improvement in eGFR, including 25% who had improvement of 50% or greater. In contrast, 2% of patients in the placebo group had 50% or greater improvement (P<0.001).

At baseline 38% of the bardoxolone group had stage 4 CKD, which was reduced by 50% by week 24.

Adverse events occurred more often in the bardoxolone patients. Notable differences included muscle spasms (49% versus 12%), nausea (19% versus 4%), hypomagnesemia (18% versus 4%), and decreased appetite (15% versus 2%). Most adverse events were mild or moderate in severity.

"These encouraging results suggest that bardoxolone methyl has the potential to change the treatment landscape of chronic kidney disease," Pergola said in a statement following his presentation at a late-breaking clinical trial session.

The study was supported by Reata Pharmaceuticals and Abbott.

Pergola disclosed a relationship with Reata Pharmaceuticals.
Primary source: American Society of Nephrology
Source reference:
Pergola PE, et al "Effect of bardoxolone methyl on renal function in patients with chronic kidney disease and type 2 diabetes mellitus" ASN 2010; Late-breaking clinical trial.
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