Inhibition of IL-33 in Diabetic Kidney Disease

KEY POINTS: In 558 adults with type 2 diabetes and CKD, inhibition of IL-33 by tozorakimab was well tolerated. IL-33 signaling was blocked at all doses, eosinophil counts decreased, and urinary CC-chemokine ligand 2 decreased at the high dose versus placebo. No significant differences in urinary albumin-creatinine ratio were observed between placebo and tozorakimab on top of standard of care. BACKGROUND: In patients with type 2 diabetes and CKD, elevated inflammatory biomarkers are associated with adverse kidney outcomes. IL-33 contributes to glomerular endothelial inflammation in diabetic kidney disease (DKD). This study evaluated the therapeutic potential of tozorakimab, an IL-33-neutralizing mAb, in DKD. METHODS: FRONTIER-1 ( NCT04170543 ) was a phase 2b, randomized, double-blind, placebo-controlled trial including adults with type 2 diabetes, an eGFR of 25-75 ml/min per 1.73 m 2 , urinary albumin-creatinine ratio (UACR) of 100-3000 mg/g, and maximally tolerated renin-angiotensin-aldosterone system blocker therapy. Participants received tozorakimab (30, 60, 120, or 300 mg) or placebo every 28 days for 168 days. All participants received dapagliflozin during days 85-168. The primary end point was UACR change on treatment from baseline to day 169 (per-protocol population). Exploratory end points included inflammatory biomarkers linked to IL-33 activity. RESULTS: Among 558 randomized participants (mean [SD] age 67 [10] years, 30% female, mean [SD] eGFR 48 [15] ml/min per 1.73 m 2 , geometric mean UACR 460 mg/g), tozorakimab ( N =425) was well tolerated with no safety concerns identified. In the per-protocol population ( N =465), IL-33 signaling was inhibited by >95% across all doses, eosinophil counts decreased by >19%, and urinary CC-chemokine ligand 2 levels were significantly decreased by 29% with the 300 mg dose (two-sided 90% confidence intervals, 14% to 42%) versus placebo. However, no statistically significant differences in UACR were observed between placebo (-22%) and treatment (-23% to -25%). CONCLUSIONS: Tozorakimab effectively inhibited IL-33 signaling but did not reduce UACR compared with placebo in patients with DKD over 24 weeks. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT04170543.