title: Dupilumab in persistent asthma with elevated eosinophil levels.
abstract: BACKGROUND
  Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels.
  
  
  METHODS
  We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)-associated biomarkers and safety and tolerability were also evaluated.
  
  
  RESULTS
  A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo.
  
  
  CONCLUSIONS
  In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.).
authors.affiliation: Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA. wenzelse@upmc.edu
authors.forename: Sally
authors.initials: S
authors.lastname: Wenzel
authors.forename: Linda
authors.initials: L
authors.lastname: Ford
authors.forename: David
authors.initials: D
authors.lastname: Pearlman
authors.forename: Sheldon
authors.initials: S
authors.lastname: Spector
authors.forename: Lawrence
authors.initials: L
authors.lastname: Sher
authors.forename: Franck
authors.initials: F
authors.lastname: Skobieranda
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Stephane
authors.initials: S
authors.lastname: Kirkesseli
authors.forename: Ross
authors.initials: R
authors.lastname: Rocklin
authors.forename: Brian
authors.initials: B
authors.lastname: Bock
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hamilton
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Ming
authors.forename: Allen
authors.initials: A
authors.lastname: Radin
authors.forename: Neil
authors.initials: N
authors.lastname: Stahl
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Neil
authors.initials: N
authors.lastname: Graham
authors.forename: Gianluca
authors.initials: G
authors.lastname: Pirozzi
mesh_terms: D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D004802:Eosinophilia / Q000150:complications*; D005260:Female; D005541:Forced Expiratory Volume; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007279:Injections, Subcutaneous; D057194:Intention to Treat Analysis; D053662:Interleukin-4 Receptor alpha Subunit / Q000276:immunology*; D007958:Leukocyte Count; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D018418:Th2 Cells; D055815:Young Adult
chemical_list: D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D005938:Glucocorticoids; D053662:Interleukin-4 Receptor alpha Subunit; C582203:dupilumab