A34-01 Relation Between Airway Damage and Disease Activity and the Effect of Dupilumab on Exacerbations and Lung Function in Chronic Obstructive Pulmonary Disease: BOREAS and NOTUS

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is characterized by progressive and irreversible lung and airways damage, which may lead to increased exacerbation risk. In BOREAS and NOTUS, dupilumab significantly reduced exacerbations and improved lung function in patients with COPD and type 2 inflammation. We assessed whether airway damage (reflected by percent predicted forced expiratory volume in 1 second ppFEV1) and disease activity (type 2 biomarkers) interact to predict future exacerbation risks and lung function decline. Methods BOREAS (NCT03930732) and NOTUS (NCT04456673), two phase 3, randomized, placebo-controlled trials, enrolled patients (40-85 years) with COPD and type 2 inflammation (screening blood eosinophils ≥300 cells/µL) on inhaled triple therapy. Patients received dupilumab 300 mg every 2 weeks or placebo for 52 weeks. This post hoc analysis of pooled data from BOREAS and NOTUS included patients with available data for baseline fractional exhaled nitric oxide (FeNO) and blood eosinophil count. Continuous spline regression was used to assess adjusted annualized exacerbation rate by baseline eosinophil count and FeNO, and Week 52 change from baseline in post-bronchodilator FEV1 by baseline FeNO, in patients stratified by baseline post-bronchodilator ppFEV1 of ≤ 40%, 40%-60%, and 60%. Results 1726 patients were included (dupilumab: N = 861; placebo: N = 865). Continuous spline regression showed that, in both arms, patients with baseline post-bronchodilator ppFEV1 ≤40% experienced more exacerbations than those with ppFEV1 of 40%-60% or 60%. Greater reductions in moderate or severe exacerbations occurred across all subgroups for dupilumab compared with corresponding placebo arms, with a greater magnitude observed in patients with higher baseline FeNO (Figure 1A) or eosinophil count (Figure 1B), though the biomarker interaction was not statistically significant. Continuous spline regression also indicated that dupilumab vs placebo improved post-bronchodilator FEV1 at Week 52, with a greater magnitude of change observed in patients with higher baseline FeNO (interaction P = 0.049) (Figure 1C). Patients with baseline post-bronchodilator ppFEV1 ≤40% overall had smaller improvements compared with those with baseline ppFEV1 of 40%-60% or 60%. Conclusion Dupilumab reduced exacerbations and improved lung function across all subgroups, regardless of baseline post-bronchodilator ppFEV1. Patients with better preserved lung function and higher type 2 biomarkers showed better outcomes. This may suggest that starting dupilumab treatment earlier in the disease, when lung function impairment is smaller and lung damage has a greater reversible component, may result in greater benefits than initiating treatment later, especially in patients with more active disease. This abstract is funded by: Sanofi and Regeneron Pharmaceuticals Inc. ClinicalTrials.gov Identifiers: NCT03930732 and NCT04456673