S93 Phase 3 NOTUS trial: dupilumab efficacy and safety in patients with moderate-to-severe chronic obstructive pulmonary disease and type 2 inflammation

Introduction Patients with type 2 inflammation in COPD suffer from frequent exacerbations and high symptom burden. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component of interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation. The second pivotal phase 3 NOTUS (NCT04456673) trial aimed to evaluate the efficacy and safety of dupilumab in patients with COPD and type 2 inflammation. Methods The NOTUS trial was a 52-week phase 3, randomized, double-blind, placebo-controlled trial of efficacy and safety of subcutaneous add-on dupilumab 300 mg q2w or placebo. Enrolled patients had COPD with moderate-to-severe airflow limitation and type 2 inflammation (blood eosinophils ≥300 cells/μL at screening) and were on triple therapy with inhaled corticosteroids (ICS), long-acting β2-agonists (LABA), and long-acting muscarinic antagonists (LAMA) (or LABA/LAMA if ICS was contraindicated). Primary analysis was performed on interim data, with 92% information fraction for the primary endpoint (annualized rate of moderate or severe exacerbations). Secondary endpoints included change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) at Weeks 12 and 52, change from baseline in St George’s Respiratory Questionnaire (SGRQ) total score, exacerbation-associated annualized total systemic corticosteroid (SCS) courses, and safety. Results Participants (N=935) were randomized to placebo (n=465) or dupilumab (n=470). Compared with placebo, dupilumab reduced the annualized rate of moderate or severe exacerbations by 34% (relative risk vs placebo [95% confidence interval {CI}] 0.66 [0.54–0.82], P<0.001). Over the 52-week period, adjusted annualized total exacerbation-associated SCS courses were reduced by 39% in patients receiving dupilumab (relative risk vs placebo [95% CI] 0.61 [0.47–0.80], nominal P<0.001). At Week 12, dupilumab significantly increased pre-BD FEV1 (least-squares [LS] mean difference 82 mL, P<0.001) compared with placebo, and this was maintained at Week 52 (LS mean difference 62 mL, P=0.018). Dupilumab improved SGRQ total score at Week 52 (LS mean difference −3.37, nominal P=0.007) vs placebo. Safety findings were similar to BOREAS and treatment-emergent adverse events were balanced between groups. Conclusions Dupilumab significantly reduced moderate or severe exacerbations, decreased SCS exposure, and improved lung function, in patients with COPD and type 2 inflammation in 2 phase 3 trials.