Following an FDA advisory committee’s guidance in December that unanimously concluded the benefits of Reata Pharmaceuticals Inc.’s bardoxolone methyl do not outweigh the risks in treating a rare kidney disease, the FDA issued the company a complete response letter (CRL).

The CRL, revealed by Plano, Texas-based Reata on Feb. 25, the drug’s PDUFA date, noted the data doesn’t show bardoxolone can effectively slow the loss of kidney function in those with Alport syndrome (AS). The agency wants more evidence “from an adequate and well-controlled study showing a clinically relevant effect.” The FDA also wants evidence of bardoxolone having a clinically relevant effect on the QT interval.

Warren Huff, Reata’s CEO, did not outline what the company’s reaction will be to the CRL other than it will “continue to work with the FDA to confirm our next steps on our Alport syndrome program.”

Bardoxolone is an Nrf2 activator designed to slow the progression of chronic kidney disease (CKD) caused by AS in those 12 years of age and older.

The CRL is deeply reminiscent of the Dec. 8 Cardiovascular and Renal Drugs Advisory Committee discussion. In a briefing document for that meeting, the agency wrote that despite the phase III trial meeting its endpoints, “the FDA review team does not believe the submitted data demonstrate that bardoxolone is effective in slowing the loss of kidney function in patients with AS and reducing the risk of progression to kidney failure.”

There are no approved therapies for AS, while leads to progressive kidney function loss and kidney failure. Some patients eventually lose their hearing and vision.

Much of the December adcom discussion centered around the phase III CARDINAL study of bardoxolone that used as a surrogate endpoint the estimated glomerular filtration rate (eGFR), an endpoint with precedent in other studies resulting in approval of drugs for treating kidney disease.

That endpoint didn’t go quite far enough, according to Aliza Thompson, the FDA’s deputy director of cardiology and nephrology. The surrogate only suggests the clinical benefit, she said, but does not measure it.

Using eGFR, she added, was also troublesome as some drugs can have reversible pharmacodynamic effects on eGFR that could take months to fully manifest. CARDINAL used the eGFR change in a four-week washout period as a secondary endpoint following the last dose at years 1 and 2. Aside from questioning if four weeks was an adequate washout period, FDA reviewers noted that the eGFR changes after year two were measured as early as 14 days after the last dose. The treatment effect was smaller when the 28-day cutoff was used for the analysis window.

Another sticking point was the difference between treatment and control arms narrowed between years one and two. If the drug were effective, the panelists noted, then the narrowing wouldn’t occur.

Reata is also developing bardoxolone to treat autosomal dominant polycystic kidney disease. The company is enrolling for the phase III.

Reata owns exclusive, worldwide rights to develop, manufacture and commercialize bardoxolone, excluding certain indications in some Asian markets, which are licensed to Kyowa Kirin Co. Ltd.

Reata submitted a marketing authorization application to the EMA in October for bardoxolone to treat CKD caused by AS.