Precision medicine in COPD: review of mepolizumab for eosinophilic COPD

Study design

The study by Pavord et al. [16] was constructed into two multicentre, phase 3, randomised, placebo-controlled, double-blind, parallel-group trials: mepolizumab versus placebo as add-on treatment for frequently exacerbating COPD patients (METREX), and mepolizumab versus placebo as add-on treatment for frequently exacerbating COPD patients characterised by eosinophil level (METREO). Table 1 summarises the key study characteristics and methods.

Patients were aged ≥40 years with at least a 1-year diagnosis of COPD, taking maximal triple inhaled therapy, and who had a history of two or more moderate exacerbations (treated with systemic glucocorticoids, antibiotics or both) or one or more severe exacerbation (hospitalisation). Those with a history of asthma were excluded. Smoking status and pack-years were not part of the inclusion criteria. In METREX, patients were randomised 1:1 to receive subcutaneous injections of either mepolizumab 100 mg or placebo (0.9% saline), while in METREO patients were randomised 1:1:1 to receive either mepolizumab 100 mg, mepolizumab 300 mg or placebo (0.9% saline) every 4 weeks for 52 weeks.

METREX patients were stratified by blood eosinophils at screening visit: either ≥150 cells·μL⁻¹, ≥300 cells·μL⁻¹ at any point in the previous year, or those who were non-eosinophilic (<150 cells·μL⁻¹); while METREO included only those with an eosinophilic phenotype. The primary end-point of both trials was yearly rate of moderate or severe exacerbations. Secondary end-points were time to first exacerbation, emergency department visits, hospitalisation, and average yearly changes in St George's Respiratory Questionnaire and COPD Assessment Test scores. Results were controlled for smoking status, number of exacerbations in the previous year, baseline disease severity (percentage of predicted FEV₁) and geographic region.

Key results

Strengths and limitations

These were the largest trials of targeted IL-5 therapy in COPD. METREX and METREO set out to ask the specific question of whether mepolizumab can reduce the rate of exacerbations in patients with severe COPD. Pavord et al. [16] have highlighted a population of COPD patients that may specifically benefit from targeted therapy in this form, namely those with raised blood eosinophils who have a high rate of exacerbations despite maximal standard therapy. These studies showed that patients with high blood eosinophils in the context of severe COPD with frequent exacerbations benefit from a 4-weekly 100-mg subcutaneous injection of mepolizumab. This benefit is realised in terms of reduced exacerbation rate and time to next exacerbation. Despite this, lung volumes and quality of life indices were not significantly altered. Although mortality was only measured as part of a composite end-point (i.e. COPD exacerbations), the death rate was low overall and broadly comparable between groups.

Prior to METREX/METREO, Brightling et al. [12] reported hopeful results on the use of benralizumab, an IL-5 receptor monoclonal antibody, in COPD patients with raised blood eosinophils. They experienced a significant improvement in lung function, albeit with no change in exacerbation rate. The discrepancy in results between mepolizumab and benralizumab is most likely due to differences in trial population. The benralizumab trial population had fewer exacerbations at baseline, had slightly less severe COPD, and included only current smokers or ex-smokers. Similarly, the difference in trial populations may explain why those in the benralizumab trial experienced a significant improvement in pre-bronchodilator FEV₁, unlike with mepolizumab. Interestingly, this may reflect an important relationship between smoking status, blood eosinophils and treatment response.

This study by Pavord et al. [16] relies upon stratifying patients by blood eosinophil level at a single time point. This strategy is clinically feasible and applicable to practical medicine. Blood eosinophil levels have been previously demonstrated to be stable over time: Southworth et al. [18] showed that >80% of patients using the blood eosinophil cut-off of 150 cells·μL⁻¹ will remain either eosinophilic or non-eosinophilic after 6 months or 2 years, suggesting that blood eosinophil level is a stable marker of phenotype.

In these two trials, the incidence of pneumonia was higher (9–11%) than in other trials involving a similar cohort of COPD patients (2–7%) [11]. The authors posit that this may be due to all patients taking inhaled corticosteroids. There was no statistically significant difference in the incidence of pneumonia between the mepolizumab and placebo groups in both trials. This potentially highlights the need for steroid-sparing agents in the treatment of COPD.

Conclusion

Mepolizumab benefits patients with severe, treatment-resistant COPD who frequently exacerbate and have raised blood eosinophil levels, to reduce the rate of exacerbations and time to next exacerbation. The treatment effect increases with increasing baseline blood eosinophil level. Despite the heterogeneity of COPD, this study draws attention to a phenotype based solely on blood eosinophils, which may benefit from personalised treatment when standard therapies fall short. Further research harnessing the ideals of precision medicine may lead to further unique pathways and a potential agent to replace corticosteroids.