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Background:
Review

Dupilumab for Chronic Obstructive Pulmonary Disease: A Systematic Review

by
Julia Young
1,
Taylor Spisany
1,
Corey M. Guidry
1,
Jisoo Hong
1,
Jessica Le
1,
Edward El Rassi
2 and
Paul M. Boylan
1,*
1
College of Pharmacy, The University of Oklahoma Health Sciences, Oklahoma City, OK 73117, USA
2
College of Medicine, The University of Oklahoma Health Sciences, Oklahoma City, OK 73117, USA
*
Author to whom correspondence should be addressed.
Biologics 2025, 5(1), 5; https://doi.org/10.3390/biologics5010005
Submission received: 23 December 2024 / Revised: 23 January 2025 / Accepted: 17 February 2025 / Published: 20 February 2025
(This article belongs to the Section Monoclonal Antibodies)
Browse Figures
Versions Notes

Abstract

:
Background/Objectives: Dupilumab was recently approved to treat eosinophilic phenotypes of chronic obstructive pulmonary disease (COPD). This systematic review aimed to collect and appraise the efficacy and safety of dupilumab to treat patients with COPD. Methods: Databases searched included Ovid Medline, Embase, Web of Science, Directory of Open Access Journals, and International Pharmaceutical Abstracts. Experimental and observational studies, including case reports/series, were eligible for inclusion. Reports were independently screened, appraised, and extracted by three investigators; disagreements were resolved through discussion and agreement. Quality appraisal was conducted using the Cochrane Risk of Bias Tool 2.0, Newcastle–Ottawa Scale, and JBI Checklist for experimental, observational, and case studies, respectively. Results: A total of 307 unique reports were identified, of which 17 were included in this systematic review. The majority (n = 11, 64.7%) of reports presented evidence from the BOREAS and NOTUS trials, the landmark trials serving as the basis for dupilumab’s approval to treat refractory eosinophilic COPD. The results from this systematic review found that dupilumab reduced exacerbations of COPD in patients treated with inhaled triple therapy and it was well tolerated. Conclusions: When added to inhaled triple therapy, dupilumab may decrease patients’ risk for acute exacerbations of COPD. Additional research is necessary to substantiate these findings for broader generalizability, including populations with non-eosinophilic COPD phenotypes.

1. Introduction

Chronic obstructive pulmonary disease (COPD) is a prevalent lung disease characterized by chronic respiratory symptoms due to persistent and progressive airflow obstruction [1]. An estimated 16 million adults in the United States (US) are affected by COPD, and it is the third leading cause of death worldwide and among the top 10 causes of death in the US [2]. Inhaled bronchodilators are the cornerstone for symptom management and slowing disease progression, typically administered regularly to prevent or alleviate symptoms. Additional classes of medications with approved indications for COPD include inhaled corticosteroids (ICSs), phosphodiesterase inhibitors, macrolide antibiotics, and methylxanthines [1]. The most recent Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report highlights the complexity and heterogeneity of COPD, emphasizing the need for further research into phenotypic variations and the underlying biological mechanisms that contribute to different inflammatory pathways. Among these, type 2 inflammation—mediated by interleukin (IL)-4, IL-5, and IL-13—has gained attention as a significant contributor to a subset of COPD cases. Elevated blood eosinophil levels, a biomarker of type 2 inflammation, have been associated with increased exacerbation risk and responsiveness to anti-inflammatory therapies, such as ICS. While neutrophilic inflammation remains more common in COPD, growing recognition of type 2 inflammation has spurred interest in biologics as potential adjunct treatments, given their ability to target key cytokines involved in this pathway and attenuate inflammation [3].
Previous trials conducted in patients living with COPD and investigating biologics targeting various cytokines have produced non-significant results [4]. The METREX and METREO trials evaluated the efficacy and safety of mepolizumab, an IL-5 antagonist, in COPD; however, neither demonstrated a significant difference in outcomes [5]. Similarly, the GALATHEA and TERRANOVA trials evaluated another IL-5 antagonist, benralizumab, but found no significant difference in reducing exacerbations compared to the placebo [6]. In the COURSE trial, the anti-thymic stromal lymphopoietin biologic, tezepelumab, did not significantly reduce exacerbations [7]. Thus, based on this evidence, biologics have not been routinely recommended to treat patients living with COPD [1,8]. However, the 2025 GOLD Report added a new recommendation for dupilumab to treat patients with eosinophilia at high risk for exacerbations [1,9].
Dupilumab, a human monoclonal antibody, received approval in 2024 as a therapeutic option for patients with refractory eosinophilic COPD who are inadequately controlled on standard therapies. This expanded indication was supported by the phase III randomized controlled trials, BOREAS and NOTUS, which demonstrated dupilumab’s efficacy in reducing exacerbations and highlighted its broader benefits, including improvements in lung function and quality of life [10,11]. In addition to COPD, dupilumab is US Food and Drug Administration (FDA)-approved for moderate-to-severe asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and prurigo nodularis. Mechanistically, dupilumab inhibits IL-4 and IL-13 activity, reducing type 2 inflammation. Given the landmark findings from the BOREAS and NOTUS trials and the lack of significant results among other biologics for COPD, there is a need to collect and appraise the body of evidence supporting dupilumab’s use in treating patients living with COPD. In 2024, Freund and colleagues published a systematic review exploring patient-reported outcome measures (PROMs) of several biologics in COPD; PROMs included quality of life, symptoms, self-reported exacerbations, and self-perceived COPD status [4]. This focus on real-world data, which are often under-represented in the literature, found that PROMs mostly correlated with other efficacy outcomes, with dupilumab being the only biologic to show improved PROMs compared to placebo; however, additional systematic reviews addressing clinical endpoints, including but not limited to exacerbations of COPD and adverse drug events, are necessary.
This current systematic review aimed to evaluate the available evidence on dupilumab and its use in COPD, examining the clinical outcomes, safety profiles, and patient-reported measures.

2. Methods

This was a systematic review including experimental and observational studies evaluating or describing the efficacy or safety of dupilumab in treating COPD. This project was registered in the International Prospective Register for Systematic Reviews (PROSPERO (CRD42024602890), registered 29 October 2024) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist (Supplementary File S1) [12].
A health sciences librarian was consulted to develop the search strategy and pilot it in Ovid Medline. The health sciences librarian and one author (P.M.B.) reviewed and discussed the strategy and Ovid Medline results and then made refinements and determined additional databases to be included in the search.
Databases searched included Ovid Medline, Embase, Web of Science, Directory of Open Access Journals, and International Pharmaceutical Abstracts. The health sciences librarian executed the search across the databases. Key terms were used to capture concepts of “chronic obstructive pulmonary disease” and “dupilumab”; search strategies were tailored to each database. Final database searches were completed on 9 October 2024; final in-text citation searching was completed on 10 November 2024. Exact search strategies for each database are included in the Supplementary File S2.
The results from the searches were exported as research information system files and imported into Covidence (Covidence, Melbourne, VI, Australia) for abstract screening and full-text review. Software preliminarily removed duplicate reports, and then the remaining reports were manually reviewed for duplication by one reviewer (P.M.B.). After de-duplication, abstracts and full texts were independently screened by two reviewers (P.M.B. and either J.L. or J.H.). If there were conflicts in the screening, then consensus was achieved through discussion and agreement between the two screening reviewers (P.M.B. and J.L. or J.H.).
Reports were eligible if they were experimental or observational designs (i.e., cohort, cross-sectional, case–control, case series/reports). Commentaries, editorials, and reviews were excluded; however, references within excluded reports were screened to identify eligible reports not captured by the database searches. Studies evaluating patients with comorbid asthma (i.e., asthma–COPD overlap) were excluded. Reports were eligible if they were indexed in a database up until 9 October 2024, though initial indexes varied across the databases searched (Supplementary File S2).
Data extraction points included those published in existing systematic reviews of dupilumab for treating asthma [13,14]. Information extracted included spirometry, symptoms/quality of life, COPD exacerbations (ECOPD), and adverse events. Quality appraisal of the included studies was evaluated using the Cochrane Risk of Bias Tool 2.0 (RoB 2) for experimental studies [15], Newcastle–Ottawa Scale (NOS) for observational studies [16], and the Joanna Briggs Institute (JBI) Checklist for case reports/series [17]. Two reviewers (J.L. and J.H.) independently extracted data points in Covidence and performed quality appraisal using electronic word processing documents for the RoB 2, NOS, and JBI checklists. One author (P.M.B.) independently reviewed the extracted data and quality assessment checklist; consensus was achieved through discussion and agreement among three authors (P.M.B., J.L., and J.H.). The PRISMA flow diagram figure was generated using the application PRISMA2020 Shiny, and the quality appraisal figures were generated using the application robvis [18,19].

3. Results

The record screening, appraisal, and extraction are presented in Figure 1. Summarily, 307 unique reports were screened, 39 full texts were sought for appraisal, and 17 reports included in this systematic review [10,11,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]. These include two reports including phase 3 randomized controlled trials [10,11], ten published abstracts reporting on sub-analyses of the two aforementioned clinical trials [20,21,22,23,24,25,26,27,28,30], one observational cohort study [33], and four case reports [29,31,32,34].
Citations, locations, study design, and study populations are presented in Table 1 [10,11,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]. Among the experimental studies (BOREAS and NOTUS), the control groups were placebos, and the follow-up period was 52 weeks [10,11,20,21,22,23,24,25,26,27,28,30]. Among 939 patients randomized within the BOREAS trial, 468 were randomized to receive dupilumab [10]; among 935 patients randomized within the NOTUS trial, 470 were randomized to receive dupilumab [11]. In a 7-year retrospective cohort study of US adults living with COPD identified within the TriNetX database, 1531 participants were identified as having received treatment with dupilumab over a 7-year period (between April 2017 and August 2024) [33]. Among the four case reports, three had authors’ affiliated locations specified in the US [32], Italy [29], and China [34]. Overall, a total of 2473 patients living with COPD and treated with dupilumab were represented across all studies in this systematic review [10,11,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34].
Risk of bias is presented in Figure 2. The full texts of the BOREAS and NOTUS studies were appraised using the RoB 2 tool [10,11,15], the observational cohort study using the NOS scale [16,33], and four case reports using the JBI checklist [17,29,31,32,34]. Given that the ten published abstracts reporting on sub-analyses of the two aforementioned clinical trials would not be able to completely address all the bias domains in the RoB tool, they were not assessed for risk of bias [20,21,22,23,24,25,26,27,28,30]. Both the BOREAS and NOTUS studies were deemed to be at low risk of bias both overall and across five individual domains including randomization, protocol deviation, missing outcome data, measurement bias, and selection bias [10,11]. The observational cohort study was deemed to be at high risk of bias using the NOS instrument because of concerns for selection bias, largely due to lack of clear ascertainment of exposures and unknown presence of outcomes prior to study start [16,33]. Among the four case reports, two cases were deemed to be at low risk for bias [29,34] and two cases were deemed to be at high risk for bias [31,32]. Per the JBI checklist, all cases provided clear information regarding patients’ current clinical situations, diagnostic methods, and takeaway lessons; however, two cases inadequately reported adverse effects and were unclear in their description of treatments [31,32].
Table 2 presents NOTUS and BOREAS information [10,11]. Summarily, the majority of patients enrolled in these landmark trials were white, older adults using inhaled triple therapy (i.e., LABA/LAMA/ICS). Given that the mean number of ECOPD within the last 12 months was approximately two, most patients were classified as GOLD Category E. Though the average serum eosinophil count was approximately 400 cells/microliter in both studies, there was significant variability in these levels given standard deviations of approximately 300 cells/liter.

3.1. BOREAS Trial

The BOREAS trial was an international, double-blinded, placebo-controlled randomized control trial which aimed to assess the efficacy and safety of dupilumab in patients living with COPD and type 2 inflammation and who were treated with inhaled triple therapy (ICS/LABA/LAMA). Dupilumab 300 mg was administered via subcutaneous route every 2 weeks over a 52-week study period. The primary study endpoint was the annualized rate of moderate-to-severe ECOPD. Secondary endpoints included lung function measurements and scores on the St. George’s Respiratory Questionnaire. Ultimately, 939 patients were randomized (468 to dupilumab and 471 to placebo) and adequately powered to meet the primary outcome. The results demonstrated that the annualized rate ratio of moderate-to-severe ECOPD was 0.70 (95% CI 0.58 to 0.86, p < 0.001), in favor of dupilumab. As early as 2 weeks into the study, dupilumab increased lung function via pre-bronchodilator FEV1 measurements and sustained these improvements through study completion at 52 weeks (83 mL, 95% CI 38 to 128, p < 0.001). Participants also reported symptomatic improvements measured via the St. George’s Respiratory Questionnaire score. By study completion at week 52, 51.5% of dupilumab-treated patients experienced the minimum clinically important difference (4-point change) versus 43.1% of placebo-treated participants (odds ratio 1.4, 95% CI 1.1. to 1.9, p = 0.009) [10].

3.2. NOTUS Trial

The NOTUS trial had a study design similar to the BOREAS trial [11]. It served as a confirmatory investigation to corroborate the positive findings observed in the BOREAS trial and included an interim analysis of the primary endpoint (i.e., annualized rate of moderate-to-severe ECOPD). Ultimately, 935 patients were randomized (470 to dupilumab and 465 to placebo), providing adequate power to assess the primary outcome. The results demonstrated an annualized rate ratio of moderate-to-severe ECOPD of 0.66 (95% CI 0.54 to 0.82, p < 0.001) in favor of dupilumab. Dupilumab increased lung function via pre-bronchodilator FEV1 measurements at 52 weeks (62 mL, 95% CI 11 to 113, p = 0.02). The least-squares mean difference in the St. George’s Respiratory Questionnaire total score between dupilumab and placebo at 52 weeks was −3.4 points (95% CI, −5.8 to −0.9; not adjusted for multiplicity or hypothesis-tested) [11].

3.3. Efficacy and Safety Outcomes

Table 3 presents the efficacy (i.e., spirometry and symptoms) and safety (i.e., exacerbations and adverse events) data from the included studies.

3.3.1. Lung Function

The results from the BOREAS and NOTUS trials and their published abstracts demonstrated improvements in lung function among patients treated with dupilumab. Statistically significant improvements were observed in forced expiratory volumes, forced vital capacities, and pre–post-bronchodilator measurements [10,11,21,22,27,30], though these increases did not reach the clinically meaningful threshold of 200 mL [35]. Two case reports commented on lung function, wherein one patient’s baseline spirometry revealed very severe COPD [31] and another patient’s lung function declined during treatment on dupilumab [32].

3.3.2. Quality of Life and Symptoms

Among the 17 studies included in this systematic review, only the BOREAS and NOTUS trials completely reported on quality of life and symptoms [10,11,24]. Both studies used the St. George’s Respiratory Questionnaire and assessed changes in total tool score, defined as a minimum clinically important difference of 4 points [36]. In the BOREAS study, the odds of achieving a minimum clinically important difference were greater in those who were treated with dupilumab versus placebo [10]. In the NOTUS trial, dupilumab-treated patients showed greater reductions in total St. George’s Respiratory Questionnaire scores versus the placebo, though a formal hypothesis test of these findings was unexplored [11,28].

3.3.3. Exacerbations of COPD

The results from both the BOREAS and NOTUS studies showed that dupilumab significantly reduced moderate-to-severe ECOPD. Nominally similar results were presented in both analyses: the event rate ratio reported in BOREAS was 0.70 and that reported in NOTUS was 0.66 [10,11]. In a treat-by-biomarker interaction analysis of the BOREAS trial stratified across four groups of eosinophilia, dupilumab continued to demonstrate statistically significant reductions in ECOPD, with the greatest reductions observed in patients with baseline serum eosinophils greater than 900 cells/microliter [26]. A sub-analysis of 133 Asian patients within the BOREAS study observed a reduced rate ratio of ECOPD, though statistical significance was unreported in the abstract and the confidence interval appeared to cross a line of no difference [22]. In a population-based, propensity score-weighted cohort study including adults treated with LABAs with or without dupilumab, dupilumab-treated patients had an approximately 40% lower risk for ECOPD compared to matched controls on LABA therapy [33]. In one case report of a patient living with GOLD severity 3 COPD and treated with triple therapy, dupilumab prevented all ECOPD (including mild, moderate, and severe categories) over 51 months [32].

3.3.4. Adverse Events

The results from the BOREAS and NOTUS studies showed that dupilumab was well tolerated compared to placebo. Between 60 and 80% of all patients reported adverse events [10,11]. The most prevalent events included headache, nasopharyngitis, and upper respiratory tract infection and/or inflammation. Though not hypothesis-tested for significance, the BOREAS and NOTUS trials observed that dupilumab-treated patients had a lower incidence of major adverse cardiovascular events versus placebo. In a 7-year retrospective cohort study of 1521 dupilumab-treated patients propensity-score-matched to comparators on LABAs, dupilumab significantly reduced adverse events attributable to pneumonia, acute respiratory failure, acute respiratory distress syndrome, and eosinophilia [33]. Three case reports described possible adverse effects among dupilumab-treated patients: eosinophilic pneumonia [34], bullous pemphigoid worsening [29], and tracheal stenosis [31].

4. Discussion

This systematic review identified 17 reports (of 7 unique studies) describing the efficacy and safety of dupilumab in patients living with COPD [10,11,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]. In total, 2473 patients living with COPD and treated with dupilumab were represented across the seventeen included reports. Of the 17 reports, 12 (70.6%) reported on results from the BOREAS and NOTUS landmark studies, which helped dupilumab achieve approval for COPD. Both the BOREAS and NOTUS studies were appraised as low risk of bias per the RoB 2 tool, and two case reports also deemed at low risk of bias; however, one observational study and two case reports were appraised as high risk for bias using the NOS and JBI tools, respectively.
The two experimental studies demonstrated that dupilumab reduced the annualized rate of moderate-to-severe ECOPD by 30 and 34% compared to placebo [10,11]. The propensity-weighted observational cohort study demonstrated an even greater reduction in ECOPD with dupilumab, approximately 41.5%, compared to patients living with COPD and prescribed an LABA [33]. When evaluating other biologics for reducing ECOPD, the METREX trial initially demonstrated a statistically significant 18% reduction in COPD exacerbations with mepolizumab 100 mg; however, in the confirmatory METREO trial, a 20% exacerbation reduction with the 100 mg dose and a 14% exacerbation reduction with the 300 mg dose of mepolizumab did not reach statistical significance [5]. The GALATHEA and TERRANOVA studies evaluating benralizumab found no statistically significant reductions in ECOPD with either the lower 30 mg or higher 100 mg dose; however, the study observed greater reductions in exacerbations in patients with higher eosinophil levels [6]. Collectively, these findings may suggest significance with dupilumab in a subset of patients diagnosed with COPD where both type 2 and non-type 2 inflammation overlap. David and colleagues demonstrated that 25 to 30% of patients with COPD have a raised number of circulating eosinophils, while D’Silva and colleagues found 8 to 10% have persistently elevated eosinophils in their sputum [37,38]. The Agency for Health Care Research and Quality considers COPD a potentially preventable cause for hospital readmission and one of the top conditions associated with 30-day all-cause readmissions [39]. In the 2025 GOLD Report, dupilumab is recommended with evidence level A for patients already maximized on triple-inhaler therapy (LABA/LAMA/ICS) with moderate-to-severe COPD who have a history of exacerbations, chronic bronchitis, and blood eosinophils greater than or equal to 300 cells/microL. Dupilumab is now a part of the exacerbation pharmacotherapy pathway, along with azithromycin in former smokers, and roflumilast in patients with an FEV of less than 50% and chronic bronchitis [1].
Recently, concerns regarding the design and results of the BOREAS and NOTUS trials have come to light. Though patients with a formal asthma diagnosis were excluded from these trials, some argue that trial participants might not be representative of COPD alone. Asthma and COPD are discrete disorders, though they may share similar traits, and making a differential diagnosis is often difficult [1,40]. Additionally, it has been postulated that eosinophilic COPD may represent the disease process historically referred to as asthma–COPD overlap, as, unlike in COPD, eosinophilia has been shown to positively correlate with increased asthma activity, steroid requirements, and exacerbation risk [41,42,43]. Individuals with a current or previous smoking history typically have higher circulating blood eosinophil levels than never-smokers, though the use of high-dose ICS has been shown to greatly reduce peripheral eosinophil counts [44,45]. Mean blood eosinophil counts in the BOREAS and NOTUS trials were 401 and 407 cells per microL, respectively, both with standard deviations of approximately 300 cells per microL [10,11]. With nearly 28% of patients in each study taking high-dose ICS at baseline (further decreasing baseline eosinophil counts), it may be hypothesized that a portion of included patients might have had undiagnosed asthma at baseline, potentially explaining the significant reduction in exacerbations [46]. Notably, patients randomized to placebo in the BOREAS trial experienced reductions in ECOPD from 2.1 events per year at baseline to 1.3 per year, which would no longer qualify them for inclusion in the study; similar findings were seen in the NOTUS trial, bringing into question the true utility of dupilumab [10,11,47]. While study investigators agreed that increased treatment adherence, health care visits, and other effects might have influenced this finding, they referenced similar exacerbation rates in placebo groups of other recent COPD trials of triple therapy and reaffirmed the significant differences found between dupilumab and placebo [48]. It has been hypothesized that other non-eosinophilic mechanisms may explain dupilumab’s success in reducing ECOPD. Through its effects on IL-4 and IL-13, dupilumab reduces goblet cell size and mucus production and decreases smooth muscle activity and remodeling in the airways [49]. Additionally, downstream signaling of other interleukins and T-helper cells may boost host defenses and the eradication of respiratory pathogens [50]. This may explain why the IL-5 inhibitors and thymic stromal lymphopoietin monoclonal antibody were unsuccessful.
The practical implications of introducing dupilumab for COPD must consider both the clinical and financial challenges of real-world patients. Cost-related medication nonadherence is already a significant concern for COPD patients receiving standard-of-care therapies [51]. Evidence of cost-related medication nonadherence with single-inhaler triple therapy is still limited, but introducing newer treatments like dupilumab could exacerbate any challenges. Biologics for asthma were introduced in 2003, and their use expanded substantially between 2015 and 2017, yet their high cost continues to meaningfully influence treatment guidelines. The 2024 GINA Report and 2020 National Heart, Lung, and Blood Institute guideline update recommends biologics only for severe asthma after optimizing non-biologic therapies [52,53]. In contrast, the 2025 GOLD Report does not address biologic costs [1]. Analyses comparing biologics to standard asthma care show that incremental cost-effectiveness ratios, which measure the additional cost per quality-adjusted life year gained, consistently exceed willingness-to-pay thresholds in both the US and Europe [13,54]. Notably, access to biologics likely varies geographically based on health care structure, reimbursement policies, and economic resources. In addition, these evaluations included biologics often requiring medical administration, increasing costs—a factor less applicable to dupilumab, which is self-administered. While COPD differs from asthma, similar economic concerns arise with added considerations. The more severe nature of COPD, with more frequent hospitalizations and long-term care, may enhance the cost effectiveness of dupilumab. However, advanced disease stages and shorter life expectancy may diminish its effects. Until more is known, cost effectiveness may rely on targeting patients with eosinophilia already optimized on triple therapy, guided by precise diagnostics and well-established clinical criteria. Therapy duration also requires careful consideration; current asthma guidelines lack clear criteria for biologic response but recommend reassessment after 6 to 12 months [52,53]. Developing clear criteria for dupilumab’s use in COPD will be crucial to balancing clinical benefits with economic sustainability. This aligns with Freund and colleagues’ 2024 review, which emphasizes the need for more evidence when considering the potential placebo effects, as discussed earlier, and the financial burden of utilizing biologics [4].

Limitations

This systematic review possesses limitations. Four studies (two randomized trials, one cohort study, and one case report) reported reductions in ECOPD [10,11,32,33], compared to two reports (one case report and one abstract) reporting worsening ECOPD and non-significant reductions in ECOPD [22,31]; thus, there may be potential for publication bias. Though we appraised the observational cohort study at high risk of bias because of concerns for selection bias and outcome reporting, this may be a function of the limitations imposed on the brief-report article type [33]; further elaborate research reports on Sun and colleagues’ findings may refute this appraisal. Much of the BOREAS and some of the NOTUS trials were conducted during COVID-19 pandemic, a period marked by a reduction in ECOPD possibly due to reduced exposure to respiratory viruses through social distancing. The patient population in both studies was predominately white, limiting their generalizability to individuals of other ethnicities. Both studies had large variability in the participants’ blood eosinophil counts, leaving room for self-interpretation on when to add dupilumab [10,11]. Further experimental and observational studies are warranted to determine dupilumab’s place in therapy, including in populations with non-type 2 inflammation (the more common COPD phenotype).

5. Conclusions

When added to inhaled triple therapy, dupilumab may decrease patients’ risk for acute exacerbations of COPD. Additional research is necessary to substantiate these findings for broader generalizability, including populations with non-eosinophilic phenotypes.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/biologics5010005/s1. Supplementary File S1: PRISMA 2020 Checklist; Supplementary File S2: Database Search Strategies.

Author Contributions

Conceptualization, J.Y. and P.M.B.; methodology, J.Y. and P.M.B.; software, P.M.B.; validation, J.Y., T.S., C.M.G., J.L., J.H., E.E.R. and P.M.B.; formal analysis, P.M.B.; investigation, J.L., J.H. and P.M.B.; resources, P.M.B.; data curation, P.M.B.; writing—original draft preparation, J.Y., T.S., C.M.G., J.L., J.H., E.E.R. and P.M.B.; writing—review and editing, J.Y., T.S., C.M.G., J.L., J.H., E.E.R. and P.M.B.; visualization, P.M.B.; supervision, P.M.B.; project administration, P.M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Acknowledgments

The authors acknowledge Shari Clifton for her assistance developing and executing the search strategy.

Conflicts of Interest

Paul M. Boylan reports unrelated and unrestricted research grant funding to The University of Oklahoma Health Sciences from Pfizer, Inc. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Figure 1. PRISMA Flow Diagram for Record Screening, Appraisal, and Extraction.
Figure 1. PRISMA Flow Diagram for Record Screening, Appraisal, and Extraction.
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Figure 2. Risk of Bias Assessments [10,11,15,16,17,29,31,32,33,34]. (A) Risk of bias in experimental studies; (B) Risk of bias in observational studies. (C) Risk of bias in case reports.
Figure 2. Risk of Bias Assessments [10,11,15,16,17,29,31,32,33,34]. (A) Risk of bias in experimental studies; (B) Risk of bias in observational studies. (C) Risk of bias in case reports.
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Table 1. Experimental and observational studies evaluating dupilumab for treating COPD.
Table 1. Experimental and observational studies evaluating dupilumab for treating COPD.
Study Name or Author (Year)Location(s)Study DesignStudy Population or Patient Case or Sub-Group Analyzed 1
BOREAS [10,20,21,23,25,26,27,30]InternationalRCTModerate-to-severe COPD and T2 inflammation (blood eosinophils > 300 cells/µL at screening), on ICS/LABA/LAMA
Bhatt (2023) [22] Asian patients with moderate-to-severe COPD and T2 inflammation (blood eosinophils > 300 cells/µL at screening), on ICS/LABA/LAMA
NOTUS [11,24]InternationalRCTModerate-to-severe COPD and T2 inflammation (blood eosinophils > 300 cells/µL at screening), on ICS/LABA/LAMA
Bhatt (2024) [28] Pooled analysis of BOREAS and NOTUS studies; moderate-to-severe COPD and T2 inflammation (blood eosinophils > 300 cells/µL at screening), on ICS/LABA/LAMA
Mariotti (2024) [29]ItalyCase report70-year-old male with a history of (unstaged) COPD experiencing exacerbations of bullous pemphigoid which was exacerbated by dupilumab
Parekh (2024) [31]NPCase report58-year-old male with severe COPD on ICS/LABA/LAMA, dupilumab, and OCS
Pham (2024) [32]USCase reportPatient (age and sex unreported) with GOLD severity 3 COPD requiring LABA/LAMA/ICS and dupilumab
Sun (2024) [33]USCohort US patients living with COPD and identified from the TriNetX database
Zhou (2023) [34]ChinaCase report71-year-old male with GOLD severity 3 COPD (10-year history) and recurrent erythematosus treated with dupilumab
1 Study populations nested under BOREAS or NOTUS headings are indicated in the section header, unless a specific sub-group analysis is presented. Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β agonist; LAMA, long-acting muscarinic antagonist; NP, not provided; OCS, oral corticosteroid; RCT, randomized controlled trial; T2, type 2; US, United States.
Table 2. Characteristics of patients enrolled in the BOREAS and NOTUS trials.
Table 2. Characteristics of patients enrolled in the BOREAS and NOTUS trials.
CharacteristicBOREAS NOTUS
Total number of patients939935
Age, years 65.1 ± 8.165.0 ± 8.3
Sex, male 620 (66.0%)632 (67.6%)
White race 790 (84.1)838 (89.6)
Former smoker657 (70.0)659 (70.5)
Prescribed inhaled triple therapy916 (97.6)924 (98.8)
Blood eosinophil count (cells/µL) at randomization401 ± 298407 ± 336
Number of moderate or severe COPD exacerbations in previous year2.3 ± 1.02.1 ± 0.9
Pre-bronchodilator FEV1 (liters)1.30 ± 0.461.36 ± 0.50
Post-bronchodilator FEV1 (liters)1.40 ± 0.471.45 ± 0.49
SGRQ total score48.4 ± 17.451.5 ± 17.0
Data reported as frequency (percentage) or mean ± standard deviation. Abbreviations: COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; SGRQ, St. George’s Respiratory Questionnaire.
Table 3. Efficacy and safety of dupilumab for treating COPD.
Table 3. Efficacy and safety of dupilumab for treating COPD.
Author (Year)SpirometrySymptoms/QoLECOPDAdverse Events
Bhatt (2023) [22]In Asian patients, increased week 12 pre-bronchodilator FEV1 by 43 mLNRIn Asian patients, RR 0.541 (95% CI 0.289 to 1.101, p-value NR)NR
Bhatt (2023) [10]LSM change versus baseline pre-bronchodilator FEV1 at week 12:
Dupilumab, 160 mL (95% CI, 126 to 195);
Placebo, 77 mL (95% CI, 42 to 112);
Between-group, 83 mL (95% CI, 42 to 125, p < 0.001), favors dupilumab		SGRQ total score improvement (exceeding MCID) at week 52:
Dupilumab 51.5% vs. 43.1% placebo (OR 1.4, 95% CI 1.1 to 1.9, p = 0.009), favors dupilumab		Annualized rate of moderate-to-severe ECOPD:
Dupilumab, 0.78 (95% CI 0.64 to 0.93);
Placebo, 1.10 (95% CI 0.93 to 1.30);
Between-group RR, 0.70 (95% CI 0.58 to 0.86, p < 0.001), favors dupilumab		77.4% of dupilumab-treated patients reported AEs including nasopharyngitis (9.4%), headache (8.1%), and URTI (7.9%);
AEs resulting in death: 1.5% dupilumab versus 1.7% placebo (p-value unreported);
Adjudicated MACEs: 0.9% dupilumab versus 1.9% (p-value unreported)
Bhatt (2023) [21]Sustained 83 mL pre-bronchodilator FEV1, study weeks 12 to 52 (p < 0.05) NR30% reduction in moderate-to-severe ECOPD versus placebo (p = 0.0005)NR
Bhatt (2024) [24]NRAt week 52:
LSM difference from baseline for dupilumab vs. placebo for SGRQ was −3.4 (95% CI −5.8 to −0.9, p = 0.0068);
42.8% dupilumab vs. 34.5% placebo had ≥8-point SGRQ improvement (OR 1.371, 95% CI 1.002 to 1.878, p = 0.0489);
35.4% dupilumab vs. 25.9% placebo had ≥12-point SGRQ improvement (OR 1.529, 95% CI 1.096 to 2.135, p = 0.0125)		NRNR
Bhatt (2024) [11]LSM change versus baseline pre-bronchodilator FEV1 at week 12:
Dupilumab, 139 mL (95% CI, 105 to 173);
Placebo, 57 mL (95% CI, 23 to 91);
Between-group, 82 mL (95% CI, 40 to 124, p < 0.001), favors dupilumab		At week 52 SGRQ decreases were as follows:
Dupilumab, −9.8 points (95% CI, −11.6 to −8.0);
Placebo, −6.4 points (95% CI, −8.3 to −4.6);
Between-group LSM difference, −3.4 points (95% CI, −5.8 to −0.9, p-value unreported).
SGRQ total score improvement (exceeding MCID) at week 52:
Dupilumab 51.4% vs. 46.5% (OR 1.16, 95% CI, 0.86 to 1.58).		Annualized rate of moderate-to-severe ECOPD:
Dupilumab, 0.86 (95% CI 0.70 to 1.06);
Placebo, 1.30 (95% CI 1.05 to 1.60);
Between-group RR, 0.66 (95% CI 0.54 to 0.82, p < 0.001), favors dupilumab.
Annualized rate of severe ECOPD:
Dupilumab, 0.07 (95% CI, 0.04 to 0.12);
Placebo, 0.12 (95% CI, 0.07 to 0.22);
Between-group RR, 0.56 (95% CI, 0.31 to 1.02, p-value unreported).		66.7% of dupilumab-treated patients reported AEs including COVID-19 (9.4%), headache (7.5%), and nasopharyngitis (6.2%);
Adjudicated MACEs: 0.6% dupilumab versus 1.4% placebo (p-value unreported)
Christenson (2024) [26]NRNRSignificant reduction in moderate or severe ECOPD by baseline eosinophils levels (p = 0.006 for interaction):
≥300 cells/µL: 0.75 (95% CI 0.62 to 0.92);
≥500 cells/µL: 0.71 (95% CI 0.58 to 0.86);
≥700 cells/µL: 0.61 (95% CI 0.48 to 0.78);
≥900 cells/µL: 0.48 (95% CI 0.31 to 0.73)		NR
Hanania (2024) [27]LSM difference from baseline in post-bronchodilator FEV1 and FEV1/FVC ratio improved at 12 and 52 weeks:
FEV1, 12 weeks: 156 mL (95% CI 30 to 115, p = 0.001);
FEV1, 52 weeks: 79 mL (95% CI 34 to 124, p < 0.001);
FEV1/FVC ratio, 12 weeks: 14 mL (95% CI 5 to 23, p = 0.002);
FEV1/FVC ratio, 52 weeks: 10 mL (95% CI 0 to 19 mL, p = 0.055)		NRNRNR
Mariotti (2024) [29]NRNRNRBullous pemphigoid worsening
Papi (2024) [30]LSM difference from baseline in pre-bronchodilator FEV1 and FVC improved with dupilumab at 52 weeks versus placebo (153 mL [95% CI 115 to 189, p < 0.001] and 88 mL [95% CI 29 to 148, p = 0.004], respectively)NRNRNR
Parekh (2024) [31]FEV1 16% predicted and FEV1/FVC 30%NRPatient experienced ECOPDTracheal stenosis
Pham (2024) [32]FEV1 declined 21 mL/yearNRNo ECOPD over 51 monthsNR
Sun (2024) [33]NRNRHR 0.585 (95% CI 0.530 to 0.646, p < 0.001)Reduced AEs:
Pneumonia HR, 0.654 (95% CI, 0.501 to 0.855, p = 0.005);
Acute respiratory failure HR, 0.570 (95% CI 0.443 to 0.732, p < 0.001);
Acute respiratory distress syndrome HR, 0.355 (95% CI 0.216 to 0.583, p < 0.001);
Serum eosinophilia HR, 0.666 (95% CI, 0.498 to 0.890, p = 0.012)
Zhou (2023) [34]NRCOPD Assessment Score: 25 pointsNRAcute eosinophilic pneumonia (1600 cells/µL)
Abbreviations: AE, adverse event; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ECOPD, COPD exacerbation; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HR, hazard ratio; LSM, least-squares mean; MACEs, major adverse cardiovascular events; MCID, minimum clinically important difference; NR, not reported; OR, odds ratio; QoL, quality of life; RR, rate ratio; SGRQ, St. George’s Respiratory Questionnaire; URTI, upper respiratory tract infection.
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Young, J.; Spisany, T.; Guidry, C.M.; Hong, J.; Le, J.; El Rassi, E.; Boylan, P.M. Dupilumab for Chronic Obstructive Pulmonary Disease: A Systematic Review. Biologics 2025, 5, 5. https://doi.org/10.3390/biologics5010005

AMA Style

Young J, Spisany T, Guidry CM, Hong J, Le J, El Rassi E, Boylan PM. Dupilumab for Chronic Obstructive Pulmonary Disease: A Systematic Review. Biologics. 2025; 5(1):5. https://doi.org/10.3390/biologics5010005

Chicago/Turabian Style

Young, Julia, Taylor Spisany, Corey M. Guidry, Jisoo Hong, Jessica Le, Edward El Rassi, and Paul M. Boylan. 2025. "Dupilumab for Chronic Obstructive Pulmonary Disease: A Systematic Review" Biologics 5, no. 1: 5. https://doi.org/10.3390/biologics5010005

APA Style

Young, J., Spisany, T., Guidry, C. M., Hong, J., Le, J., El Rassi, E., & Boylan, P. M. (2025). Dupilumab for Chronic Obstructive Pulmonary Disease: A Systematic Review. Biologics, 5(1), 5. https://doi.org/10.3390/biologics5010005

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