Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD.

Methods: We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel included in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George's Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with ClinicalTrials.gov, number NCT01227278.

Findings: We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68-1·29; n=40) versus 0·92 (0·67-1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per μL or more or 300 cells per μL or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related.

Interpretation: Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia.

Funding: MedImmune.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Study design (A) and trial profile (B)

*These patients comprised the intention-to-treat and safety population; six patients were excluded from the per-protocol population for major protocol violations: eligibility criteria not checked appropriately (n=4), use of restricted drugs (n=1), and non-compliance with maintenance treatment (n=1).†Neither death was considered related to treatment.

Figure 2. Rate of annualised moderate and severe acute exacerbations of COPD at week 56 (per-protocol population)

Values above the bars show rate reduction (95% CI) with benralizumab. One patient in the benralizumab group was not included in the subgroup analyses because no baseline eosinophil count was available. One patient in the placebo group did not have baseline blood eosinophil count, resulting in one patient less for subgroup analyses in this group. COPD=chronic obstructive pulmonary disease. *Number of patients in each subgroup.

Figure 3. Mean (SE) eosinophil count over time in peripheral blood (A) and induced sputum (B) in the safety population

Arrows represent when doses were given; bold arrow shows time of final dose. *Number of patients for each timepoint. †Out of 400 cells.

Figure 4

Mean (SE) change from baseline in pre-bronchodilator forced expiratory volume in 1 second for the overall study population (A) and over time for the 200 cells per µL cutoff subgroup (B), the 300 cells per µL cutoff subgroup (C), and to week 56 by eosinophil subgroup (D; per-protocol population) Values above the bars in panel D show the difference (95% CI) between treatment groups. Tables show number of patients for each timepoint or in each subgroup. One patient in the benralizumab group was not included in the subgroup analyses because no baseline eosinophil count was available. *p=0·014. †p=0·03. ‡p=0·035.

Figure 5. Subpopulation treatment effect pattern plots by blood and sputum eosinophil cutoffs

Rate reduction of acute exacerbations of chronic obstructive pulmonary disease by blood (A) and sputum eosinophils (B), and FEV1 by blood (C) and sputum eosinophils (D). Each subpopulation contains roughly 40% of the patients with eosinophil counts around the selected cutoff; cutoffs correspond to the 20th, 30th, 40th, 50th, 60th, 70th, and 80th percentiles. Data below panels show number of patients in each percentile. Y axes show the difference in measure between between benralizumab and placebo. Shaded areas represent 95% CIs. FEV1=forced expiratory volume in 1 second.