title: Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.
abstract: BACKGROUND
  Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist, irrespective of baseline eosinophil count.
  
  
  METHODS
  We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16.
  
  
  RESULTS
  769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06-0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11-0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup (overall population: 200 mg every 2 weeks, p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per μL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70·5%), the subgroup with at least 300 eosinophils per μL (71·2-80·7%), and the subgroup with fewer than 300 eosinophils per μL (59·9-67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%).
  
  
  CONCLUSIONS
  Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone.
  
  
  BACKGROUND
  Sanofi-Genzyme and Regeneron Pharmaceuticals.
authors.affiliation: Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: wenzelse@upmc.edu.
authors.forename: Sally
authors.initials: S
authors.lastname: Wenzel
authors.affiliation: Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Corren
authors.affiliation: Allergy and Respiratory Research Unit, Fundación CIDEA, Buenos Aires, Argentina.
authors.forename: Jorge
authors.initials: J
authors.lastname: Maspero
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Bingzhi
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Pirozzi
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: E Rand
authors.initials: ER
authors.lastname: Sutherland
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Evans
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Vijay N
authors.initials: VN
authors.lastname: Joish
authors.affiliation: Sanofi, Chilly-Mazarin, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Eckert
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Neil M H
authors.initials: NM
authors.lastname: Graham
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Stahl
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Louis-Tisserand
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Teper
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001944:Breath Tests; D000069502:Budesonide, Formoterol Fumarate Drug Combination / Q000627:therapeutic use; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D000068297:Fluticasone-Salmeterol Drug Combination / Q000627:therapeutic use; D005541:Forced Expiratory Volume; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D000068758:Mometasone Furoate, Formoterol Fumarate Drug Combination / Q000627:therapeutic use; D009569:Nitric Oxide / Q000032:analysis; D016896:Treatment Outcome
chemical_list: D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069502:Budesonide, Formoterol Fumarate Drug Combination; D000068297:Fluticasone-Salmeterol Drug Combination; D000068758:Mometasone Furoate, Formoterol Fumarate Drug Combination; D009569:Nitric Oxide; C582203:dupilumab