A34-06 Causal Mediation Analysis Describes the Proportion of Dupilumab Effect on Patient-reported Outcomes Linked to Exacerbation Reduction, Lung Function Improvements, or Decline in Feno: BOREAS and NOTUS

Abstract Rationale In BOREAS and NOTUS, add-on dupilumab vs placebo significantly reduced moderate or severe exacerbations and improved lung function and patient-reported outcomes (PROs) in patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation. Mechanisms underlying PRO improvements, including quality of life and daily symptom burden, are not well understood. We used causal mediation analysis to evaluate the effect of dupilumab on PROs. Methods BOREAS (NCT03930732) and NOTUS (NCT04456673), phase 3, randomized, placebo-controlled trials, enrolled 1,874 patients (aged 40 − 85 years) with COPD, moderate-to-severe airflow limitation, and type 2 inflammation (screening blood eosinophils ≥300 cells/µL). Endpoints: changes in St. George’s Respiratory Questionnaire (SGRQ) and Evaluating Respiratory Symptoms in COPD (E-RS:COPD) total scores from baseline to Week 52. Mediators considered: change in number of moderate or severe exacerbations, change in pre- and post-bronchodilator forced expiratory volume in 1 second (FEV1), and change in fractional exhaled nitric oxide (FeNO) level; the analysis was controlled for potential confounding factors (age, sex, smoking status, region, number of moderate or severe exacerbations in the year prior to study). Results Dupilumab vs placebo total effect on change in SGRQ total score was estimated as − 3.55, −3.54, −3.52, and −3.60 with change in exacerbation frequency, change in pre- and post-bronchodilator FEV1, and change in FeNO as mediators, respectively. Mediators indirectly affected total effect by estimates of − 0.61, −0.78, −0.75, and −0.64 for change in number of exacerbations, change in pre- and post- bronchodilator FEV1, and change in FeNO, respectively, mediating 17% (95% CI: 5%, 29%; P=0.006), 22% (95% CI: 8%, 37%; P=0.003), 21% (95% CI: 7%, 36%; P=0.004), and 18% (95% CI: 4%, 31%; P=0.010), respectively, of total effect. Dupilumab vs placebo total effect on change in E-RS:COPD total score was estimated as − 1.02, −0.99, −0.97, and −1.06 with change in exacerbation frequency, change in pre- and post-bronchodilator FEV1, and change in FeNO as mediators, respectively. Mediators indirectly affected total effect by estimates of − 0.09, −0.17, −0.15, and −0.13 for change in number of exacerbations, change in pre- and post- bronchodilator FEV1, and change in FeNO, respectively, mediating 9% (95% CI: 0%, 17%; P=0.048), 18% (95% CI: 3%, 32%; P=0.016), 15% (95% CI: 2%, 29%; P=0.022), and 12% (95% CI: −1%, 26%; P=0.066), respectively, of total effect. Conclusions Change in exacerbation frequency, lung function, and FeNO partially mediate improvements in PROs with dupilumab, supporting the interplay between type 2 inflammatory biomarkers, clinical events, and PROs in COPD. This abstract is funded by: Sanofi and Regeneron Pharmaceuticals Inc. ClinicalTrials.gov Identifiers: NCT03930732 and NCT04456673