Rare Daily Staff
Reata Pharmaceuticals reported that the phase 3 portion of a study of bardoxolone treatment in patients with chronic kidney disease caused by Alport syndrome met its primary and key secondary endpoints.
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 patients experience a progressive loss in the kidney’s capacity to filter waste products out of the blood that can lead to end stage kidney failure (ESKD) and the need for chronic dialysis treatment or a kidney transplant. A majority of patients with Alport syndrome develop ESKD, and approximately 50 percent of patients with the most severe form of the disease require dialysis or a kidney transplant by the age of 25. According to the Alport Syndrome Foundation, Alport syndrome affects approximately 30,000 to 60,000 people in the United States. There are currently no approved therapies to treat Alport syndrome.
Bardoxolone methyl is an experimental, oral, once-daily 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 phase 3 portion of the CARDINAL study is an international, multi-center, double-blind, placebo-controlled, randomized registrational trial that enrolled 157 patients with Alport syndrome. Pediatric patients represented approximately 15 percent of enrolled patients. Patients were randomized 1:1 to bardoxolone or placebo. The primary endpoint for the study was the change in the estimated glomerular filtration rate (eGFR), an important measure of the ability of the kidney to filter waste products out of the blood, after 48 weeks of treatment. The key secondary endpoint for the study was the change in the retained eGFR after 48 weeks of treatment and four weeks of drug withdrawal.
After 52 weeks, patients who completed the first 48 weeks of treatment are restarted on study drug with their original treatment assignments and continue on study drug for a second year. The second-year on-treatment eGFR will be measured after 100 weeks of treatment and the retained eGFR will be measured at week 104 after withdrawal of drug for four weeks.
The study results showed that patients treated with bardoxolone had a statistically significant improvement compared to placebo in mean estimated glomerular filtration rate (eGFR) after 48 weeks of treatment. After treatment and a four-week withdrawal period, patients treated with bardoxolone had a statistically significant improvement compared to placebo in mean retained eGFR. Bardoxolone treatment was generally reported to be well-tolerated and showed a similar safety profile to the phase 2 portion of the study. Based on these positive results, and subject to discussions with regulatory authorities, Reata plans to proceed with the submission of regulatory filings for marketing approval in the United States and internationally.
“The first year results from the CARDINAL study are very promising. This provides hope to the entire Alport syndrome community that we could finally have the first therapy to treat this rare, genetic kidney disease,” said Lisa Bonebrake, Executive Director of the Alport Syndrome Foundation.
“Patients living with Alport syndrome experience a severe and progressive loss of kidney function that can lead to the need for chronic dialysis treatment or a kidney transplant in the prime of their lives. The CARDINAL trial of bardoxolone is the first study in which a therapy halted the progression of chronic kidney disease in patients with Alport syndrome,” said Warren Huff, Reata’s president and CEO.
The U.S. Food and Drug Administration and the European Commission have granted Orphan Drug designation to bardoxolone for the treatment of Alport syndrome.
Photo: Warren Huff, president and CEO of Reata Pharmaceuticals