SAFETY OF BARDOXOLONE METHYL IN PEDIATRIC PATIENTS WITH ALPORT SYNDROME IN CARDINAL PHASE 3 TRIAL

Abstract Background and Aims Alport syndrome is a genetic disease accounting for an estimated 3% of children with end-stage kidney disease (ESKD) in the US (USRDS, 2014). Current management recommendations include the use of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with proteinuria, but no specific therapies have been approved for this disease. A Phase 3 study (CARDINAL; NCT03019185) assessed the safety and efficacy of bardoxolone methyl (Bard) in adult and adolescent patients with Alport syndrome. Method CARDINAL was an international, multicenter, double-blind, placebo-controlled, randomized trial. Eligible participants were 12 to 70 years old, had confirmed diagnosis of Alport syndrome, baseline eGFR 30-90 mL/min/1.73 m2 and urinary albumin to creatinine ratio (UACR) ≤ 3500 mg/g. For pediatric patients (12 to < 18 years of age), eGFR was calculated using the Bedside Schwartz equation. Patients were randomized 1:1 to Bard or placebo and were to be followed for up to 104 weeks (2 treatment periods of 48 weeks and 4 weeks off treatment between Weeks 48 and 52). The primary efficacy endpoints were changes from baseline in eGFR in patients randomized to Bard compared to placebo at Week 48 and Week 100. The key secondary endpoints were the off-treatment changes from baseline in eGFR in patients randomized to Bard compared to placebo at Week 52 and Week 104, 4 weeks after withdrawal. Results A total of 23 (15%) pediatric patients were randomized to Bard (n=11) or placebo (n=12). The average age was 15.3 years, mean (± SD) baseline eGFR was 69.9 ± 15.4 mL/min/1.73 m2 and geometric mean (± SE) baseline UACR was 230.9 ± 95.8 mg/g. A total of 19 of 23 (83%) pediatric patients were male, and 14 (61%) patients had X-linked Alport syndrome, while 6 (26%) patients had autosomal disease. Mean (± SD) baseline body weight was 65.5 ± 10.2 kg and 57.8 ± 16.0 kg and baseline height was 171.7 ± 5.9 cm and 166.3 ± 14.9 cm for Bard and placebo patients, respectively. Seventeen (74%) pediatric patients were on RAASi treatment. Treatment of pediatric patients with Bard resulted in a significantly higher mean change from baseline in on-treatment eGFR relative to placebo at Week 100 (13.8 mL/min/1.73 m2; p = 0.017) and higher mean off-treatment eGFR relative to placebo at Week 104 (14.6 mL/min/1.73 m2; p = 0.0035). In pediatric patients treated with Bard, UACR remained generally unchanged relative to baseline at Week 100 (geometric mean ± SE to baseline ratio: 0.7 ± 0.3), while placebo patients had an increase in UACR (geometric mean ± SE to baseline ratio: 2.1 ± 0.9). Pediatric patients generally continued along their baseline growth curves for height and weight in both treatment groups. At Week 100, mean ± SD changes from baseline in body weight were 0.5 ± 3.9 kg and 3.2 ± 3.5 kg and those for height were 1.6 ± 1.4 cm and 4.3 ± 5.1 cm for Bard and placebo patients, respectively. Changes in blood pressure (BP) were similar across treatment groups. As seen in the adult population, treatment with Bard resulted in transient increases in mean aminotransferase levels in pediatric patients that remained below 3 x ULN for a majority (8/11 [73%]) of patients and returned to baseline at Week 104, 4 weeks after drug withdrawal (mean ± SD change from baseline in ALT: 0.4 ± 3.7 U/L; AST: -0.9 ± 5.6 U/L). Increases in ALT did not coincide with increases in total bilirubin and no Hy’s law cases were reported. No serious adverse events (AEs) were reported in pediatric patients treated with Bard and reported AEs were consistent with those observed in previous studies. One placebo-treated pediatric patient and no Bard patients developed ESKD during the trial. Conclusion In CARDINAL, the addition of Bard to RAASi in pediatric patients with chronic kidney disease due to Alport syndrome appeared to preserve kidney function and very importantly from a safety standpoint, was safe and well-tolerated.