title: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  MedImmune.
authors.affiliation: Institute for Lung Health, National Institute for Health Research Respiratory Biomedical Research Unit, Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, UK. Electronic address: ceb17@leicester.ac.uk.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Brightling
authors.affiliation: Wake Forest University Health Sciences, Winston-Salem, NC, USA.
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.affiliation: University of Pennsylvania Medical Center, Philadelphia, PA, USA.
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.affiliation: Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Mona
authors.initials: M
authors.lastname: Bafadhel
authors.affiliation: MedImmmune, Gaithersburg, MD, USA.
authors.forename: Dewei
authors.initials: D
authors.lastname: She
authors.affiliation: MedImmmune, Gaithersburg, MD, USA.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Ward
authors.affiliation: AstraZeneca, Gaithersburg, MD, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xu
authors.affiliation: MedImmune, Cambridge, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Birrell
authors.affiliation: MedImmune, Cambridge, UK.
authors.forename: René
authors.initials: R
authors.lastname: van der Merwe
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D004802:Eosinophilia / Q000150:complications / Q000188:drug therapy*; D004804:Eosinophils; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D053666:Interleukin-5 Receptor alpha Subunit / Q000037:antagonists & inhibitors*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D012720:Severity of Illness Index; D013183:Sputum / Q000166:cytology*; D011795:Surveys and Questionnaires
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053666:Interleukin-5 Receptor alpha Subunit; C571386:benralizumab