Dupilumab significantly reduced exacerbations in adults with chronic obstructive pulmonary disease by approximately 30% compared with placebo, based on data from approximately 900 individuals.
Chronic obstructive pulmonary disease (COPD) is associated with decreased lung function and increased risk of exacerbations, and previous studies of anti-interleukin-5 biologics have yielded mixed results, according to Surya Bhatt, MD, of the University of Alabama at Birmingham, and colleagues. Dupilumab, a fully human monoclonal antibody, is designed to target receptors for interleukin-4 and interleukin-13, known drivers of type 2 inflammation, the researchers said.
In a study known as the BOREAS trial, simultaneously published in the New England Journal of Medicine and presented at the 2023 American Thoracic Society International Conference in Washington, DC, the researchers randomized 468 COPD patients to 300 mg of dupilumab and 471 to a subcutaneous placebo injection once every 2 weeks.
The patients met criteria for type 2 inflammation, defined as blood eosinophil counts of at least 300 per microliter, and demonstrated an increased risk of exacerbations despite a history of triple inhaler therapy. The patients ranged in age from 40 to 80 years (mean age 65 years) and had physician-diagnosed COPD for at least 12 months. Approximately two thirds were men, and 84% were White. The study population overall had an average of 2.3 moderate or severe COPD exacerbations in the past year, and 30% were current smokers.
Meeting Primary and Secondary Endpoints
The primary outcome was the annualized rate of COPD exacerbations, which was 0.78 in the dupilumab group vs. 1.10 in the placebo group, (rate ratio 0.70, P < .001).
Secondary endpoints included change in prebronchodilator forced expiratory volume in 1 second (FEV1). This change was significantly greater from baseline to 12 weeks in the dupilumab group compared with the placebo group (mean of 0.160 L vs. 0.077 L, P < .001); this difference continued at 52 weeks.
Other secondary endpoints examined quality of life using St. George’s Respiratory Questionnaire (SGRQ) and the Evaluating Respiratory Symptoms in COPD (E-RS: COPD). On these measures, lower scores indicated better quality of life and less severe symptoms, respectively.
SGRQ total scores improved by 4 or more points in 51.5% of dupilumab patients and 43.1% of placebo patients, and the least squares mean difference in the dupilumab group vs. the placebo group from baseline to 52 weeks was -3.4 (P = .002). The least squares mean difference in E-RS: COPD total score from baseline to 52 weeks in dupilumab patients vs. placebo patients was -1.1 (P = .001).
Notably, patients reported improvement in SGRQ as early as 4 weeks after starting treatment, the researchers wrote.
In addition, a subgroup analysis of patients with levels of fractional exhaled nitric oxide (FeNO) of 20 ppb or higher also showed significantly greater 38% reduction in exacerbations with dupilumab compared with placebo after 52 weeks (P = .005).
Overall, 77.4% of dupilumab patients and 76.0% of placebo patients reported any adverse events during the study. The most common were nasopharyngitis, upper respiratory tract infection, and headache, which occurred in approximately 6%-10% of patients in both groups.
Serious adverse events occurred in 13.6% of dupilumab patients and 15.5% of placebo patients, and adverse events resulting in death occurred in 1.5% and 1.7% of dupilumab and placebo patients, respectively.
The improvements associated with dupilumab "confirm the role of interleukin-4 or interleukin-13 (or both) in the pathophysiological characteristics of this COPD subpopulation with type 2 inflammation that extends beyond the role of interleukin-5 and eosinophils," the researchers noted in their discussion. By inhibiting the interleukin-4 and interleukin-13 pathways, dupilumab may contribute to reducing goblet-cell hyperplasia, mucus secretion, and airway remodeling, they said.
"This trial showed that dupilumab has the potential to impact the vicious cycle of exacerbations and lung function decline in patients with uncontrolled COPD with type 2 inflammation, and significantly improve respiratory symptoms," Bhatt said in a press release accompanying the presentation and publication of the findings. "Dupilumab also helped improve health-related quality of life measures, which, from my years of experience as a physician, are just as meaningful for patients as being able to breathe easier."
The findings were limited by several factors including the conduction of the study during the COVID-19 pandemic, which may have contributed to reduced exacerbations because of changes in patient exposures and behaviors, the researchers noted in their discussion. Other limitations included the underrepresentation of Black patients and the lack of stratification of patients by smoking status at the time of randomization, they said. However, the results were consistent across multiple COPD endpoints and support the safety and efficacy of dupilumab to improve outcomes and quality of life in COPD patients, they concluded.
A replication of the phase 3 study of dupilumab for management of COPD exacerbations, known as NOTUS, is underway, with results expected in 2024, according to the press release from manufacturer Regeneron.
Dupilumab is currently indicated for individuals aged 6 months and older with moderate-to-severe atopic dermatitis and for individuals 6 years and older with moderate-to-severe eosinophilic or oral steroid-dependent asthma who are not adequately managed with other therapies; it also is indicated for use in conjunction with other medications for chronic rhinosinusitis with nasal polyps in adults aged 18 years and older.
The study was sponsored by Sanofi and Regeneron. Dr. Bhatt disclosed serving as a consultant for Sanofi and Boehringer Ingelheim.
N Engl J Med. May 22, 2023. Abstract.
ATS International Conference 2023. Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts. Presented May 21, 2023.
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Cite this: Dupilumab Curbs Acute COPD Exacerbations - Medscape - May 22, 2023.