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