What is the role of dupilumab (Dupixent) in treating Chronic Obstructive Pulmonary Disease (COPD) patients with a history of exacerbations and elevated eosinophil counts, based on the NOTUS trial?

Dupilumab for COPD with Type 2 Inflammation: The NOTUS Trial

Dupilumab 300 mg subcutaneously every 2 weeks significantly reduces exacerbations and improves lung function in COPD patients with elevated blood eosinophils (≥300 cells/μL) and a history of exacerbations, and is now FDA-approved for this indication. 1, 2

Key NOTUS Trial Results

The NOTUS trial was a phase 3, double-blind, randomized controlled trial that enrolled 935 patients with COPD and type 2 inflammation 2. The trial demonstrated:

Exacerbation Reduction (Primary Endpoint)

• Dupilumab reduced the annualized rate of moderate or severe exacerbations by 34% compared to placebo (0.86 vs 1.30 exacerbations/year; rate ratio 0.66,95% CI 0.54-0.82; P<0.001) 1, 2
• Time to first exacerbation was significantly delayed with dupilumab (HR 0.71,95% CI 0.57-0.89) 1
• This benefit was consistent regardless of emphysema status, with 29-31% reductions in both groups 3

Lung Function Improvements

• Prebronchodilator FEV1 increased by 82 mL at week 12 (least-squares mean difference vs placebo, P<0.001) and 62 mL at week 52 (P=0.02) 2
• Post-bronchodilator FEV1 showed similar improvements: 68 mL at week 12 and 67 mL at week 52 1
• These improvements were sustained throughout the 52-week treatment period 1, 2

Quality of Life

• The SGRQ responder rate (≥4-point improvement) at week 52 was 51% with dupilumab versus 47% with placebo, though this did not reach statistical significance (odds ratio 1.16,95% CI 0.86-1.58) 1
• Real-world data showed median COPD Assessment Test scores decreased from 18 to 15 4

Patient Selection Criteria from NOTUS

The trial enrolled patients meeting specific criteria that define the target population 1, 2:

Required Characteristics

• Blood eosinophil count ≥300 cells/μL at screening (mean screening count was 538 cells/μL) 1
• History of ≥2 moderate or ≥1 severe exacerbations in the prior year (mean 2.1 exacerbations) 1
• Moderate-to-severe airflow limitation with mean post-bronchodilator FEV1 of 50.1% predicted 1
• Medical Research Council dyspnea score ≥2 1
• Nearly all patients (99.9%) had chronic bronchitis 1

Background Therapy

• 98.8% were on triple therapy (ICS/LAMA/LABA) at randomization, representing maximal inhaled therapy 1
• Mean smoking history was 40.3 pack-years, with 29.5% current smokers 1

Biomarker-Driven Treatment Response

Post-hoc analyses from the companion BOREAS trial (which showed nearly identical results to NOTUS) revealed important predictive factors 5:

• Higher baseline blood eosinophil counts predicted greater exacerbation reduction (p=0.0056) 5
• Elevated baseline FeNO also predicted better treatment response (p=0.043) 5
• Dupilumab reduced type 2 inflammatory biomarkers at week 52: total IgE by 22.5%, FeNO by 28.6%, eotaxin-3 by 8.8%, and PARC by 14.4% 5
• Treatment efficacy was consistent regardless of baseline BODE index scores, demonstrating benefit across disease severity 6

Safety Profile

The safety profile in NOTUS was consistent with dupilumab's established profile from other indications 1, 2:

• Adverse event incidence was similar between dupilumab and placebo groups 2
• Real-world data showed only 1 of 23 patients (4%) experienced skin-related side effects 4
• No new safety signals emerged specific to the COPD population 1

Clinical Implementation Algorithm

For COPD patients on triple inhaled therapy with persistent exacerbations:

1. Check blood eosinophil count - must be ≥300 cells/μL 1, 2
2. Verify exacerbation history - ≥2 moderate or ≥1 severe exacerbation in prior year 1
3. Confirm adequate background therapy - patient should be on ICS/LAMA/LABA combination 1
4. Assess for chronic bronchitis - nearly universal in responders 1
5. Consider FeNO measurement - higher levels predict better response 5
6. Initiate dupilumab 300 mg subcutaneously every 2 weeks as add-on therapy 1

Comparison to Existing Guidelines

While the 2017 GOLD guidelines recognized blood eosinophils as a biomarker for ICS response 7, they predated dupilumab's availability for COPD. The 2023 Canadian Thoracic Society guidelines emphasized triple therapy for high-risk patients 7, but dupilumab now provides an additional targeted option for those with type 2 inflammation who continue to exacerbate despite maximal inhaled therapy 1, 2.

Earlier guidelines discussed the theoretical potential of monoclonal antibodies for eosinophilic COPD 7, noting that IL-5 blocking antibodies had proven ineffective 7. Dupilumab's success lies in targeting the IL-4/IL-13 pathway rather than IL-5, blocking key drivers of type 2 inflammation 2.

Real-World Experience

A prospective single-center study of 23 patients treated with dupilumab for a median of 320 days showed 4:

• 55% reduction in annualized exacerbation rate (3.47 to 1.55) 4
• Decrease in severe exacerbations (median 1 to 0) 4
• 61% of patients were content with treatment, and 74% would recommend it to others 4
• Using the Global Evaluation of Treatment Effectiveness tool, 30% reported marked improvements 4
• Main limitations were cost (48%) and repeated injections (21%) 4

Critical Caveats

• The NOTUS trial specifically excluded patients without elevated eosinophils - dupilumab should not be used in COPD patients with eosinophil counts <300 cells/μL 1, 2
• Patients must have failed maximal inhaled therapy before considering dupilumab 1
• The quality of life improvements, while numerically favorable, did not reach statistical significance in NOTUS, unlike the exacerbation and lung function benefits 2
• This is not a replacement for triple inhaled therapy but an add-on treatment for persistent exacerbators 1