Dupilumab for chronic obstructive pulmonary disease with type 2 inflammation: a pooled analysis of two phase 3, randomised, double-blind, placebo-controlled trials

Abstract

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, which are key drivers of type 2 inflammation. We aimed to characterise the efficacy and safety of dupilumab in patients with COPD and type 2 inflammation.

Methods: For this pooled analysis, we pooled and analysed data from all patients in the intention-to-treat populations of the phase 3, randomised, double-blind, placebo-controlled BOREAS and NOTUS trials, which comprised 206 hospitals and clinics in BOREAS and 217 in NOTUS in 38 countries across Europe, Asia, North America, South America, Africa, and Australia. Eligible patients were current or former smokers with 10 pack-years or more of smoking history, were aged 40-85 years, had physician-diagnosed COPD for at least 12 months before randomisation, had a post-bronchodilator FEV₁/forced vital capacity (FVC) ratio of less than 0·7, had a post-bronchodilator percentage predicted FEV₁ of 30-70%, had documented evidence of two moderate or one severe exacerbations of COPD in the previous year (at least one exacerbation had to have occurred on triple therapy), and had blood eosinophil counts 300 cells per μL or more during screening. Patients had to have symptomatic COPD and a reported chronic productive cough for at least 3 months in the previous year. Key exclusion criteria were history of asthma, pulmonary disease other than COPD, or other diagnosed pulmonary or systemic disease associated with elevated blood eosinophil. In both trials, eligible patients were randomly assigned (1:1) via block randomisation with block size 4 to receive subcutaneous dupilumab 300 mg or matching placebo once every 2 weeks for 52 weeks, alongside established background therapy with inhaled corticosteroids, a long-acting β2-agonist, and a long-acting muscarinic antagonist. The primary endpoint was the annualised rate of moderate or severe exacerbations over 52 weeks.

Findings: 1874 patients were randomly assigned in BOREAS and NOTUS from May 9, 2019, to May 23, 2023; 938 (50·1%) were randomly assigned to the dupilumab groups and 936 (49·9%) were randomly assigned to the placebo groups. Mean age across both groups was 65·1 years (SD 8·2). 622 (33·2%) of 1874 patients were female and 1252 (66·8%) were male. 1628 (86·9%) patients were White, 719 (38·4%) were from Eastern Europe, and 1316 (70·2%) were former smokers. During the 52-week treatment period, 559 moderate or severe exacerbations were reported in 338 (36·0%) of 938 patients in the dupilumab group and 774 exacerbations were reported in 394 (42·1%) of 936 patients in the placebo group. There was a reduction in the annualised rate of moderate or severe exacerbations compared with placebo (annualised exacerbation rate 0·794 in the dupilumab group and 1·156 in the placebo group; incidence rate ratio 0·687, 95% CI 0·595-0·793; p<0·0001). In the dupilumab group, the time to first severe exacerbation was longer than in the placebo group (0·611, 0·409-0·912; p=0·016). However, there was no reduction in the annualised rate of severe exacerbations (annualised exacerbation rate 0·084 in the dupilumab group and 0·124 in the placebo group; 0·674, 0·438-1·037; p=0·073). Treatment-emergent adverse events, serious adverse events, adverse events that led to permanent treatment discontinuation, and adverse events that led to death were similar between the two groups.

Interpretation: Dupilumab, as an add-on to standard triple therapy, reduced the annualised rate of moderate or severe exacerbations compared with placebo, highlighting its potential for personalised treatment approaches in patients with COPD with specific clinical endotypes.

Funding: Sanofi and Regeneron Pharmaceuticals.