Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: a randomized clinical trial

Background

The interleukin (IL)-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 monoclonal antibody, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (Type 2-high), but limited options are available for patients with low blood eosinophils (Type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics.

Objective

This study evaluated astegolimab efficacy and safety in patients with severe asthma.

Methods

This double-blind, placebo-controlled, dose-ranging study (ZENYATTA) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at Week 54. Enrollment caps ensured ∼30 eosinophil-high (≥300 cells/μL) and ∼95 eosinophil-low (<300 cells/μL) patients per arm.

Results

Overall, adjusted AER reductions relative to placebo were 43% (p=0.005), 22% (p=0.18), and 37% (p=0.01) for 490-mg, 210-mg, and 70-mg astegolimab, respectively. Adjusted AER reductions for eosinophil-low patients were comparable to reductions in the overall population: 54% (p=0.002), 14% (p=0.48), and 35% (p=0.05) for 490-mg, 210-mg, and 70-mg astegolimab. Adverse events were similar in astegolimab and placebo-treated groups.

Conclusion

Astegolimab reduced AER in a broad population of patients, including eosinophil-low patients, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.

Trial registration

EudraCT 2016-001549-13; ClinicalTrials.gov, NCT02918019 CLINICAL IMPLICATIONS: Inhibiting IL-33/ST2-mediated inflammation with astegolimab reduces asthma exacerbations in a broad population of patients with severe, uncontrolled asthma, including those with low blood eosinophils who have limited treatment options.