Reata Pharmaceuticals announced that the Phase 3 CARDINAL study of bardoxolone methyl (bardoxolone) in patients with chronic kidney disease (CKD) caused by Alport syndrome met its primary and key secondary endpoints at the end of Year 2. Results showed statistically significant improvements in estimated glomerular filtration rate (EGFR) versus placebo at Week 100 and 104, the primary and secondary endpoints, respectively. Based on these results and following a recently completed pre-NDA meeting with the U.S. FDA, Reata intends to submit an NDA for full marketing approval in the first quarter of 2021. The company also plans to pursue marketing approval outside of the United States, and preparations are underway to file for marketing approval in Europe.
CARDINAL was an international, multi-center, double-blind, placebo-controlled, randomized clinical trial that enrolled 157 patients with Alport syndrome. Patients were randomized 1:1 to bardoxolone or placebo. The primary endpoint for Year 2 of the study was the change from baseline in eGFR after 100 weeks of treatment (end-of-treatment). The key secondary endpoint for Year 2 of the study was the change from baseline in eGFR at Week 104 (four weeks after last dose in second year of treatment).
At Week 100, in the intent-to-treat (ITT) population, which included eGFR values for patients who either remained on or discontinued study drug, patients treated with bardoxolone had a statistically significant improvement compared to placebo in mean change from baseline in eGFR of 7.7 mL/min/1.73 m2. In the modified ITT (mITT) analysis, which assessed the effect of receiving treatment by excluding values after patients discontinued treatment, patients treated with bardoxolone had a statistically significant improvement compared to placebo in mean change from baseline in eGFR at Week 100 of 11.3 mL/min/1.73 m2. At Week 104 (four weeks after last dose in second year of treatment), patients in the ITT population treated with bardoxolone had a statistically significant improvement compared to placebo in mean change from baseline in eGFR of 4.3 mL/min/1.73 m2.
Efficacy was observed across multiple subgroups at Week 100 and Week 104, including pediatric patients and patients with different genetic subtypes of Alport syndrome. The largest treatment effect at Week 104 was observed in the pediatric subgroup where the difference between treatment groups was 14.6 mL/min/1.73 m2. The risk of kidney failure events (defined as end stage kidney disease, confirmed 30% eGFR decline, or confirmed eGFR < 15 mL/min/1.73 m2) was reduced by approximately 50% in bardoxolone-treated patients (9 patients versus 17 patients in placebo).
Bardoxolone was generally reported to be well tolerated in this study, and the safety profile was similar to that observed in prior trials. The reported AEs were generally mild to moderate in intensity, and the most common AEs observed more frequently in patients treated with bardoxolone compared to patients treated with placebo were muscle spasms and increases in aminotransferases.
Reata also reported data from EAGLE, a long-term extension study that included enrollment of eligible patients with Alport syndrome who completed the CARDINAL study. Change from baseline in eGFR was assessed for 14 patients with Alport syndrome who were treated with bardoxolone for three years, with four-week off treatment periods occurring at Weeks 48 and 100. Bardoxolone produced a mean increase from baseline in eGFR of 11.5 mL/min/1.73 m2 at Year 1, 13.3 mL/min/1.73 m2 at Year 2, and 11.0 mL/min/1.73 m2 at Year 3.
About Bardoxolone Methyl
Bardoxolone methyl is an 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.
Orphan Drug designation has been granted by the FDA and European Commission to bardoxolone for the treatment of Alport syndrome.
About Alport Syndrome
Alport syndrome is a rare, genetic form of 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. 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. Alport syndrome affects both children and adults. In patients with the most severe forms of the disease, approximately 50% progress to dialysis by age 25, 90% by age 40, and nearly 100% 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 approved therapies to treat CKD caused by Alport syndrome.