Mepolizumab in Chronic Obstructive Pulmonary Disease (COPD): A new frontier in biologic therapy

Abstract

Mepolizumab, a comprehensible monoclonal antibody that inhibits interleukin-5 (IL-5), offers a new therapeutic option for a subset of patients with chronic obstructive pulmonary disease (COPD) marked by eosinophilic inflammation. Despite the success of conventional inhaled therapies, a significant proportion of COPD patients continue to experience exacerbations. This review discusses the mechanism, clinical trials, safety profile, and future potential of mepolizumab, the first and only FDA-approved biologic for COPD.

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is an advancing, irreversible respiratory disease characterised by limitation of airflow, chronic inflammation, and airway remodelling, particularly prevalent among chronic smokers. Despite optimised inhaled treatment strategies including long-acting bronchodilators and inhaled corticosteroids (ICS), many patients remain symptomatic and prone to exacerbations.

Traditional therapies often fail due to the absence of validated biomarkers and the heterogeneity of COPD’s pathophysiological subtypes. COPD phenotypes can be categorised based on the type of cellular inflammation present, including: 1) neutrophilic, 2) eosinophilic, 3) a combination of eosinophilic and neutrophilic, and 4) paucigranulocytic. Blood biomarkers, such as eosinophil levels in the blood, may show a correlation with eosinophil levels in sputum for patients exhibiting eosinophilic airway inflammation. Novel strategies for treating COPD emphasise the comprehension and targeting of molecular processes related to airway inflammation, airway blockage, remodelling, and lung damage. The eosinophilic phenotype of COPD has gained recent attention, revealing a targetable inflammatory pathway involving eosinophils and IL-5.

Mepolizumab, a humanised IgG1 monoclonal antibody that aims to inhibit circulating IL-5, acts by inhibiting the binding of IL-5 to the alpha chain of IL-5 receptor and neutralises its effect.[1,2] It is already used for maintenance treatment of severe eosinophilic asthma, and has recently been approved for the treatment of the eosinophilic subtype of COPD (≥300 cells/μL).[3,4]

Molecular pathogenesis of eosinophilic COPD

Eosinophilic COPD represents a distinct endotype characterised by persistent airway eosinophilia, contributing to exacerbations and corticosteroid responsiveness. Research suggests that eosinophilic inflammation occurs in as many as 40% of COPD cases.[5] Furthermore, around 20% of exacerbations are believed to be linked to an eosinophilic exacerbation.[6,7,8] In eosinophilic COPD, IL-5 plays a central role in eosinophil differentiation, activation, and survival, and the elevated levels of IL-5 drive airway inflammation and tissue damage. Samples such as biopsies from the respiratory airway system and sputum samples taken during an acute episode of COPD showed an increased number of eosinophil concentrations compared with stable COPD. Eosinophils produce eosinophilic cationic protein (ECP) and eosinophil peroxidase (EPO), which are harmful to bronchial epithelium and trigger the secretion of cytokines that promote airway inflammation.[9] Additionally, the presence of eosinophils in the airway has been found to have a higher likelihood of exacerbations and lung parenchyma and airway remodelling, along with an elevated expression of interleukin IL-5.[10] Stratified analyses from the Genetic Epidemiology of COPD (COPD Gene) study and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study indicated that the heightened risk of exacerbations linked to an eosinophil count of 300 cells/µL or higher was primarily influenced by individuals having a prior history of frequent exacerbations.[11]

Clinical evidence supporting mepolizumab in COPD

A post-hoc analysis of the MENSA and DREAM trials in patients with severe asthma indicated that mepolizumab led to a reduction in exacerbation rates (requiring systemic steroids or hospitalisation) compared to placebo in individuals with severe eosinophilic asthma who exhibited clinical characteristics of COPD.[12]

METREX and METREO trials

Two pivotal phase 3 trials, METREX and METREO, evaluated the efficacy and safety of mepolizumab in patients with moderate to severe COPD and frequent exacerbations despite triple inhaled therapy.

• METREX enrolled 836 patients and stratified them based on blood eosinophil counts. In the eosinophilic subgroup, mepolizumab significantly reduced the annual rate of moderate-to-severe exacerbations (rate ratio 0.82; 95% CI, 0.68–0.98) compared to placebo.[12,13,14]

• METREO examined two dosing regimens (100 mg and 300 mg) and found a dose-dependent, though modest, reduction in exacerbations among eosinophilic patients.[12,13,14]

These trials underscore the need for biomarker-directed therapy in COPD, confirming the benefit of IL-5 inhibition in selected patients.

MATINEE study (2025)

In a landmark study published in the New England Journal of Medicine in 2025, Sciurba et al.[3] evaluated mepolizumab in 403 patients with eosinophilic COPD. Mepolizumab led to a 30% reduction in exacerbation rate, improvement in symptom scores, and preservation of lung function over 52 weeks.

Real-world data: NEST study

The Nucala Effectiveness Study (NEST) was a real-world, multi-country observational study involving 525 patients treated with mepolizumab between 2021 and 2023. Results showed a 76% reduction in exacerbations, a 36% reduction in systemic corticosteroid use, and statistically significant improvement in lung function and quality of life.[15]

This evidence reinforces clinical trial data, suggesting consistent efficacy across diverse populations and healthcare settings.

Safety profile and tolerability

Mepolizumab has demonstrated an excellent safety profile in both trial and real-world settings.

• Common adverse effects include nasopharyngitis and headache, each occurring in ≤1% of patients.[14]

• Long-term safety has been validated by the COSMOS, COSMEX, and COLUMBA extension trials, which revealed no new safety signals over 4 years.[14]

• In a phase 3 trial for hyper-eosinophilic syndrome, mepolizumab maintained a favourable risk-benefit ratio, reducing exacerbations by 50% over 32 weeks.[16]

No significant immunogenicity or hypersensitivity reactions have been consistently reported, making it a well-tolerated option for long-term disease control.

Comparative biologic therapies

Omalizumab, an anti-IgE monoclonal antibody, was the first biologic approved for asthma but not COPD. Other biologics targeting the IL-5 pathway, such as benralizumab (IL-5R blocker) and reslizumab, have shown promise in asthma but are not yet approved for COPD.[12,14]

Mepolizumab remains the only FDA-approved biologic for COPD, specifically tailored for the eosinophilic endotype.

Patient selection and biomarkers

Appropriate patient selection is critical to achieving optimal outcomes with mepolizumab. The following criteria guide treatment initiation:

• Eosinophil count ≥300 cells/μL (or ≥150 cells/μL with a history of ≥2 exacerbations/year)

• Frequent exacerbations despite optimal triple inhaled therapy

• Absence of alternative uncontrolled comorbidities

Peripheral eosinophil count has emerged as a robust, accessible biomarker predicting response to anti-IL-5 therapy.

Future perspectives and research directions

Future treatment paradigms in COPD are likely to shift from generalised strategies to personalised approaches targeting treatable traits. Mepolizumab exemplifies this shift by focusing on the eosinophilic phenotype, thereby ushering in a new era of precision medicine.

Conclusion

Mepolizumab represents a significant advance in the management of eosinophilic COPD. With robust evidence supporting its efficacy, excellent safety profile, and a clear mechanism of action, it offers a viable option for patients who continue to suffer exacerbations despite optimal inhaled therapy. As biologic therapies expand in respiratory medicine, the focus must now shift to refining biomarkers and personalising treatment to ensure the right drug reaches the right patient.

Author contributions

Conceptualization: AM, KC, Writing initial draft preparation: KC, Writing—review and editing: all the authors. Supervision: AS.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.