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ByMark E. Neumann

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December 15, 2021
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Advisory group recommends FDA not approve drug to treat Alport syndrome

ByMark E. Neumann
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In a unanimous vote, an advisory group recommended the FDA not approve the drug baraxodone ethyl to treat Alport syndrome, citing concerns about results and study design.

The 13-member Cardiovascular and Renal Drugs Advisory Committee met on Dec. 8 to review whether the evidence in Reata Pharmaceuticals Inc.’s CARDINAL phase 3 studies of baraxodone ethyl demonstrated that the drug is effective in slowing the progression of chronic kidney disease in patients with Alport syndrome and that its benefits outweigh its risks.

That determination was difficult to reach, committee members said during the hearing.

“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, said.

The FDA has until Feb. 25 to act on the committee’s vote.

Bardoxolone is a once-daily, orally administered activator “of a critical transcription factor that regulates the expression of over 1,000 genes in the cell under normal and stressed conditions,” according to a press release from Reata Pharmaceuticals. The transcription factor induces molecular pathways “that promote the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress and inhibiting pro-inflammatory signaling,” according to the release.

The FDA has granted orphan drug designation to bardoxolone for the treatment of Alport syndrome and autosomal dominant polycystic kidney disease, the company said.

“We are disappointed with today’s outcome of the committee’s vote regarding bardoxolone, an investigational drug with a novel mechanism of action,” Warren Huff, president and CEO of Reata Pharmaceuticals, said in a statement. “We believe the scientific evidence supports bardoxolone approval in the U.S. for CKD in patients with Alport syndrome, which is one of the most rapidly progressive forms of CKD.

“We will continue to work with the FDA to answer any questions they may have.”

Trade halted

The company halted trade of its common stock on Dec. 8. After the Cardiovascular and Renal Drugs Advisory Committee’s unanimous recommendation to deny approval of the drug, the stock value of the company plunged 46.5%.

Alport syndrome is a genetic form of CKD that affects both children and adults. The kidneys of patients with Alport syndrome progressively lose the capacity to filter waste products out of the blood, which can lead to end-stage kidney disease and the need for dialysis or a kidney transplant.

“In patients with the most severe forms of the disease, approximately 50% progress to dialysis by age 25 [years], 90% by age 40 [years], and nearly 100% by age 60 [years],” according to the Reata release.

Lisa Bonebrake

In response to the advisory group vote, Lisa Bonebrake, executive director of the Alport Syndrome Foundation, told Healio Nephrology the group “recognizes that rare disease drug development is complicated and challenging. While we await the final decision of the FDA on the use of bardoxolone methyl for Alport syndrome, we want to express our gratitude to the patients for fully enrolling this first clinical study, for participating in the advancement of research for the community of patients and families and for so openly sharing their insights and experiences at the advisory committee meeting,” she said.

Preserve kidney function

In a study presented at ASN Kidney Week, bardoxolone methyl preserved kidney function in patients and provided eGFR benefits for those with CKD.

Laura H. Mariani, MD, a nephrologist and clinical researcher in the division of nephrology at the University of Michigan, looked at data pooled from a placebo-controlled set of 2,462 patients in the CARDINAL phase 3 trial, TSUBAKI trial and BEACON trial. Of these patients, 1,232 received placebo and 1,230 received bardoxolone methyl for between approximately 6 months and 2 years.

From between 16 and 100 weeks, the group that received bardoxolone methyl showed statistically significantly increased eGFR rates compared with the placebo group.

"After 4 weeks after drug withdrawal, that difference between the two groups was still statistically significant," Mariani said. "Bardoxolone has an acceptable safety profile, and importantly, since the risk mitigation strategy was implemented, there have been no serious cardiac failure events reported with bardoxolone-treated patients who have CKD," Mariani said.

References:

  • Meeting of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC). FDA.                   www.youtube.com/watch?v=ljTHjAcHbls. Published Dec. 8, 2021. Accessed Dec. 14, 2021.
Sources/Disclosures

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