title: Mepolizumab and exacerbations of refractory eosinophilic asthma.
abstract: BACKGROUND
  Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations.
  
  
  METHODS
  We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum.
  
  
  RESULTS
  Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma.
  
  
  CONCLUSIONS
  Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)
authors.affiliation: Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom.
authors.forename: Pranabashis
authors.initials: P
authors.lastname: Haldar
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Brightling
authors.forename: Beverley
authors.initials: B
authors.lastname: Hargadon
authors.forename: Sumit
authors.initials: S
authors.lastname: Gupta
authors.forename: William
authors.initials: W
authors.lastname: Monteiro
authors.forename: Ana
authors.initials: A
authors.lastname: Sousa
authors.forename: Richard P
authors.initials: RP
authors.lastname: Marshall
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Green
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wardlaw
authors.forename: Ian D
authors.initials: ID
authors.lastname: Pavord
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004802:Eosinophilia / Q000188:drug therapy*; D004804:Eosinophils; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000276:immunology*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D011239:Prednisolone / Q000627:therapeutic use; D011788:Quality of Life; D055502:Secondary Prevention; D013183:Sputum / Q000276:immunology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D015848:Interleukin-5; C434107:mepolizumab; D011239:Prednisolone