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

Background Dupilumab, a fully human anti-interleukin-4 receptor a 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 beta(2) 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 beta(2) 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 beta(2) 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 mu L 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. Findings 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 mu L, the greatest increases (200 mg every 2 weeks, p=0.0008; 300 mg every 2 weeks, p=0.0063) in FEV 1 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 mu L subgroup (overall population: 200 mg every 2 weeks, p< 0.0001; 300 mg every 2 weeks, p< 0.0001; < 300 eosinophils per mu L: 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 mu L (71.2-80.7%), and the subgroup with fewer than 300 eosinophils per mu L (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%). Interpretation 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 beta(2)-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone.