Inhibition of Interleukin-33 in Diabetic Kidney Disease

Background: In patients with type 2 diabetes and chronic kidney disease, elevated inflammatory biomarkers are associated with adverse kidney outcomes. Interleukin-33 (IL-33) contributes to glomerular endothelial inflammation in diabetic kidney disease (DKD). This study evaluated the therapeutic potential of tozorakimab, an IL-33-neutralizing monoclonal antibody, 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/1.73 m 2 , urinary albumin-to-creatinine ratio (UACR) of 100–3,000 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 24 weeks. All participants received dapagliflozin during Days 85–168. The primary endpoint was UACR change on treatment from baseline to Day 169 (per protocol population). Exploratory endpoints included inflammatory biomarkers linked to IL-33 activity. Results: Among 558 randomized participants (mean age 67 years, 30% female, mean eGFR 48 mL/min/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 CCL2 levels were significantly decreased by 29% with the 300 mg dose (two-sided 90% CI, 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 to placebo in patients with DKD over 24 weeks.