New England Journal of Medicine JUNE 08, 2023

Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts

Surya P. Bhatt, Klaus F. Rabe, Nicola A. Hanania, et al.

Bottom Line

In this phase 3 trial, the addition of dupilumab to standard triple therapy significantly reduced the rate of moderate-to-severe exacerbations and improved lung function in patients with moderate-to-severe COPD and evidence of type 2 inflammation.

Key Findings

1. Dupilumab significantly reduced the annualized rate of moderate-to-severe COPD exacerbations by 30% compared to placebo over 52 weeks (rate ratio 0.70; 95% CI 0.58–0.86; p=0.0005).

2. Patients receiving dupilumab demonstrated a significant improvement in pre-bronchodilator FEV1 at week 12 (least-squares mean change of 160 mL vs 77 mL for placebo; p<0.0001), a benefit that was sustained through week 52.

3. Significant improvements in health-related quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score, were observed in the dupilumab group compared to placebo at week 52 (least-squares mean difference −3.4 points; p=0.0002).

4. Safety profiles were generally balanced between the dupilumab and placebo groups, with serious adverse events reported in 18% of patients in the dupilumab group versus 18% in the placebo group.

Study Design

Design

RCT

Double-Blind

Sample

939

Patients

Duration

52 wk

Median

Setting

Multicenter, international

Population Adults (40-85 years) with moderate-to-severe COPD, airflow limitation, and type 2 inflammation (blood eosinophils ≥300 cells/µL) despite background triple therapy.

Intervention Dupilumab 300 mg subcutaneous every 2 weeks.

Comparator Matching placebo every 2 weeks.

Outcome Annualized rate of moderate or severe COPD exacerbations.

Study Limitations

• The study was conducted during the COVID-19 pandemic, which may have influenced exacerbation rates and healthcare utilization patterns.

• The trial specifically selected for a type 2 inflammatory phenotype (blood eosinophils ≥300 cells/µL), limiting the generalizability of these results to the broader, more heterogeneous COPD population.

• The study did not evaluate the long-term impact on mortality or sustained disease progression beyond 52 weeks.

Clinical Significance

This study establishes the first evidence that a biologic therapy targeting type 2 inflammation (via IL-4 and IL-13 inhibition) can provide clinically meaningful benefits in a targeted subgroup of patients with symptomatic, uncontrolled COPD despite optimal maintenance triple therapy.

Historical Context

COPD management has traditionally relied on inhaled bronchodilators and corticosteroids, with limited success in reducing exacerbations for patients with underlying type 2 inflammatory signatures. The BOREAS trial represents a paradigm shift toward precision medicine in COPD, identifying eosinophilic biomarkers to guide the use of biologic therapies.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of dupilumab, and why would targeting IL-4 and IL-13 be beneficial in a subset of patients with COPD, which is traditionally considered a neutophilic inflammatory disease?

Key Response

Dupilumab is a monoclonal antibody that inhibits the IL-4 receptor alpha subunit, blocking both IL-4 and IL-13 signaling. While COPD is often driven by Type 1 or Type 17 (neutrophilic) inflammation, roughly 20-40% of patients exhibit Type 2 inflammation. IL-4 and IL-13 drive this pathway, leading to goblet cell hyperplasia, mucus hypersecretion, and airway hyperresponsiveness, which contribute to the exacerbation frequency targeted in the study.

Resident

According to the BOREAS trial inclusion criteria, which specific COPD patient population should be considered for dupilumab therapy, and what is the primary clinical endpoint they should expect to improve?

Key Response

Candidates are patients with moderate-to-severe COPD already on maximal inhaled triple therapy (ICS/LABA/LAMA) who have a blood eosinophil count of at least 300 cells per microliter. The primary clinical benefit demonstrated was a 30% reduction in the annual rate of moderate or severe exacerbations, alongside significant improvements in pre-bronchodilator FEV1.

Fellow

In contrast to the success of dupilumab in BOREAS, previous trials of anti-IL-5 therapies (mepolizumab and benralizumab) in COPD showed inconsistent or less robust results. What physiological or molecular differences between IL-5 inhibition and IL-4/IL-13 dual blockade might explain this discrepancy?

Key Response

IL-5 primarily regulates eosinophil maturation and survival, whereas IL-4 and IL-13 have broader effects on the airway epithelium, including stimulating mucus production and promoting subepithelial fibrosis. The dual blockade of IL-4 and IL-13 may more effectively address the structural components of Type 2 inflammation in the COPD airway that IL-5 inhibition alone does not target.

Attending

The BOREAS trial represents a shift toward 'precision medicine' in COPD. How does this study impact the 'treatable traits' framework, and what practical barriers do you foresee in integrating biologic therapy into the chronic management of COPD in a typical pulmonary practice?

Key Response

This trial validates blood eosinophils as a actionable biomarker for biologic intervention in COPD. However, practical barriers include the high cost of dupilumab compared to standard inhalers, the logistical requirements of regular subcutaneous injections, and the need for serial eosinophil monitoring to confirm a stable Type 2 phenotype before committing to expensive long-term therapy.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The BOREAS trial used a blood eosinophil cutoff of 300 cells per microliter for enrichment. Discuss the statistical implications of using this specific threshold on the trial's power and the potential risk of 'regression to the mean' if patients were selected based on a single laboratory value.

Key Response

Using a high threshold (300) increases the likelihood of including patients with true Type 2 drivers, thereby increasing the treatment effect size and the study's power. However, eosinophil counts are inherently labile; a single high reading may be an outlier. This necessitates careful interpretation of the 'Type 2' phenotype and potentially suggests that future trials should require longitudinal evidence of eosinophilia to ensure generalizability.

Journal Editor

As a reviewer, how would you address the potential confounding factor of 'Asthma-COPD Overlap' (ACO) in the BOREAS trial, given that the study excluded patients with a current diagnosis of asthma but utilized a therapy primarily approved for asthma?

Key Response

A critical reviewer would flag whether the exclusion of asthma was based strictly on physician report or if objective testing (like bronchodilator reversibility) was used to ensure the results aren't merely reflecting a latent asthma population. If the cohort included many 'stealth' asthmatics, the internal validity regarding dupilumab's efficacy in 'pure' COPD would be significantly challenged.

Guideline Committee

Currently, GOLD 2023 guidelines recommend triple therapy with ICS for patients with eosinophils ≥300. Based on the BOREAS findings, how should the next iteration of the GOLD guidelines categorize the use of dupilumab for Group E patients?

Key Response

The BOREAS trial provides Level A evidence that for patients in Group E (high exacerbators) who remain symptomatic on triple therapy with eosinophils ≥300, dupilumab significantly reduces exacerbations. The committee must decide if this warrants a 'preferred' recommendation for this phenotype or if it should be reserved as a step-up therapy after triple therapy failure, effectively creating a new tier in the COPD management algorithm.

Clinical Landscape

Noteworthy Related Trials

2007

TORCH Trial

n = 6,112 · NEJM

Tested

Salmeterol/Fluticasone propionate

Population

Patients with COPD and FEV1 less than 60%

Comparator

Placebo, salmeterol alone, or fluticasone alone

Endpoint

All-cause mortality

Key result: The combination therapy reduced the rate of exacerbations and improved lung function, establishing the standard for COPD exacerbation management.

2018

SUNSET Trial

n = 530 · JAMA

Tested

Withdrawal of inhaled corticosteroids (ICS)

Population

COPD patients with low exacerbation risk taking triple therapy

Comparator

Continued triple therapy (ICS/LABA/LAMA)

Endpoint

Annualized rate of moderate or severe COPD exacerbations

Key result: Withdrawal of ICS was non-inferior to continued triple therapy in patients with low exacerbation frequency, highlighting the importance of patient selection.

2024

NOTUS Trial

n = 935 · NEJM

Tested

Dupilumab 300 mg

Population

COPD with blood eosinophil count of 300 or more per microliter

Comparator

Placebo

Endpoint

Annualized rate of moderate or severe exacerbations

Key result: Dupilumab significantly reduced the rate of moderate or severe exacerbations compared to placebo, confirming the findings of the BOREAS trial.

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