Available online 23 April 2024

What is already known about this topic? Prior analyses of SIROCCO and CALIMA demonstrated that benralizumab provides enhanced clinical benefits for those with increased blood eosinophil counts and higher exacerbation rates, worse lung function, oral corticosteroid use, nasal polyposis, and adult-onset asthma. (35 words)

What does this article add to our knowledge?

These post-hoc analyses of the pooled SIROCCO and CALIMA data use a novel multivariate approach to characterize asthma clinical heterogeneity and benralizumab-responsiveness using predefined Severe Asthma Research Program clinical clusters. (30 words)

How does this study impact current management guidelines?

This report introduces a new paradigm that can inform phenotype-guided benralizumab treatment decisions for patients with severe asthma. (17 words)

An improved understanding of how severe asthma heterogeneity affects response could inform treatment decisions.

Characterize heterogeneity and benralizumab responsiveness in patients grouped by predefined Severe Asthma Research Program clusters using a multivariate approach.

In post-hoc analyses of the randomized, double-blind, placebo-controlled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) studies, patients with severe asthma who received benralizumab or placebo were assigned to clusters using an established discriminant function to simultaneously analyze 11 clinical characteristics. Annualized asthma exacerbation rate, exacerbation incidence, and lung function were analyzed across clusters.

Patients (N = 2,281) met criteria for 4 of 5 clusters: Cluster 2 (early-onset moderate asthma, n = 393), Cluster 4 (early-onset severe, n = 386), Cluster 3 (late-onset severe, n = 641), and Cluster 5 (late-onset severe, obstructed, n = 861); no patients met Cluster 1 criteria. Exacerbation rate reductions were significant in late-onset severe (−48% [95% CI: –61%, –31%], P<.0001) and late-onset severe, obstructed asthma (−50% [95% CI: –59%, –38%], P<.0001), with non-significant reductions in early-onset clusters. These differences could not be fully explained by blood eosinophil count differences. Forced expiratory volume in 1 second improvements were significant in late-onset severe (+133 mL [95% CI: 66 mL, 200 mL], P=.0001) and late-onset severe, obstructed asthma (+160 mL [95% CI: 85 mL, 235 mL], P<.0001) while maintaining acute bronchodilator responsiveness.

Benralizumab reduced exacerbations and improved lung function, primarily in late-onset asthma clusters. This multivariate approach to identify subphenotypes, potentially reflecting pathobiological mechanisms, can guide therapy beyond univariate approaches.

© 2024 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology