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

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Summary

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.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterised by partly irreversible airflow obstruction through a combination of emphysema and destruction of small airways.1, 2 Acute exacerbations of COPD are associated with airflow obstruction, a substantial reduction in health-related quality of life, and high levels of mortality and morbidity.3 Inflammation, predominantly neutrophilic, contributes to the narrowing of small airways in patients with COPD1 and is increased during acute exacerbations.4 However, in 10–20% of patients with COPD, evidence has been reported of eosinophilic airway inflammation both during stable periods and during acute exacerbations;4, 5, 6, 7, 8 titration of corticosteroid treatment to reduce concentrations of airway eosinophils attenuates the frequency of severe acute exacerbations of COPD.6

Because of the potential role of eosinophil-mediated inflammation in patients with COPD, development of treatment options that reduce eosinophil concentrations is of great interest. Interleukin-5 regulates the differentiation, proliferation, survival, and activation of eosinophils via the interleukin-5 receptor.9 Antibodies to interleukin-5 greatly reduce severe asthma exacerbations in patients with evidence of eosinophilic inflammation.10, 11, 12

Benralizumab, a humanised, afucosylated monoclonal antibody to interleukin-5 receptor α, reduces sputum and blood eosinophil counts by enhancement of antibody-dependent cell-mediated cytotoxic effects.13, 14 We did this study to assess the efficacy and safety of benralizumab in patients with eosinophilic COPD.

Section snippets

Study design and participants

We did this phase 2a, randomised, double-blind, placebo-controlled study between November, 2010 (the first patient was enrolled on Nov 18, 2010, and the first dose of study drug was given on Feb 25, 2011), and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Patients had to be exacerbation free in the 4-week run-in period, hence the delay between screening and delivery of the first dose.

We enrolled adults aged 40–85 years, with moderate-to-severe COPD2

Results

Figure 1 shows the trial profile. We randomly assigned 101 patients to receive benralizumab (n=51) or placebo (n=50), of whom 88 (87%) completed the study. The entry criterion for sputum eosinophil count (≥3·0%) was met historically in 32 (32%) patients, and in 69 (68%) patients at screening. However, of 95 participants with assessable baseline sputum, only 62 (65%) had a sputum eosinophil count of 3·0% or more, showing variability. No participants withdrew because of subcutaneous injections.

Discussion

To our knowledge, this study is the first of a biological treatment for eosinophilic COPD. Consistent with a previous study in the asthma setting,14 benralizumab rapidly depleted both sputum and blood eosinophils in patients with COPD to a much greater extent than did inhaled or oral corticosteroids in other studies,5, 26 and was reversible after treatment washout. The primary endpoint in this study was not met because benralizumab did not reduce the rate of acute exacerbations of COPD compared

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