Benralizumab for allergic asthma: a randomised, double-blind, placebo-controlled trial

Abstract

Background: Benralizumab induces rapid and near-complete depletion of eosinophils from blood and lung tissue. We investigated whether benralizumab could attenuate the allergen-induced late asthmatic response (LAR) in participants with allergic asthma.

Methods: Participants with allergic asthma who demonstrated increased sputum eosinophils and LAR at screening were randomised to benralizumab 30 mg or matched placebo given every 4 weeks for 8 weeks (3 doses). Allergen challenges were performed at weeks 9 and 12 when blood, sputum, bone marrow and bronchial tissue eosinophils and LAR were assessed.

Results: 46 participants (mean age 30.9 years) were randomised to benralizumab (n=23) or placebo (n=23). Eosinophils were significantly reduced in the benralizumab group compared with placebo in blood at 4 weeks and sputum and bone marrow at 9 weeks after treatment initiation. At 7 h after an allergen challenge at week 9, sputum eosinophilia was significantly attenuated in the benralizumab group compared to placebo (least squares mean difference -5.81%, 95% CI -10.69- -0.94%; p=0.021); however, the LAR was not significantly different (least squares mean difference 2.54%, 95% CI 3.05-8.12%; p=0.363). Adverse events were reported for seven (30.4%) and 14 (60.9%) participants in the benralizumab and placebo groups, respectively.

Conclusion: Benralizumab administration over 8 weeks resulted in a significant attenuation of blood, bone marrow and sputum eosinophilia in participants with mild allergic asthma; however, there was no change in the LAR, suggesting that eosinophils alone are not a key component of allergen-induced bronchoconstriction.

FIGURE 1

Study schematic. FEV₁: forced expiratory volume in 1 s (pre-bronchodilator); MCh: methacholine (assessment for airway hyperresponsiveness). ^#: primary end-point assessment.

FIGURE 2

Effect of benralizumab on a) sputum eosinophils and b) change in forced expiratory volume in 1 s (FEV₁) during the week 9 allergen challenge. Data are presented as mean±sd. Shaded values are co-primary end-points. Analyses are based on the primary efficacy analysis set that excluded one patient in the placebo group who received a higher dose of allergen at week 9 than in the screening challenge. Tabular results are based on repeated-measures analyses that estimated the mean change from before to after allergen exposure in the benralizumab group compared with the placebo group. The model for the sputum eosinophils percentage estimates was: allergen-induced change = treatment group +time post-allergen challenge + treatment group × time post-allergen challenge + allergen-induced change at screening. The model for the maximum percentage decrease in FEV₁ estimates was: maximum percentage decrease in FEV₁ in airway response = treatment group + maximum percentage decrease in airway response at screening. LS: least squares; AUC: area under the curve; EAR_0–2 h: early asthmatic response (hours 0–2); LAR_3–7 h: late asthmatic response (hours 3–7).

FIGURE 3

Effect of benralizumab versus placebo on eosinophil levels measured before and after allergen challenge in a) blood, b) bone marrow, c) sputum and d) bronchial submucosa. Data are presented as mean±sd based on the full analysis set. Blood eosinophils were measured using the Advia 2120i system, bone marrow eosinophils from smears stained with DiffQuik and haemocytometer total leukocyte count, sputum eosinophils stained with DiffQuik on a cytospin and expressed as a percentage of leukocytes, and endobronchial eosinophils measured in haematoxylin/eosin-stained submucosa. *: p<0.05; ^#: p<0.0001 based on t-tests between means of treatment groups at each visit. Comparisons of between-group changes in eosinophils are presented in supplementary table E2.

FIGURE 4

Effect of benralizumab versus placebo on basophil levels measured before and after allergen challenge in a) blood, b) bone marrow, c) sputum and d) bronchial submucosa. Data are presented as mean±sd based on the full analysis set. Blood, bone marrow and sputum basophils were measured by flow cytometry, taken as an average of CD45⁺FcεRI⁺CD123⁺, CD45⁺FcεRI⁺CRTH2⁺ or CD45⁺FcεRI⁺CCR3⁺; endobronchial basophils were measured using 2D7 antibody and immunofluorescence microscopy. *: p<0.05; ^#: p<0.0001 based on t-tests between means of treatment groups at each visit. In ANCOVA analyses performed to compare between-group changes in basophils from week 0 to 9 (24 h post-challenge), the least squares (LS) mean difference for benralizumab versus placebo was −26.9 (95% CI −37.2–16.5) cells·µL⁻¹ (p<0.0001) in blood (n=17 versus 20), −39.1 (95% CI −64.5– −13.7) cells·µL⁻¹ (p=0.005) in bone marrow (n=11 versus 10) and −0.29 (95% CI −0.77–0.19) cells·µg⁻¹ (p=0.231) in sputum (n=18 versus 19). In the ANCOVA analysis for bronchial submucosa comparing changes from baseline to week 8, the LS mean difference for benralizumab (n=18) versus placebo (n=17) was −1.5 (95% CI −6.1–3.2) cells·mm⁻² (p=0.522).