The New England Journal of Medicine MAY 20, 2024

Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation

Surya P. Bhatt, Klaus F. Rabe, et al.

Bottom Line

The NOTUS phase 3 trial demonstrated that add-on therapy with the IL-4/IL-13 inhibitor dupilumab significantly reduces moderate or severe exacerbations and improves lung function in patients with uncontrolled COPD and type 2 inflammation despite maximal inhaled triple therapy.

Key Findings

1. Dupilumab treatment resulted in a 34% reduction in the annualized rate of moderate or severe COPD exacerbations compared to placebo (rate ratio 0.66; 95% CI 0.54–0.82; P<0.001).

2. Patients receiving dupilumab showed rapid and sustained improvement in lung function, with a least-squares mean increase in pre-bronchodilator FEV1 of 139 mL versus 57 mL in the placebo group at week 12 (P<0.001), which remained significant at week 52.

3. Exacerbation-associated systemic corticosteroid courses were reduced by 39% in the dupilumab arm compared to placebo (relative risk 0.61; 95% CI 0.47–0.80; P<0.001).

4. Safety profiles were balanced between groups, with adverse event rates of 67% in the dupilumab group and 66% in the placebo group.

Study Design

Design

RCT

Double-Blind

Sample

935

Patients

Duration

52 wk

Median

Setting

International, 29 countries

Population Adults aged 40-85 years with moderate-to-severe COPD, uncontrolled on maximal inhaled triple therapy, and evidence of type 2 inflammation (blood eosinophils ≥300 cells/μL).

Intervention Subcutaneous dupilumab 300 mg every 2 weeks.

Comparator Subcutaneous matched placebo every 2 weeks.

Outcome Annualized rate of moderate or severe COPD exacerbations.

Study Limitations

• The trial was limited to patients with type 2 inflammatory markers (blood eosinophil count ≥300 cells/μL), meaning results may not be generalizable to the broader COPD population.

• Patients with a history of asthma were explicitly excluded, which is a common comorbid phenotype in COPD that might alter treatment response.

• While lung function and exacerbation frequency improved, there were no significant between-group differences in quality-of-life scores measured by the St. George's Respiratory Questionnaire (SGRQ).

• The analysis was based on interim data, though the overwhelming efficacy met criteria for early study conclusion.

Clinical Significance

This trial provides the necessary confirmatory evidence that biologics targeting type 2 inflammation can successfully mitigate exacerbation risk in patients with COPD who remain symptomatic despite optimized, maximal inhaled triple therapy, representing a potential paradigm shift toward precision medicine in COPD management.

Historical Context

COPD treatment has historically relied on bronchodilators and inhaled corticosteroids with limited innovation in systemic therapies for decades. The NOTUS trial, serving as a replicate for the earlier BOREAS study, confirms the role of type 2 inflammation—driven by IL-4 and IL-13—as a targetable pathway in a specific subset of COPD patients, challenging the traditional view of COPD as primarily a non-allergic, neutrophilic process.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of dupilumab specifically target the pathophysiology of the 'type 2' inflammatory phenotype in COPD, and why is this distinct from standard bronchodilator therapy?

Key Response

Dupilumab is a monoclonal antibody that inhibits the IL-4 receptor alpha subunit, effectively blocking both IL-4 and IL-13 signaling. This targets the 'Type 2' inflammatory pathway (often characterized by eosinophilia, mucus hypersecretion, and airway remodeling), whereas standard bronchodilators (LABAs/LAMAs) only address airway smooth muscle tone and do not modify the underlying inflammatory cascade.

Resident

In a patient with COPD who continues to experience frequent exacerbations despite maximal triple therapy (ICS/LABA/LAMA), what specific biomarker threshold was utilized in the NOTUS trial to determine eligibility for dupilumab, and how stable is this biomarker in clinical practice?

Key Response

The NOTUS trial required a blood eosinophil count of at least 300 cells per microliter. Residents must be aware that eosinophil counts can fluctuate; while the trial used a single baseline measurement, clinical practice often requires longitudinal assessment to confirm a persistent type 2 endotype before initiating expensive biologic therapy.

Fellow

The NOTUS trial demonstrated a significant increase in pre-bronchodilator FEV1 (82 mL difference vs placebo at week 12). How does this improvement compare to the typical FEV1 response seen with the addition of a third inhaled agent, and what does this suggest about the role of IL-4/IL-13 in fixed airflow obstruction?

Key Response

The 82 mL improvement (extending to 139 mL in some analyses) is comparable to or exceeds the incremental benefit often seen when moving from dual to triple inhaled therapy. This suggests that type 2 inflammation contributes significantly to airflow limitation in this subset of patients, potentially through mechanisms like mucus plugging and wall thickening that are reversible with targeted biologics.

Attending

With the NOTUS trial successfully replicating the BOREAS findings, how should we prioritize dupilumab relative to long-term macrolide therapy or phosphodiesterase-4 inhibitors in the 'frequent exacerbator' phenotype with high eosinophils?

Key Response

Dupilumab provides a more targeted, albeit more expensive, approach compared to the broad anti-inflammatory effects of roflumilast or the antimicrobial/immunomodulatory effects of azithromycin. In patients with eosinophils ≥300, the magnitude of exacerbation reduction (34% in NOTUS) and the improvement in lung function may make it the preferred escalation step over roflumilast, which is often limited by gastrointestinal side effects.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The NOTUS trial utilized a negative binomial regression model to analyze the annualized rate of moderate or severe exacerbations. Discuss the statistical rationale for this choice over a Poisson distribution and how 'overdispersion' in COPD exacerbation frequency might impact the trial's power.

Key Response

COPD exacerbations are discrete count events that often exhibit overdispersion (variance exceeds the mean) because certain 'frequent exacerbator' patients are prone to clusters of events. A negative binomial model includes an extra parameter to account for this heterogeneity, ensuring that the standard errors are not underestimated and the resulting p-values for the treatment effect are robust.

Journal Editor

As a reviewer, how do you evaluate the generalizability of NOTUS given that patients with a history of asthma were excluded, yet the inclusion criteria (eosinophils ≥300) specifically select for an asthma-like endotype?

Key Response

This is a critical 'threat' to external validity. While the trial aims to prove dupilumab works in 'pure' COPD with type 2 inflammation, in real-world settings, the distinction between high-eosinophil COPD and Asthma-COPD Overlap (ACO) is blurry. A skeptical reviewer would question if the trial is simply treating undiagnosed asthma or if it truly defines a distinct COPD endotype.

Guideline Committee

The current GOLD 2024 report suggests ICS-containing triple therapy as the ceiling for most patients. Based on the NOTUS and BOREAS data, should the committee create a new 'Group E - Subgroup T2' recommendation for biologics, and what level of evidence (A, B, or C) would you assign?

Key Response

With two large-scale, concordant Phase 3 RCTs (BOREAS and NOTUS), the level of evidence for dupilumab in this specific population is 'A.' The committee should consider adding dupilumab as a Grade 1A recommendation for patients on triple therapy with ≥300 eosinophils/μL, marking the first time a biologic has reached this threshold in COPD guidelines.

Clinical Landscape

Noteworthy Related Trials

2007

TORCH Trial

n = 6,112 · NEJM

Tested

Salmeterol and fluticasone propionate combination

Population

Patients with moderate-to-severe COPD

Comparator

Placebo, salmeterol alone, or fluticasone alone

Endpoint

All-cause mortality

Key result: The combination therapy did not reach statistical significance for mortality reduction, but reduced exacerbations and improved health status.

2018

QUEST Trial

n = 1,902 · NEJM

Tested

Dupilumab 200 mg or 300 mg every 2 weeks

Population

Patients 12 years or older with uncontrolled persistent asthma

Comparator

Placebo

Endpoint

Annualized rate of severe asthma exacerbations

Key result: Dupilumab reduced the rate of severe exacerbations and improved lung function, particularly in patients with higher baseline eosinophil counts.

2023

BOREAS Trial

n = 939 · NEJM

Tested

Dupilumab 300 mg subcutaneous every 2 weeks

Population

Patients with moderate-to-severe COPD and blood eosinophil counts of at least 300 per microliter

Comparator

Placebo

Endpoint

Annualized rate of moderate or severe COPD exacerbations

Key result: Dupilumab significantly reduced the annualized rate of moderate or severe COPD exacerbations compared to placebo.

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