MP142
A PHASE 2/3 STUDY OF THE EFFICACY AND SAFETY OF BARDOXOLONE METHYL IN PATIENTS WITH ALPORT SYNDROME

INTRODUCTION AND AIMS: Alport syndrome is a rare and serious hereditary disease, for which there are no approved therapies, that is caused by mutations in the genes encoding type IV collagen. The genetic defect results in structural deficits of the glomerular basement membrane, resulting in proteinuria. Like other forms of chronic kidney disease (CKD), excessive filtration and tubular reabsorption of protein in Alport syndrome induces oxidative stress, renal interstitial inflammation and fibrosis, promoting loss of kidney function. Bardoxolone methyl (BARD) and related analogs improve renal function, reduce inflammation, and prevent fibrosis in multiple animal models of renal injury and disease, including protein and pressure overload. In previous studies that enrolled over 2,600 patients, including primarily patients with CKD caused by type 2 diabetes, BARD improved eGFR and inulin clearance. The eGFR increases were sustained through one year of treatment and partially retained four weeks after drug cessation, suggesting disease-modifying activity. BARD was generally well tolerated, except for fluid overload occurring in a subset of Stage 4 CKD patients with known risk factors for heart failure. BARD may therefore slow progression of kidney disease and prevent GFR loss in patients with Alport syndrome. As a result, a Phase 2/3 trial was initiated to test the hypothesis that bardoxolone methyl will improve renal function in patients with Alport syndrome.

METHODS: The Phase 2/3 trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome (CARDINAL NCT03019185) is a multinational, multicenter study that will enroll patients on stable RAAS blockade, ages 12 to 60 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR values between 30 to 90 mL/min/1.83 m², and albumin to creatinine ratios < 3500 mg/g. The Phase 2 portion of the trial will be open-label and enroll up to 30 patients; the Phase 2 primary efficacy endpoint will be the change from baseline in eGFR after 12 weeks of treatment. The Phase 3 portion of the trial will be double-blind, randomized, placebo-controlled, enroll up to 180 patients, and the primary efficacy endpoint will be the change from baseline in eGFR in BARD-treated patients relative to placebo after 48 weeks of treatment. The key secondary endpoint will be the change from baseline in eGFR in BARD-treated patients relative to placebo at Week 52 following a 4-week drug treatment withdrawal period. All patients enrolled in the study will be followed for two years.

RESULTS: -

CONCLUSIONS: CARDINAL is the first large scale trial to test the hypothesis that BARD will reduce the progression of CKD in patients with Alport syndrome.