Dupilumab in type 2 airway inflammation-a step forward in targeted therapy for COPD

Chronic obstructive pulmonary disease (COPD) is characterized by persistent symptoms and airflow limitation due to a combination of small airway obliteration and alveolar destruction.1Global Initiative for Chronic Obstructive Lung Disease (GOLD)Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report.https://goldcopd.org/2023-gold-report-2/Date accessed: September 1, 2023Google Scholar Underpinning its diverse nature and phenotypic heterogeneity is a complex interplay of genetics, lung development, dysanapsis, and environmental exposures, in particular cigarette smoking, over time.1Global Initiative for Chronic Obstructive Lung Disease (GOLD)Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report.https://goldcopd.org/2023-gold-report-2/Date accessed: September 1, 2023Google Scholar The adoption of precision medicine in fields such as asthma has spurred efforts in phenotyping and endotyping COPD to guide management. Closely related to this is the concept of “treatable traits,” which is defined as the identification of distinct aspects of a disease with specific therapeutic targets. Eosinophilic COPD may be one such treatable trait. COPD was conventionally thought to be characterized mainly by neutrophilic airway inflammation mediated by exposure to tobacco smoke, microbes, and oxidative stress. However, eosinophilic airway inflammation, classically seen in asthma, can also be found in a sizable subgroup of patients with COPD even after detailed exclusion of asthma.1Global Initiative for Chronic Obstructive Lung Disease (GOLD)Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report.https://goldcopd.org/2023-gold-report-2/Date accessed: September 1, 2023Google Scholar The prevalence of eosinophilic COPD varies depending on the definitions used and thresholds for sputum or blood eosinophil count as a biomarker (eg, ∼20% with a blood eosinophil count of >300 cells/μL).2Watz H. Tetzlaff K. Wouters E.F. Kirsten A. Magnussen H. Rodriguez-Roisin R. et al.Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial.Lancet Respir Med. 2016; 4: 390-398Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar The Global Initiative for Chronic Obstructive Lung Disease report has emphasized that asthma and COPD are distinct disorders, although they can share treatable traits.1Global Initiative for Chronic Obstructive Lung Disease (GOLD)Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report.https://goldcopd.org/2023-gold-report-2/Date accessed: September 1, 2023Google Scholar Indeed, eosinophilic COPD might have underlying mechanisms different from those of eosinophilic asthma, with differences in bronchial epithelium gene expression observed between these conditions.3George L. Taylor A.R. Esteve-Codina A. Soler Artigas M. Thun G.A. Bates S. et al.Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma.Allergy. 2019; 75: 370-380Crossref Scopus (32) Google Scholar Alternatively, eosinophilic COPD might reflect a spectrum of airway diseases along a continuum classified as asthma-COPD overlap.4Global Initiative for AsthmaGlobal strategy for asthma management and prevention, 2023.www.ginasthma.orgDate accessed: September 1, 2023Google Scholar Asthma-COPD overlap is an umbrella term for a heterogeneous entity, comprising subgroups, including asthma with progressive airflow obstruction, asthma in smokers, and COPD with features of asthma such as airway hyperresponsiveness. Identifying eosinophilic COPD as a treatable trait has practical implications for treatment. Inhaled corticosteroids (ICSs), either in combination with a single long-acting bronchodilator or a dual long-acting β-agonist and muscarinic antagonist as triple therapy, have been shown to reduce exacerbations; improve symptoms, lung function, and quality of life; and potentially reduce mortality in patients with COPD and a high exacerbation risk and elevated blood eosinophil count. These clinical outcomes demonstrate a dose-response relationship with greater magnitude of effects at higher blood eosinophil counts,1Global Initiative for Chronic Obstructive Lung Disease (GOLD)Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report.https://goldcopd.org/2023-gold-report-2/Date accessed: September 1, 2023Google Scholar highlighting the mechanistic role of eosinophilic inflammation in exacerbations. These studies provide the scientific basis for the Global Initiative for Chronic Obstructive Lung Disease recommendation for the use of combination ICSs and long-acting bronchodilators in patients with a high exacerbation risk and blood eosinophil count of 300 cells/μL or higher.1Global Initiative for Chronic Obstructive Lung Disease (GOLD)Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report.https://goldcopd.org/2023-gold-report-2/Date accessed: September 1, 2023Google Scholar Conversely, ICS use is not recommended in the absence of exacerbations or a blood eosinophil count less than 100 cells/μL, owing to an increased risk of pneumonia and a low likelihood of beneficial treatment effect.1Global Initiative for Chronic Obstructive Lung Disease (GOLD)Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report.https://goldcopd.org/2023-gold-report-2/Date accessed: September 1, 2023Google Scholar Although biologics targeting the type 2 cytokines IL-5, IL-4, and IL-13 or their cognate receptors have proven efficacy in asthma, their efficacy in eosinophilic COPD has been less convincing. Among high-risk patients who are already receiving triple therapy and have received the anti–IL-5 mAb mepolizumab, the METREX trial showed a modest 18% reduction in annual rate of moderate or severe exacerbations in those with an eosinophilic phenotype (defined as a blood eosinophil count of ≥150 cells/μL at screening or ≥300 cells/μL in the previous year) but no significant difference in the overall intention-to-treat population, which also comprised patients with a noneosinophilic phenotype.5Pavord I.D. Chanez P. Criner G.J. Kerstjens H.A.M. Korn S. Lugogo N. et al.Mepolizumab for eosinophilic chronic obstructive pulmonary disease.N Engl J Med. 2017; 377: 1613-1629Crossref PubMed Scopus (376) Google Scholar The parallel METREO study showed a 14% to 20% reduction in exacerbations with use of mepolizumab in patients with an eosinophilic phenotype, but this finding did not reach statistical significance.5Pavord I.D. Chanez P. Criner G.J. Kerstjens H.A.M. Korn S. Lugogo N. et al.Mepolizumab for eosinophilic chronic obstructive pulmonary disease.N Engl J Med. 2017; 377: 1613-1629Crossref PubMed Scopus (376) Google Scholar The GALATHEA and TERRANOVA studies did not find any significant reduction in exacerbations with the use of benralizumab, an anti–IL-5Rα mAb, in a similar group of patients with a blood eosinophil count of 220 cells/μL or higher.6Criner G.J. Celli B.R. Brightling C.E. Agusti A. Papi A. Singh D. et al.Benralizumab for the prevention of COPD exacerbations.N Engl J Med. 2019; 381: 1023-1034Crossref PubMed Scopus (166) Google Scholar These biologics also did not improve lung function, symptoms, or quality of life despite depleting peripheral blood eosinophils,5Pavord I.D. Chanez P. Criner G.J. Kerstjens H.A.M. Korn S. Lugogo N. et al.Mepolizumab for eosinophilic chronic obstructive pulmonary disease.N Engl J Med. 2017; 377: 1613-1629Crossref PubMed Scopus (376) Google Scholar,6Criner G.J. Celli B.R. Brightling C.E. Agusti A. Papi A. Singh D. et al.Benralizumab for the prevention of COPD exacerbations.N Engl J Med. 2019; 381: 1023-1034Crossref PubMed Scopus (166) Google Scholar calling the utility of targeting eosinophilic airway inflammation in COPD into question. The results of the Boreal Ecosystem-Atmosphere Study (BOREAS),7Bhatt S.P. Rabe K.F. Hanania N.A. Vogelmeier C.F. Cole J. Bafadhel M. et al.Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts.N Engl J Med. 2023; 389: 205-214Crossref PubMed Scopus (23) Google Scholar which was recently published in the New England Journal of Medicine, provide more promise for targeting type 2 inflammation in COPD. The BOREAS was a 52-week, phase 3, double-blind, multicenter randomized trial involving 939 patients with high-risk COPD and a blood eosinophil count of 300 cells/μL or higher.7Bhatt S.P. Rabe K.F. Hanania N.A. Vogelmeier C.F. Cole J. Bafadhel M. et al.Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts.N Engl J Med. 2023; 389: 205-214Crossref PubMed Scopus (23) Google Scholar These patients had a mean age of 65 years, with asthma carefully excluded. Administration of dupilumab, 300 mg every 2 weeks subcutaneously as add-on treatment to baseline triple therapy, resulted in a 30% reduction in annualized rate of moderate or severe exacerbations (rate ratio vs placebo = 0.70; 95% CI = 0.58-0.86; P < .001), improved and sustained lung function through 52 weeks (least-squares mean difference in FEV1 value = 83 mL [95% CI = 38-128 mL), improved St. George’s Respiratory Questionnaire scores, and reduced symptoms based on Evaluating Respiratory Symptoms in COPD score. The effects of treatment on exacerbations and lung function were greater among patients with a baseline Feno level of 20 ppb or higher, which is consistent with dupilumab’s modulation of type 2 inflammation. The improvement in lung function was rapid, perhaps in part reflecting the inhibition of the direct effects of IL-13 on airway smooth muscle tone and consequently airway lumen.8Brightling C.E. Nordenmark L.H. Jain M. Piper E. She D. Braddock M. et al.Effect of anti–IL-13 treatment on airway dimensions in severe asthma.Am J Respir Crit Care Med. 2016; 194: 118-120Crossref PubMed Scopus (14) Google Scholar The pattern of benefits was similar to but observed to be of a lesser extent than that seen in asthma. For example, the rate reductions in exacerbations for those receiving dupilumab in a dose 200 mg or 300 mg versus placebo in the phase 3 QUEST asthma study were 0.34 (95% CI = 0.24-0.48) and 0.33 (95% CI = 0.23-0.45), respectively.9Castro M. Corren J. Pavord I.D. Maspero J. Wenzel S. Rabe K.F. et al.Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma.N Engl J Med. 2018; 378: 2486-2496Crossref PubMed Scopus (1147) Google Scholar What could account for the positive findings of the BOREAS when previous studies of anti–IL-5 therapies failed to show significant effects on clinical outcomes? We offer a few postulations. First, eosinophilic inflammation may not be the sole mechanism of acute exacerbations. By blocking both IL-4 and IL-13 via the shared receptor IL-4Rα, dupilumab exerts broader inhibition of type 2 inflammation, modulating effector cells and reducing goblet cell hyperplasia, mucus production, airway smooth muscle reactivity, and remodeling. The resultant clinical effects could include reductions in exacerbations and airflow limitation not derived from mepolizumab or benralizumab. Second, depletion of eosinophils with mepolizumab or benralizumab might potentially promote exacerbations that are not mediated by type 2 inflammation but are instead driven by infections not responsive to steroids or biologics. However, the observations to date do not suggest that the airway microbiome is adversely affected by targeting IL-5 in COPD. Third, patient selection might account for the different findings across trials. A prespecified meta-analysis of METREX and METREO showed a greater reduction in exacerbations, with a higher blood eosinophil count of 300 cells/μL or higher at screening,5Pavord I.D. Chanez P. Criner G.J. Kerstjens H.A.M. Korn S. Lugogo N. et al.Mepolizumab for eosinophilic chronic obstructive pulmonary disease.N Engl J Med. 2017; 377: 1613-1629Crossref PubMed Scopus (376) Google Scholar whereas a post hoc analysis of the GALATHEA and TERRANOVA trials suggested a treatment response with 3 or more exacerbations, higher blood eosinophil counts, and use of triple therapy. The magnitude of the exacerbation reduction in these post hoc analyses was similar to that observed in the BOREAS, highlighting the need for refinement in patient selection. Lastly, the BOREAS was conducted during the coronavirus disease 2019 (COVID-19) pandemic, with an observed reduction in COPD exacerbations triggered by respiratory infections typically associated with non–type 2 inflammation.10Aung H. McAuley H. Porter K. Richardson M. Wright A. Brightling C.E. et al.Differences in hospital admissions for acute exacerbations of COPD during the COVID-19 pandemic stratified by stable blood eosinophil count.Eur Respir J. 2023; 622301125Crossref Scopus (1) Google Scholar The between-group differences in the BOREAS could thus be magnified secondary to a lower exacerbation frequency in the placebo group, with potentially lower treatment effects once infective triggers return to nonpandemic frequency. Notwithstanding these possible limitations, dupilumab appears promising with its broad effects on type 2 inflammation, representing a potential step forward in the treatment armamentarium for patients with high-risk COPD who are already receiving maximal inhaler therapy. The findings from the BOREAS need to be confirmed in the replicate phase 3 study, and if they are confirmed, then further explored in pragmatic, real-life settings. Importantly, further replicate studies of mepolizumab and benralizumab are also ongoing, and biologics targeting the “alarmins” thymic stromal lymphopoietin and IL-33/ST2 might offer effects beyond type 2 inflammation. Future, effective treatment strategies to better address disease components such as emphysema, airway microbial dysbiosis (beyond antibiotics therapies), comorbidities, and exposure prevention also need to be devised (Fig 1). Continued success in targeting these different COPD phenotypes and endotypes by using precision medicine strategies presents a real opportunity to transform future COPD care. Supported by the National Institute for Health and Care Research (NIHR), Leicester Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Disclosure of potential conflict of interest: N. J. Greening has received honoraria for lectures, conference travel and advisory boards from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKleine and Pulmonx; his institute has received grants and consultation fees from Genentech, Roche and GlaxoSmithKleine. C. E. Brightling has received grants and consultancy fees from 4D Pharma, AstraZeneca, Chiesi, Genentech, GlaxoSmithKline, Mologic, Novartis, Regeneron Pharmaceuticals, Roche, and Sanofi. The rest of the authors declare that they have no relevant conflicts of interest.