Conclusions. In this pair of placebo-controlled double-blind randomized parallel studies, there was a significant decline in annual exacerbation rate in patients with an eosinophilic phenotype treated with mepolizumab in a stratified intention-to-treat analysis of one of two parallel studies (METREX). However, there was no significant difference in the primary outcome of the other parallel study (METREO), which included only those patients with an eosinophilic phenotype. Additionally, there was no significant difference in any secondary endpoints in either study. The medication was generally safe and well tolerated.
Commentary
Mepolizumab is a humanized monoclonal antibody that targets and blocks interleukin-5, a key mediator of eosinophilic activity. Due to its ability to decrease eosinophil number and function, it is currently approved as a therapy for severe asthma with an eosinophilic phenotype [1]. While asthma and COPD have historically been thought of as separate entities with distinct pathophysiologic mechanisms, recent evidence has suggested that a subset of COPD patients experience significant eosinophilic inflammation. This group may behave more like asthmatic patients, and may have a different response to medications such as inhaled corticosteroids, but the role of eosinophils to guide prognostication and treatment in this group is still unclear [2,3].
In this study, Pavord and colleagues investigated the use of the anti-IL5 drug mepolizumab in COPD patients at risk of exacerbations who demonstrated an eosinophilic phenotype. The physiologic rationale for the study was that eosinophilic inflammation is thought to be a driver of exacerbations in COPD patients with an eosinophilic phenotype, and therefore a decrease in eosinophilic number and function should result in a decrease in exacerbations. The authors conducted a well-designed placebo-controlled double-blind study with a clearly defined endpoint, met their enrollment goals as determined by their power calculations, and used COPD patients at high risk of exacerbations to enrich their study.
There was no difference in the primary outcome in the METREO arm of the study, which included patients with baseline eosinophilia (> 150 cells/uL) or in the overall intention-to-treat analysis in METREX (which did not screen patients on baseline eosinophil count). Only when stratified on baseline eosinophil count in the METREX study was a significant treatment effect found, where patients with high eosinophil count at baseline (> 150 cells/uL) had a decreased risk of exacerbations when treated with mepolizumab. Notably there was no difference in any secondary outcome in METREO or in METREX aside from a longer time to first exacerbation in METREX in the mepolizumab group. The authors use this data to conclude that mepolizumab treatment results in a lower rate of exacerbations and a longer time to the first exacerbation in COPD patients with an eosinophilic phenotype, and the extent of the treatment effect is related to blood eosinophil counts.
The authors conducted a well-designed and rigorous study, and used robust and appropriate statistical analysis; however, significant questions remain regarding their conclusions. The primary concern is the role of mepolizumab in the treatment of COPD patients to decrease exacerbations may be overstated. When including only those with baseline eosinophilia in the METREO arm, there was no significant difference between placebo and low or high dose of mepolizumab; however, there was an appropriate and expected decrease in blood eosinophils, indicating the medication worked as intended. In the overall intention-to-treat analysis in the METREX arm, there was no difference between mepolizumab and placebo, and only in the analysis of METREX stratified to eosinophil count was there a significant difference (with an upper confidence interval rate ratio [0.98] approaching unity).
Additionally there was no significant difference between the 2 groups across a number of clinically important secondary endpoints, including pulmonary function measurements and symptomatic scores. Only the time to exacerbation was significantly longer in the mepolizumab group in METREX.
Taken together, this calls into question the conclusion that a decrease in eosinophil counts due to mepolizumab has resulted in a lower rate of exacerbations, particularly as a higher dose of mepolizumab did not result in a stronger effect. The lack of difference between groups in secondary endpoints is also concerning, as those would be expected to improve with a decrease in exacerbations [4,5]. As the authors point out, their evidence suggests that eosinophils may be an important biomarker in COPD and may aid in the therapeutic decision-making process. However, given the inconsistencies in the data as noted above, it would be difficult to rely on the evidence from this study alone to support their conclusion regarding the clinical utility of mepolizumab in COPD.
The authors discuss a number of limitations that may account for the lack of consistent effect seen in this study. Aside from the standard limitations applicable to any clinical trial, they note the potential confounding effect of previous oral glucocorticoid therapy in reducing eosinophil counts. This may have masked the eosinophilic phenotype in some study patients, leading to the attenuated effect of mepolizumab seen in this study.
The authors also note that information that might be potentially valuable for identifying treatment responders, such as a history of allergies and atopy, were not available. Inclusion of those patients may be helpful in enriching the trial with potential treatment-responders, and future studies may benefit from focusing on COPD patients with a more atopic phenotype who more closely resemble those with the asthma-COPD overlap syndrome.
A final limitation to discuss is the focus on blood eosinophilic counts. Due to the difficulty of measuring sputum eosinophils, and the reasonable degree of correlation between blood and sputum in asthmatic patients, blood eosinophils have largely supplanted sputum eosinophils as markers of TH2 CD4 T-cell activity in the pulmonary system [6]. This substitution is also used in the COPD population, however, due to the differences in pathophysiology it is unclear if eosinophils in asthmatic patients behave similarly to those in COPD patients [7]. Additionally, the cutoff of 150 cells/uL has been obtained primarily from sub-group analysis of previous studies on COPD patients, but it is unclear if this cutoff truly reflects elevated sputum eosinophilia. While there is likely some degree of correlation between blood and sputum eosinophilia in COPD patients, a lack of significant effect seen in this study may be due to an incorrect cutoff for elevated eosinophilia and a reliance on blood eosinophils over sputum counts. Further studies utilizing sputum eosinophils may be of value in addressing this limitation.