Postbronchodilator lung function improvements with benralizumab for patients with severe asthma
Authors: Sameer K. Mathur, Brian D. Modena, Hanneke Coumou, Peter Barker, James L. Kreindler, James G. Zangrilli
Journal: Allergy (2020)

Airway remodeling and loss of lung function are prominent features of asthma.1 Activated eosinophils release an array of inflammatory cytokines and lipid mediators that play a role in airway remodeling.2 Imaging studies using quantitative computed tomography have demonstrated correlations between parameters of airway remodeling and postbronchodilator forced expiratory volume in 1 second (FEV1) as well as changes over time.3, 4 Therefore, we sought to determine whether a reduction in eosinophils could affect airway remodeling by examining postbronchodilator FEV1. SIROCCO and CALIMA phase III trials demonstrated that benralizumab, an interleukin (IL)-5 receptor alpha–directed cytolytic monoclonal antibody that depletes eosinophils via enhanced antibody-dependent cell-mediated cytotoxicity,5 reduces exacerbations, lessens asthma symptoms, and augments prebronchodilator lung function for patients with severe, eosinophilic asthma.6, 7 Post hoc analysis of pooled SIROCCO and CALIMA data identified subgroups of patients with long-term oral corticosteroid (OCS) use, nasal polyposis (based on medical history), prebronchodilator forced vital capacity (FVC) <65% predicted at baseline, ≥3 asthma exacerbations in the year prior to enrollment, or age at diagnosis ≥18 years with demonstrated enhanced clinical response to benralizumab.8, 9 In this analysis, we examined whether subcutaneous benralizumab 30 mg every 8 weeks (first three doses every 4 weeks) also improved postbronchodilator lung function for these same enhanced responder subgroups, providing further evidence that benralizumab may alter inflammation-induced airway changes. Methods, statistics (including confidence intervals for reported results), and study limitations are provided in the Supplement. All P-values are nominal, with P < .05 considered nominally significant. The demographics and baseline clinical characteristics were similar between benralizumab and placebo arms (Table S1).8 At the end of treatment (EOT), postbronchodilator FEV1 improvements from baseline were greater with benralizumab (n = 693) than placebo (n = 717) for all patients (least squares [LS] mean difference vs placebo 0.09 L, P = .0001) and for each enhanced responder subgroup (Figures 1 and S1, Tables S2 and S3). The greatest differences vs placebo were for patients with nasal polyps (0.33 L, P < .0001), long-term OCS use (0.26 L, P = .0001), and baseline FVC < 65% predicted (0.23 L, P = .0001). Improvements in postbronchodilator FEV1 were similar for patients with baseline blood eosinophil counts ≥300 and <300 cells/µL, with numerically greater changes for those with ≥300 cells/µL (Figure 2, Table S3). Of patients with baseline blood eosinophil counts <300 cells/µL, the greatest increases in postbronchodilator FEV1 with benralizumab vs placebo were for those with nasal polyps (LS mean difference vs placebo 0.34 L, P = .0031) and those with ≥3 exacerbations in the previous year (LS mean difference vs placebo 0.14 L, P = .0219). Greater improvements in postbronchodilator FVC and forced expiratory flow 25%-75% predicted (FEF25-75) from baseline to EOT were observed with benralizumab compared with placebo (Tables S4 and S5). For all patients, mean postbronchodilator FVC improved by 0.06 L (P = .0084) vs placebo at EOT. Patients with nasal polyposis again had the greatest improvement (0.30 L, P < .0001) (Table S4). Of patients with baseline blood eosinophil counts ≥300 or <300 cells/µL, those with nasal polyps had the greatest improvements from baseline to EOT in postbronchodilator FVC with benralizumab vs placebo (Table S4). Postbronchodilator FEF25-75 improved from baseline to EOT with benralizumab vs placebo for all patients by 0.11 L/s (P = .0016). Treatment effects for patients with baseline OCS use, nasal polyps, or baseline FVC <65% predicted were more than double those of the unselected, total population (Table S5). For patients with blood eosinophil counts ≥300 cells/µL, baseline OCS use was associated with the greatest improvement in postbronchodilator FEF25-75. Patients with baseline nasal polyps had the greatest response of those with blood eosinophil counts <300 cells/µL. Bronchodilator responses, measured after up to 8 puffs of albuterol, were similar between patients receiving placebo and benralizumab at EOT relative to baseline, regardless of baseline clinical characteristics, including blood eosinophil counts (Figure S2 and Table S2). For the overall population of benralizumab-treated patients, mean reversibility changed from 0.41 L (standard deviation [SD] = 0.36) at baseline to 0.25 L (SD = 0.24) at EOT. For placebo, mean reversibility changed from 0.41 L (SD = 0.36) to 0.26 L (SD = 0.25) at EOT. Thus, the postbronchodilator lung function changes are more likely to result from airway structural changes rather than changes in airway hyperreactivity. By evaluating postbronchodilator lung function in pooled SIROCCO and CALIMA data, this analysis provides further evidence that benralizumab improves lung function and perhaps modulates airway remodeling pathways related to chronic eosinophil-driven inflammation.1, 2 The presence of nasal polyposis, maintenance OCS use, and baseline FVC <65% predicted were all associated with enhanced benralizumab response and may provide important clues to the pathogenetic effects of uncontrolled eosinophilic inflammation.2 Blood eosinophil counts are a practical but indirect and imperfect indicator of airway eosinophilia. In our analysis, patients with nasal polyposis and lesser blood eosinophil counts had numerically greater improvements in postbronchodilator FEV1 compared with patients with nasal polyposis and greater blood eosinophil counts from baseline to EOT with benralizumab vs placebo. Nasal polyposis is likely a marker for IL-5 and eosinophil-driven inflammation.2 Thus, nasal polyps may be an important surrogate marker for uncontrolled eosinophilic inflammation in the lower airways or other IL-5-dependent pathways for patients with asthma. Patients receiving maintenance OCS also had an enhanced postbronchodilator FEV1 benralizumab response. Similar to the finding with nasal polyps, this suggested that eosinophilic inflammation or other IL-5-dependent pathways persisted in the airways of some patients while OCS use suppressed peripheral eosinophilia. This may be particularly true for patients with declined lung function, because baseline FVC <65% predicted was one of the three strongest clinical characteristics associated with enhanced benralizumab response. Although these findings should be confirmed with a larger population over a longer observation period, they suggest that some patients with asthma have occult eosinophilic inflammation, which may not be detected with blood eosinophil counts alone as the surrogate marker and may result in loss of lung function. In summary, we demonstrated that benralizumab improves postbronchodilator lung function for patients with eosinophilic asthma. Elevated blood eosinophil counts, nasal polyposis, decreased lung function, and long-term OCS use were all potential indicators of an enhanced response. Benralizumab may improve structural changes associated with eosinophil-driven, chronic airway inflammation, which are not always detected with blood eosinophil counts alone. Funding for this study was provided by AstraZeneca. Writing and editing support, including preparation of the draft manuscript under the direction and guidance of the authors, incorporating author feedback, and manuscript submission, was provided by Alan Saltzman, PhD, of JK Associates, Inc (Conshohocken, PA, USA), and Michael A. Nissen, ELS, of AstraZeneca (Gaithersburg, MD, USA). Writing support was funded by AstraZeneca. Sameer K. Mathur is a consultant for and received honorarium from AstraZeneca and received research funds for his institution from Novartis. Brian D. Modena has received consulting fees from AstraZeneca. Hanneke Coumou has nothing to declare. Peter Barker, James L. Kreindler, and James G. Zangrilli are employees of AstraZeneca. Data underlying the findings described in this manuscript may be requested in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagroup-dt.pharmacm.com/DT/Home. 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