Safety Profile of Tozorakimab (an Anti-IL-33 Monoclonal Antibody): Data from the FRONTIER Phase 2 Program of 1076 Patients

Rationale: Interleukin (IL)-33 exists in both a reduced (IL-33red) and oxidized form (IL-33ox). Dysregulation is implicated in a range of inflammatory diseases. The FRONTIER program comprises four phase 2 signal-finding studies of tozorakimab, a human anti-IL-33 immunoglobulin G1 monoclonal antibody, in diabetic kidney disease (DKD; FRONTIER-1, NCT04170543), moderate-to-severe atopic dermatitis (AD; FRONTIER-2, NCT04212169), moderate-to-severe asthma (FRONTIER-3, NCT04570657) and moderate-to-severe chronic obstructive pulmonary disease with chronic bronchitis (COPD; FRONTIER-4, NCT04631016). Methods: FRONTIER 1-4 were randomized, double-blind, placebo-controlled, parallel-group studies to evaluate the efficacy, safety, pharmacokinetics and immunogenicity of tozorakimab in adults. Tozorakimab or matched placebo was administered subcutaneously every 4 weeks for 4-7 doses and patients were monitored for 24-36 weeks from the first dose. Tozorakimab doses varied across the studies (FRONTIER-1 [DKD], 30-300 mg; FRONTIER-2 [AD], 60-600 mg; FRONTIER-3 [asthma], 300-600 mg; FRONTIER-4 [COPD and chronic bronchitis], 600 mg). This analysis assessed the safety and tolerability of tozorakimab versus placebo across all four FRONTIER studies, with a focus on adverse events of special interest including heart failure- (HF) related adverse events. HF was studied as an adverse event of special interest (AESI) because soluble ST2, a decoy receptor for IL-33, has been described as a prognostic serum biomarker for HF.1Results: A total of 1076 patients were included in this safety analysis (tozorakimab, n=738; placebo, n=338). Deaths were only reported in one study (FRONTIER-1 [DKD]) and occurred in similar proportions for both tozorakimab and placebo. No deaths were attributed to tozorakimab. The proportion of patients with treatment-emergent adverse events (TEAEs) and serious TEAEs was generally similar between treatment groups within each trial. The frequency of injection site reactions was higher for patients treated with tozorakimab than for placebo (tozorakimab, 1.2-20.9%; placebo, 0.0-4.9%; Table). The proportion of patients who experienced an adverse event in the AESI category of HF was low (tozorakimab, 0.0-1.5%; placebo, 0.0-0.8%; Table) with no meaningful differences between the groups. The occurrence of anti-drug antibodies was also low across the studies. Tozorakimab showed target engagement and pharmacological activity through reduction in blood eosinophils across all four studies. Conclusions: Across all four FRONTIER studies, tozorakimab was well tolerated with no safety concerns identified. Several phase 3 studies are ongoing for tozorakimab in COPD (NCT05166889, NCT05158387, NCT06040086 and NCT05742802) and severe viral lower respiratory tract disease (NCT05624450). 1 Kakkar R, et al. Nat Rev Drug Discov. 2008;7:827-40.