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

Abstract

Rationale: Interleukin-33 (IL-33) is a key orchestrator of broad-spectrum downstream host-response mechanisms, including inflammation, tissue homeostasis, and repair. Dysregulation of IL-33 signaling is associated with several pathological conditions. The FRONTIER program comprised four phase 2 signal-finding studies of tozorakimab, an anti-IL-33 human immunoglobulin G1 monoclonal antibody, in diabetic kidney disease (FRONTIER-1), moderate-to-severe atopic dermatitis (FRONTIER-2), moderate-to-severe asthma (FRONTIER-3), and moderate-to-severe chronic obstructive pulmonary disease and chronic bronchitis (FRONTIER-4). This analysis assessed the safety data from these clinical studies.

Methods: FRONTIER-1-4 were randomized, double-blind, placebo-controlled studies evaluating the efficacy, safety, pharmacokinetics, and immunogenicity of tozorakimab in adults. Participants received subcutaneous tozorakimab (FRONTIER-1, 30-300 mg; FRONTIER-2, 60-600 mg; FRONTIER-3, 300-600 mg; FRONTIER-4, 600 mg) or placebo every 4 weeks for 4-7 doses, with follow-up periods ranging from 24-36 weeks from the first dose. Safety (adverse events [AEs], serious AEs, and AEs of special interest) and immunogenicity endpoints from the FRONTIER studies were summarized.

Results: In total, 1076 patients were included in this analysis (tozorakimab, n=738; placebo, n=338). Deaths occurred only in FRONTIER-1, in similar proportions between treatment groups (tozorakimab, 0.9%; placebo, 0.8%), and were unrelated to tozorakimab. The proportion of participants experiencing at least one treatment-emergent AE (TEAE) or serious TEAEs was generally similar between tozorakimab and placebo groups. The proportion of participants experiencing AEs of special interest, including events of progression of heart failure, was low (tozorakimab, 0.0-1.5%; placebo, 0.0-0.8%), with no meaningful differences between groups; the frequency of injection-site reactions was however higher in tozorakimab than in placebo recipients (tozorakimab, 1.2-20.9%; placebo, 0.0-4.9%). No clinically significant trends were observed in laboratory or vital-sign parameters, and immunogenicity was low.

Conclusion: Tozorakimab was well tolerated across a range of inflammatory diseases, with no safety concerns identified.