麻豆传媒

An emotional FDA advisory panel on Wednesday unanimously rejected bardoxolone methyl as a treatment for chronic kidney disease (CKD) caused by Alport syndrome, a rare genetic disease that typically leads to renal failure.

By a tally of 13-0, the voted against recommending the drug for approval in individuals ages 12 and up, citing a combination of trial flaws and safety signals from the phase III CARDINAL study -- the primary support for the proposed indication -- in tipping the benefit-harm scale toward the latter.

"The totality of data, including the preclinical data from diabetics and the data within the CARDINAL study, is not sufficient to be assured that we would be providing patients with an effective therapy that would not actually cause harm," said committee chair Julia Lewis, MD, of Vanderbilt Medical Center in Nashville.

David Moliterno, MD, of the University of Kentucky Medical Center in Lexington, called it an "emotionally charged meeting."

"It bothered me that we might be trading one benefit for two problems," he said, alluding to some of the drug's safety issues. "I wanted to give [the sponsor] a pass, but just couldn't."

Bardoxolone acts as a nuclear factor erythroid 2-related factor 2 (Nrf2) activator. The oral triterpenoid cytoprotective agent binds to Kelch-like ECH-associated protein 1, and is able to cut back on inflammation and fibrosis in the kidney to bolster functioning in patients with CKD, according to sponsor Reata Pharmaceuticals.

Nearly every panel member referenced the inadequate trial design in part for the reasoning behind their "No" vote. One of the most highly cited problems was that the developer used estimated glomerular filtration rate (eGFR) as a proxy measure for kidney failure. Although the 157-participant did in fact meet its primary endpoints -- increasing eGFR at weeks 48 and 100 of treatment -- many said they weren't convinced that this was actually reflective of a true slowing in the progression of kidney function decline. The study included 4-week washout periods (weeks 48-52 and 100-104) where no drug was given.

"We need to have data with a larger time off of treatment to be able to see a sustained effect of the medication after the acute pharmacodynamic effect has worn off," said Paul Palevsky, MD, of the University of Pittsburgh School of Medicine.

He also suggested that he would personally need to see at least one other marker of kidney function in addition to what was included in the trial. Echoing this, other panel members suggested the sponsor measure actual GFR or cystatin C in addition to eGFR.

Other trial design concerns rattled off by the chorus of panel members included excluded data and the differential rates of treatment discontinuation.

Lewis pointed out that even despite these "troubling" concerns, it might have still been possible to overlook them if it weren't for several safety signals that popped up during the trial. Some of these safety concerns included albuminuria, heightened blood pressure, and weight loss in kids.

"I might've given it the benefit of the doubt given the orphan drug status and the lack of any Alport-specific therapies...but that's nullified by the intended effect of the proteinuria and increased blood pressure -- two conditions that have overwhelming evidence that link them to progression of kidney disease," commented Gregory H. Gorman, MD, MHS, of the Uniformed Services University in Bethesda.

C. Noel Bairey Merz, MD, of Cedars-Sinai Medical Center, said she voted 'no' not because of lack of efficacy, but instead because she was "very concerned" about the elevation seen in urine albumin-creatinine ratio. "Understanding that the target audience is relatively young, I think that's an unacceptable safety signal," she stated.

Despite this collective thumbs down for bardoxolone, one connecting theme nearly all panel members touched on was how desperately a new Alport syndrome treatment is needed. With no other available treatments on the market currently indicated for this condition, the panel encouraged Reata to forge ahead with further testing of the drug.

"I know what it's like to see a parent look at a diagnosis -- I've been there and it's tough," patient representative and temporary voting member Paul Conway, president of the American Association of Kidney Patients in Virginia, said while choking back tears. "I hope that the patients and the applicant keep going because I think there is some optimism here and a path forward."

Many suggestions were made in regards to a future bardoxolone trial that might more likely lead to a regulatory approval. Some of these recommendations included using a larger patient population that would also be restricted to pediatric patients who are experiencing a more rapid decline in eGFR, all paired with a trial design that allows for a longer washout period off treatment.

Although the FDA is not required to follow its advisory committees' recommendations, it typically does.

Comment