S90 FRONTIER-3: a randomized, phase 2a study to evaluate the efficacy and safety of tozorakimab (an anti-interleukin-33 monoclonal antibody) in early-onset asthma

Introduction

Genetic and clinical evidence has shown that interleukin-33 plays a key role in the susceptibility and progression of asthma. The phase 2a FRONTIER-3 study (NCT04570657) investigated the effect of tozorakimab on lung function in patients with moderate-to-severe uncontrolled asthma with early-onset disease (asthma diagnosed before 25 years of age).

Methods

Patients were randomized 1:1:1 to receive subcutaneous injections of tozorakimab 600 mg or 300 mg or placebo every 4 weeks for 12 weeks (four doses total). The primary endpoint was the change from baseline to week 16 in pre-BD FEV₁ measured in-clinic. Other exploratory endpoints included home spirometry, rescue medication use, pharmacodynamic biomarkers and safety.

Results

The FRONTIER-3 ITT population comprised 235 adults with moderate-to-severe uncontrolled asthma. The median time since asthma diagnosis was 34 years, and most patients (76.2%) had a baseline BEC of < 300 cells/μL. Tozorakimab did not significantly improve in-clinic measurements of pre-BD FEV₁ compared with placebo at week 16 in the ITT population. However, in a pre-specified analysis, in-clinic pre-BD FEV₁ was numerically improved compared with placebo in patients with ≥ 2 exacerbations in the previous 12 months, most notably for the tozorakimab 600 mg treatment arm (table 1). Numerical improvements were also seen for FEV₁ and peak expiratory flow measured at home, and rescue medication use compared with placebo at week 16 in the ITT population, with a greater effect observed in the tozorakimab 600 mg dose for home FEV₁ and peak expiratory flow in patients with ≥ 2 exacerbations in the previous 12 months (table 1). Results suggest tozorakimab had numerical benefits for home spirometry and rescue medication use endpoints across the BEC strata. Biomarker data showed that tozorakimab significantly reduced type 2 inflammatory biomarker levels, including fractional exhaled nitric oxide and BEC. Tozorakimab was well-tolerated.

Conclusions

The FRONTIER-3 results suggest that tozorakimab improved lung function in patients with early-onset asthma and mostly BEC of < 300 cells/μL, representing a population who are potentially less responsive to currently approved biologics. A trend towards greater numerical improvements was observed for the tozorakimab 600 mg dose compared with the 300 mg dose for several endpoints.