title: Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies.
abstract: Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma. To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies, stratifying patients by different baseline blood eosinophil thresholds.
  
  
  
  We did a post-hoc analysis of data, which was completed on Sept 25, 2015, from two randomised, double-blind, placebo-controlled studies of at least 32 weeks duration (NCT01000506 [DREAM] and NCT01691521 [MENSA]) done between 2009 and 2014. In these studies, mepolizumab (
  
  
  
  75 mg, 250 mg, or 750 mg intravenously; MENSA: 75 mg intravenously or 100 mg subcutaneously) versus placebo was given at 4-week intervals in addition to standard care (high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids) to patients aged 12 years or older with a clinical diagnosis of asthma, a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment, and evidence of eosinophilic airway inflammation. The primary endpoint in both studies was the annual rate of clinically significant exacerbations (defined as worsening of asthma that required the use of systemic corticosteroids, or admission to hospital, or an emergency-room visit, or a combination of these occurrences). In our analysis, the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts (≥150 cells per μL, ≥300 cells per μL, ≥400 cells per μL, and ≥500 cells per μL) and baseline blood eosinophil ranges (<150 cells per μL, ≥150 cells per μL to <300 cells per μL, ≥300 cells per μL to <500 cells per μL, and ≥500 cells per μL). We based our analysis on the intention-to-treat populations of the two original studies, and all mepolizumab doses were combined for analysis.
  
  
  
  Of 1192 patients, 846 received mepolizumab and 346 received placebo. The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab (47% reduction; rate ratio [RR] 0·53, 95% CI 0·44-0·62; p<0·0001). The exacerbation rate reduction with mepolizumab versus placebo increased progressively from 52%; 0·48, 0·39-0·58) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70%; 0·30, 0·23-0·40]) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL, predicted efficacy of mepolizumab was reduced.
  
  
  
  Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations. We noted clinically relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline. The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab.
  
  
  
  GlaxoSmithKline.
authors.affiliation: Respiratory Therapeutic Area Unit, GlaxoSmithKline, Research Triangle Park, NC, USA. Electronic address: ortega.hector@gene.com.
authors.forename: Hector G
authors.initials: HG
authors.lastname: Ortega
authors.affiliation: Respiratory Therapeutic Area Unit, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Yancey
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Stockley Park, Middlesex, UK.
authors.forename: Bhabita
authors.initials: B
authors.lastname: Mayer
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Stockley Park, Middlesex, UK.
authors.forename: Necdet B
authors.initials: NB
authors.lastname: Gunsoy
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Stockley Park, Middlesex, UK.
authors.forename: Oliver N
authors.initials: ON
authors.lastname: Keene
authors.affiliation: Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.affiliation: Institute for Lung Health, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Brightling
authors.affiliation: Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Pavord
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D001249:Asthma / Q000097:blood / Q000188:drug therapy*; D002648:Child; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004804:Eosinophils / Q000187:drug effects*; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D011657:Pulmonary Eosinophilia / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018927:Anti-Asthmatic Agents; D061067:Antibodies, Monoclonal, Humanized; C434107:mepolizumab