FDA: More studies needed to show bardoxolone reduces risk for ESKD
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The FDA has told Reata Pharmaceuticals Inc. that it needs to conduct further studies to show its treatment for Alport syndrome is effective in slowing the progression of kidney disease, according to a company press release.
Reata said on Feb. 25 that it received a Complete Response Letter from the FDA regarding its New Drug Application for bardoxolone methyl for the treatment of chronic kidney disease in patients with Alport syndrome, a genetic form of chronic kidney disease found in adults and children caused by gene mutations.
“Based on its review, the FDA concluded that it does not believe the submitted data demonstrates that bardoxolone is effective in slowing the loss of kidney function in patients with Alport syndrome and reducing the risk of progression to kidney failure and has requested additional data to support the efficacy and safety of bardoxolone,” according to a company press release.
“This outcome is a significant disappointment for our company, as well as the many patients, families and investigators who have participated in our development program for bardoxolone in Alport syndrome patients. We will continue to work with the FDA to confirm our next steps on our Alport syndrome program,” Warren Huff, Reata’s CEO, said in the release.
The FDA also said in the letter that Reata would “need to address whether bardoxolone has a clinically relevant effect on the QT interval and show that the demonstrated clinical benefits of bardoxolone outweigh its risks.”
Committee review
Huff said during a fourth quarter earnings call on Feb. 28 that he believed the decision by the FDA to not approve the drug was based mainly on the agency’s Cardiovascular and Renal Drugs Advisory Committee review of bardoxolone held in December 2021.
In a unanimous vote, the 13-member advisory group recommended the FDA not approve the drug, citing concerns about results and design of the company’s CARDINAL phase 3 studies.
“In reviewing the totality of the data, it is not sufficient to provide assurance that we are providing the patient a therapy that would promise efficacy,” Julia B. Lewis, MD, chair of the Cardiovascular and Renal Drugs Advisory Committee and professor of medicine in the division of nephrology at Vanderbilt University School of Medicine, concluded after the vote.
The FDA previously granted Orphan Drug designation to bardoxolone for the treatment of Alport syndrome and autosomal dominant polycystic kidney disease.
Huff said he didn’t believe members of the committee were convinced that the CARDINAL studies showed that a reduction of eGFR — the main intent of bardoxolone — led to a reduction in the number of patients who progressed to kidney failure. “A decline in eGFR is real and measurable, but is not considered a clinical endpoint,” Huff said during the earnings call. “I believe the committee was not convinced that the improvements in eGFR would translate into a real reduction in the risk of dialysis or kidney transplant.
“Without actual outcomes data, questions could be raised about on and off treatment eGFR trajectories over time” and lead to questions about whether kidney failure would be prevented, Huff said.
New study data
During the earnings call, Colin Meyer, MD, Reata’s chief innovation officer, provided details on a Phase 3 study being conducted in Japan by Kyowa Kirin, the company’s partner in developing bardoxolone to treat patients with diabetic kidney disease. The primary endpoint of the double-blind, placebo-controlled, registrational trial is time to onset of greater than or equal to a 30% decline in eGFR, or end-stage kidney disease, Meyer said. The eligibility criteria are patients with eGFR 15 and < 60 mL/min/1.73 m2 and patients who are aged 20 to 79 years with no history of heart failure.
To date, more than 1,000 patients are enrolled in the trial, and Meyer said Kyowa Kirin expects the last patient visit for collecting clinical data would be in the second half of 2022.
“If this trial is positive and demonstrates that bardoxolone reduces kidney failure events without major safety concerns, we believe these data will be very helpful in supporting our ongoing nephrology programs that show this drug can be used safely and be multi-beneficial over the long term,” Meyer said during the call.
Huff said Reata has requested a meeting with the FDA to discuss details of the Kyowa Kirin trial.
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