A Non-purine Xanthine Oxidoreductase Inhibitor Reduces Albuminuria in Patients with DKD: A Randomized Controlled Trial

Background: Diabetic kidney disease (DKD) is characterized by albuminuria and reduced renal function. Whether or not xanthine oxidoreductase inhibitors (XORIs) have a renoprotective effect in DKD patients with type 2 diabetes remains controversial. We conducted a proof-of-concept study to investigate the renal effects of a novel XORI, TMX-049, in patients with DKD and type 2 diabetes. Methods: This is a multicenter, 12-week, randomized, double-blind, placebo-controlled phase 2a trial conducted at 49 centers across the United States between April 2018 and June 2019. In total, 130 patients with type 2 diabetes, urine albumin-to-creatinine ratio (UACR) 200-3000 mg/g, estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m2, and serum uric acid (sUA) 4-10 mg/dL were randomized 1:1:1 to TMX-049 200 mg (n=44) or 40 mg (n=44), or placebo (n=42). The primary endpoint was change in log-transformed UACR at Week 12 from baseline. The secondary endpoints included changes in UACR, eGFR, and sUA from baseline. Results: The least square mean differences for changes in log-transformed UACR from baseline to Week 12 compared to placebo were -0.43 (95% confidence interval [CI], -0.82--0.04, P=0.03) for TMX-049 200 mg and -0.05 (95% CI, -0.44-0.34, P=0.8) for 40 mg; a 35% reduction in UACR was observed with TMX-049 200 mg (ratio versus placebo, 0.65; 95% CI, 0.44-0.96) but not 40 mg (0.95; 95% CI, 0.64-1.41). Throughout the treatment period, marked reductions in sUA levels but no changes in eGFR were observed with both TMX-049 doses. TMX-049 was generally well-tolerated, although 2 patients with TMX-049 200 mg developed gout. Conclusions: TMX-049 200 mg reduced albuminuria at 12 weeks in patients with DKD and type 2 diabetes. TMX-049 may exert a renoprotective effect independent of its sUA-lowering effect.