IMPACT OF DUPILUMAB ON QUALITY OF LIFE VIA LUNG FUNCTION IMPROVEMENTS AND EXACERBATION REDUCTION: CAUSAL MEDIATION ANALYSIS OF BOREAS AND NOTUS
Author(s)
Surya P Bhatt, MD1, Guy Brusselle, MD2, Francesca Puggioni, MD3, Mohit Bhutani, MD4, Nicolas Roche, MD5, Maritta Kilpeläinen, MD6, Anh Tuan Dinh-Xuan, MD7, Fuqiang Wen, MD8, Mei Zhang, MD9, Mena Soliman, MD10, Isabelle Malbouisson, MD11, Dave Singh, MD12.
1University of Alabama at Birmingham, Birmingham, AL, USA, 2Ghent University Hospital, Ghent, Belgium, 3Humanitas University; IRCCS Humanitas Research Hospital, Milan, Italy, 4University of Alberta, Edmonton, AB, Canada, 5NR Hôpital et Institut Cochin (UMR 1016), APHP Centre, Université Paris Cité, Paris, France, 6Turku University Hospital, Turku, Finland, 7Hôpital Cochin AP-HP. Centre Centre, Université Paris, Paris, France, 8West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China, 9Sanofi, Morristown, NJ, USA, 10Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA, 11Sanofi, Cambridge, MA, USA, 12University of Manchester, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
1University of Alabama at Birmingham, Birmingham, AL, USA, 2Ghent University Hospital, Ghent, Belgium, 3Humanitas University; IRCCS Humanitas Research Hospital, Milan, Italy, 4University of Alberta, Edmonton, AB, Canada, 5NR Hôpital et Institut Cochin (UMR 1016), APHP Centre, Université Paris Cité, Paris, France, 6Turku University Hospital, Turku, Finland, 7Hôpital Cochin AP-HP. Centre Centre, Université Paris, Paris, France, 8West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China, 9Sanofi, Morristown, NJ, USA, 10Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA, 11Sanofi, Cambridge, MA, USA, 12University of Manchester, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
OBJECTIVES: 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. Causal mediation analysis was used to assess whether the effect of dupilumab on PROs was mediated by lung function improvements and/or the number of moderate or severe exacerbations.
METHODS: BOREAS (NCT03930732) and NOTUS (NCT04456673), phase 3, randomized, placebo-controlled trials, enrolled 1,874 patients (40 to 85 years) with COPD, moderate-to-severe airflow limitation, a history of ≥2 moderate or ≥1 severe exacerbations in the prior year, and type 2 inflammation (screening blood eosinophils ≥300 cells/µL). Endpoints: total and indirect effects of changes in St. George’s Respiratory Questionnaire (SGRQ) total scores at Weeks 4 and 52, with change in pre-bronchodilator forced expiratory volume in 1 second (FEV1) and number of moderate or severe exacerbations as mediators. The analysis controlled for potential confounding factors (at baseline): age, smoking status, eosinophil count, pre-bronchodilator percent predicted FEV1 (ppFEV1), and SGRQ total score.
RESULTS: The total effect of dupilumab vs placebo on SGRQ total scores was partially mediated by change in pre-bronchodilator FEV1 and number of moderate or severe exacerbations. The indirect effect of these mediators represented 25.3% (95% confidence interval [CI]: 8.0, 42.6; P=0.004) at Week 4, 25.7% (95% CI: 10.7, 40.6; P<0.001) at Week 52 for improvement of pre-bronchodilator FEV1, and 13.3% (95% CI: 3.8, 22.8; P=0.006) for the reduction in exacerbation of the overall treatment effect on SGRQ total scores.
CONCLUSIONS: Changes in pre-bronchodilator FEV1 and number of moderate or severe exacerbations partially mediated improvements in quality of life in response to dupilumab treatment, indicating that improved control of important endpoints in the management of COPD with type 2 inflammation may contribute to meaningful improvements in overall health status for patients with COPD.
METHODS: BOREAS (NCT03930732) and NOTUS (NCT04456673), phase 3, randomized, placebo-controlled trials, enrolled 1,874 patients (40 to 85 years) with COPD, moderate-to-severe airflow limitation, a history of ≥2 moderate or ≥1 severe exacerbations in the prior year, and type 2 inflammation (screening blood eosinophils ≥300 cells/µL). Endpoints: total and indirect effects of changes in St. George’s Respiratory Questionnaire (SGRQ) total scores at Weeks 4 and 52, with change in pre-bronchodilator forced expiratory volume in 1 second (FEV1) and number of moderate or severe exacerbations as mediators. The analysis controlled for potential confounding factors (at baseline): age, smoking status, eosinophil count, pre-bronchodilator percent predicted FEV1 (ppFEV1), and SGRQ total score.
RESULTS: The total effect of dupilumab vs placebo on SGRQ total scores was partially mediated by change in pre-bronchodilator FEV1 and number of moderate or severe exacerbations. The indirect effect of these mediators represented 25.3% (95% confidence interval [CI]: 8.0, 42.6; P=0.004) at Week 4, 25.7% (95% CI: 10.7, 40.6; P<0.001) at Week 52 for improvement of pre-bronchodilator FEV1, and 13.3% (95% CI: 3.8, 22.8; P=0.006) for the reduction in exacerbation of the overall treatment effect on SGRQ total scores.
CONCLUSIONS: Changes in pre-bronchodilator FEV1 and number of moderate or severe exacerbations partially mediated improvements in quality of life in response to dupilumab treatment, indicating that improved control of important endpoints in the management of COPD with type 2 inflammation may contribute to meaningful improvements in overall health status for patients with COPD.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
CO39
Topic
Clinical Outcomes, Methodological & Statistical Research
Topic Subcategory
Comparative Effectiveness or Efficacy
Disease
Respiratory-Related Disorders (Allergy, Asthma, Smoking, Other Respiratory)