FDA Rejects Reata’s Bardoxolone as Treatment for Chronic Kidney Disease Caused by Alport Syndrome
February 28, 2022
The U.S. Food and Drug Administration issued a Complete Response Letter to Reata Pharmaceuticals, rejecting its New Drug Application for bardoxolone methyl for the treatment of patients with chronic kidney disease caused by Alport syndrome.
Alport syndrome is a rare, genetic form of chronic kidney disease (CKD) caused by mutations in the genes encoding type IV collagen, which is a major structural component of the glomerular basement membrane in the kidney. Alport syndrome 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 chronic dialysis treatment or a kidney transplant. In patients with the most severe forms of the disease, approximately 50 percent progress to dialysis by age 25, 90 percent by age 40, and nearly 100 percent by age 60. According to the Alport Syndrome Foundation, Alport syndrome affects approximately 30,000 to 60,000 people in the United States. There are currently no therapies approved to treat CKD caused by Alport syndrome.
Bardoxolone is an experimental, once-daily, orally administered activator of Nrf2, a transcription factor that induces molecular pathways that promote the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress, and inhibiting pro-inflammatory signaling. The FDA and European Commission have granted Orphan Drug designation to bardoxolone for the treatment of Alport syndrome and autosomal dominant polycystic kidney disease.
In the CRL, the FDA said it cannot approve Reata’s NDA in its present form. Based on its review, the agency 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. Their conclusion was based on efficacy and safety concerns primarily set forth in the FDA’s briefing book and discussed at the Cardiovascular and Renal Drugs Advisory Committee meeting held on December 8, 2021.
The FDA stated that the issues could be resolved by providing evidence of effectiveness that includes evidence from an adequate and well-controlled study showing a clinically relevant effect on the rate of loss of kidney function in patients with Alport syndrome or, alternatively, an effect on a clinical outcome, for example, an endpoint that captures how patients with Alport syndrome feel, function, or survive. In addition, the FDA stated 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.
Reata said the FDA welcomes continued discussion on the details of a path forward and the company plans to work closely with the agency to move bardoxolone to approval.
“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,” said Warren Huff, CEO of Reata Pharmaceuticals.
Reata has submitted regulatory approval requests to the European Medicines Agency and the Japanese Ministry of Health, Labor, and Welfare for bardoxolone for the treatment of CKD/improvement of renal function in patients with Alport syndrome, and these applications are currently under review. Additionally, bardoxolone is currently being studied in FALCON, a phase 3 study for the treatment of CKD caused by ADPKD, EAGLE, an open-label, extended access trial in patients with CKD caused by Alport syndrome who participated in the CARDINAL trial and patients with ADPKD who participated in the FALCON trial, and AYAME, a phase 3 study for the treatment of diabetic kidney disease that is being conducted by Kyowa Kirin in Japan.
Author: Rare Daily Staff
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