Abstract
BACKGROUND: Interleukin (IL)-33 is implicated in the initiation and progression of asthma. FRONTIER-3 (NCT04570657) was a phase 2a study to investigate tozorakimab, an anti-IL-33 monoclonal antibody, in adults with moderate-to-severe early-onset asthma receiving standard of care. METHODS: Patients were randomised 1:1:1 to tozorakimab 600 mg, tozorakimab 300 mg or placebo, once every 4 weeks subcutaneously. The primary end-point was change from baseline to week 16 in pre-bronchodilator (pre-BD) forced expiratory volume in 1 s (FEV(1)) measured in clinic. Secondary and exploratory end-points included home pre-BD FEV(1), home peak expiratory flow (PEF), rescue medication use, CompEx, pharmacokinetics, immunogenicity and safety. RESULTS: The intent-to-treat (ITT) population included 235 patients with a median disease duration of >30 years; a majority had a baseline blood eosinophil count (BEC) <300 cells·μL(-1). At week 16, tozorakimab did not show a statistically significant improvement in change from baseline in clinic pre-BD FEV(1) versus placebo (least-squares mean difference (LSMD) (80% CI), 600 mg: 4 mL (-71-79), p=0.473; 300 mg: 36 mL (-38-111), p=0.267). Compared with the ITT population, a pre-specified subgroup of patients with ≥2 prior exacerbations showed greater improvements in clinic pre-BD FEV(1) at week 16 with tozorakimab versus placebo (LSMD (80% CI), 600 mg: 212 mL (102-322), p=0.007; 300 mg: 77 mL (-34-187), p=0.186). Tozorakimab also showed greater improvements in home FEV(1) and home PEF versus placebo at week 16 in patients with ≥2 prior exacerbations than in the ITT population. Tozorakimab was well tolerated. CONCLUSIONS: Although FRONTIER-3 did not meet the primary study end-point, tozorakimab treatment showed encouraging efficacy signals in patients with early-onset asthma and a history of exacerbations.