FP110
A PHASE 2 TRIAL OF THE SAFETY AND EFFICACY OF BARDOXOLONE METHYL IN PATIENTS WITH RARE CHRONIC KIDNEY DISEASES

INTRODUCTION AND AIMS: Chronic kidney diseases (CKD) develop due to multiple pathogenic processes that cause injury to cells, disruption of structure, and reduction of function that eventually lead to development of end-stage renal disease (ESRD). Despite the diverse etiology, CKD share common pathways for tissue damage characterized by prolonged inflammation and oxidative stress, which result in mesangial expansion, glomerulosclerosis, and reduction in effective glomerular filtration surface area, tubular atrophy, and interstitial fibrosis. Bardoxolone methyl (BARD) induces Nrf2 and has been shown to improve kidney function, reduce inflammation, and prevent fibrosis in multiple animal models of kidney injury and disease, including protein and pressure overload. In previous clinical trials that enrolled over 2,600 patients, primarily patients with CKD caused by type 2 diabetes, BARD improved estimated GFR (eGFR) and more importantly, measured GFR, as assessed by inulin clearance. Additionally, initial data from an open-label Phase 2 study indicate that BARD significantly increased eGFR in patients with Alport syndrome through 12 weeks of treatment. The clinical activity of BARD in patients with Alport syndrome and diabetic nephropathy, two diseases with very distinct etiologies (type IV collagen defects versus hyperglycemia, respectively), suggest that the anti-inflammatory and anti-fibrotic effects of BARD may target the common pathways contributing to GFR loss in multiple forms of CKD. As a result, a Phase 2 trial was initiated to test the hypothesis that BARD will improve renal function in patients with four rare forms of CKD.

METHODS: The Phase 2 Trial of the Safety and Efficacy of BARD in Patients with Rare CKD (PHOENIX, NCT03366337) is a multicenter study that will enroll patients into four disease-specific cohorts. The cohorts will include patients with one of the following rare CKD: (I) Diabetic nephropathy secondary to type 1 diabetes (T1D), (II) Biopsy-confirmed IgA nephropathy (IgAN), (III) Biopsy-confirmed focal segmental glomerulosclerosis (FSGS), or (IV) Genetically-confirmed autosomal dominant polycystic kidney disease (ADPKD). Eligible patients will be 18 to 65 years of age with eGFR values between 30 to 90 mL/min/1.73 m² and spot urine albumin/creatinine ratio (UACR) ≤ 2500 mg/g. The trial will be open-label and enroll approximately 100 patients, 25 in each cohort. The starting dose of BARD will be 5 mg and will be escalated to 20 mg (for patients with baseline UACR ≤ 300 mg/g) or to 30 mg (for patients with baseline UACR > 300 mg/g). The primary efficacy endpoint will be the change from baseline eGFR after 12 weeks of treatment. The outcome will be analyzed separately for each rare CKD cohort.

RESULTS: .

CONCLUSIONS: PHOENIX is a Phase 2, open-label trial to test the hypothesis that BARD will increase eGFR in patients with CKD associated with T1D, IgAN, FSGS, and ADPKD.