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Study Overview
Objective. To determine the effect of mepolizumab on the annual rate of chronic obstructive pulmonary disease (COPD) exacerbations in high-risk patients.
Design. Two randomized double-blind placebo-controlled parallel trials (METREO and METREX).
Setting and participants. Participants were recruited from over 15 countries in over 100 investigative sites. Inclusion criteria were adults (40 years or older) with a diagnosis of COPD for at least 1 year with: airflow limitation (FEV1/FVC < 0.7); some bronchodilator reversibility (post-bronchodilator FEV1 > 20% and ≤ 80% of predicted values); current COPD therapy for at least 3 months prior to enrollment (a high-dose inhaled corticosteroid, ICS, with at least 2 other classes of medications, to obtain “triple therapy”); and a high risk of exacerbations (at least 1 severe [requiring hospitalization] or 2 moderate [treatment with systemic corticosteroids and/or antibiotics] exacerbations in past year).
Notable exclusion criteria were patients with diagnoses of asthma in never-smokers, alpha-1 antitrypsin deficiency, recent exacerbations (in past month), lung volume reduction surgery (in past year), eosinophilic or parasitic diseases, or those with recent monoclonal antibody treatment. Patients with the asthma-COPD overlap syndrome were included only if they had a history of smoking and met the COPD inclusion criteria listed above.
Intervention. The treatment period lasted for a total of 52 weeks, with an additional 8 weeks of follow-up. Patients were randomized 1:1 to placebo or low-dose medication (100 mg) using permuted-block randomization in the METREX study regardless of eosinophil count (but they were stratified for a modified intention-to-treat analysis at screening into either low eosinophilic count [< 150 cells/uL] or high [≥ 150 cells/uL]). In the METREO study, patients were randomized 1:1:1 to placebo, low-dose (100 mg), or high-dose (300 mg) medication only if blood eosinophilia was present (≥ 150 cells/uL at screening or ≥ 300 cells/uL in past 12 months). Investigators and patients were blinded to presence of drug or placebo. Sample size calculations indicated that in order to provide a 90% power to detect a 30% decrease in the rate of exacerbations in METREX and 35% decrease in METREO, a total of 800 patients and 660 patients would need to be enrolled in METREX and METREO respectively. Both studies met their enrollment quota.
Main outcome measures. The primary outcome was the annual rate of exacerbations that were either moderate (requiring systemic corticosteroids and/or antibiotics) or severe (requiring hospitalization). Secondary outcomes included the time to first moderate/severe exacerbation, change from baseline in the COPD Assessment Test (CAT) and St. George’s Respiratory Questionnaire (SGRQ), and change from baseline in blood eosinophil count, FEV1, and FVC. Safety and adverse events endpoints were also assessed.
A modified intention-to-treat analysis was performed overall and in the METREX study stratified on eosinophilic count at screening; all patients who underwent randomization and received at least one dose of medication or placebo were included in that respective group. Multiple comparisons were accounted for using the Benjamini-Hochberg Test, exacerbations were assumed to follow a negative binomial distribution, and Cox proportional-hazards was used to model the relationship between covariates of interest and the primary outcome.
Main results. In the METREX study, 1161 patients were enrolled and 836 underwent randomization and received at least 1 dose of medication or placebo. In METREO, 1071 patients were enrolled and 674 underwent randomization and received at least one dose of medication or placebo. In both studies the patients in the medication and placebo groups were well balanced at baseline across demographics (age, gender, smoking history, duration of COPD) and pulmonary function (FEV1, FVC, FEV1/FVC, CAT, SGRQ). In METREX, a total of 462 (55%) patients had an eosinophilic phenotype and 374 (45%) did not.
There was no difference between groups in the primary endpoint of annual exacerbation rate in METREO (1.49/yr in placebo vs. 1.19/yr in low-dose and 1.27/yr in high-dose mepolizumab, rate ratio of high-dose to placebo 0.86, 95% confidence interval [CI] 0.7–1.05, P = 0.14). There was no difference in the primary outcome in the overall intention-to-treat analysis in the METREX study (1.49/yr in mepolizumab vs. 1.52/yr in placebo, P > 0.99). Only when analyzing the high eosinophilic phenotype in the stratified intention-to-treat METREX group was there a significant difference in the primary outcome (1.41/yr in mepolizumab vs. 1.71/yr in placebo, P = 0.04, rate ratio 0.82, 95% CI 0.68–0.98).
There were no significant differences in any secondary endpoint in the METREO study. In the METREX study, mepolizumab treatment resulted in a significantly longer time to first exacerbation (192 days vs. 141 days, hazard ratio 0.75, 95% CI 0.60–0.94, P = 0.04) but no difference in the change in SGRQ (–2.8 vs. –3.0, P > 0.99) or CAT score (–0.8 vs. 0, P > 0.99). There was no significant difference in any measures of pulmonary function between the treatment and placebo groups (FEV1, FVC, FEV1/FVC). As expected, there was a significant decrease in peripheral blood eosinophil count in both studies in the medication arm. The incidence of adverse events and safety endpoints were similar between the trial groups in METREX and METREO.
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.
Applications for Clinical Practice
In this study, Pavord and colleagues found a potential benefit of mepolizumab treatment for reducing exacerbations in COPD patients with an eosinophilic phenotype. The conflicting results regarding the underlying physiology and the weak treatment effect suggest this medication may not be ready for use in clinical practice without additional supporting evidence. From a practical standpoint, the high cost of medication (~$2500 per month) and marginal benefit of treatment imply that treatment with mepolizumab in COPD patients may not be cost-effective, and even treatment in individual patients on a trial basis should be discouraged until additional supporting data becomes available. Of primary concern are the optimal selection of COPD patients that will achieve benefit with mepolizumab treatment, and the optimal dose of medication to achieve that benefit. The results presented here do not satisfactorily answer these questions, and additional studies are required.
—Arun Jose, MD, The George Washington University, Washington, DC
1. Pelaia C, Vatrella A, Busceti MT, et al. Severe eosinophilic asthma: from the pathogenic role of interleukin-5 to the therapeutic action of mepolizumab. Drug Des Devel Ther 2017;11:3137–44.
2. Kim VL, Coombs NA, Staples KJ, et al. Impact and associations of eosinophilic inflammation in COPD: analysis of the AERIS cohort. Eur Respir J 2017;50:pii:1700853.
3. Roche N, Chapman KR, Vogelmeier CF, et al. Blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment. Data from the FLAME trial. Am J Respir Crit Care Med 2017;195:1189–97.
4. Halpin DMG, Decramer M, Celli BR, et al. Effect of a single exacerbation on decline in lung function in COPD. Respir Med 2017;128:85–91.
5. Rassouli F, Baty F, Stolz D, et al. Longitudinal change of COPD assessment test (CAT in a telehealthcare cohort is associated with exacerbation risk. Int J COPD 2017;12:3103–9.
6. Gauthier M, Ray A, Wenzel SE. Evolving concepts of asthma. Am J Respir Crit Care Med 2015;192:660–8.
7. Negewo NA, McDonald VM, Baines KJ, et al. Peripheral blood eosinophils: a surrogate marker for airway eosinophilia in stable COPD. Int J COPD 2016;11:1495–504.
Study Overview
Objective. To determine the effect of mepolizumab on the annual rate of chronic obstructive pulmonary disease (COPD) exacerbations in high-risk patients.
Design. Two randomized double-blind placebo-controlled parallel trials (METREO and METREX).
Setting and participants. Participants were recruited from over 15 countries in over 100 investigative sites. Inclusion criteria were adults (40 years or older) with a diagnosis of COPD for at least 1 year with: airflow limitation (FEV1/FVC < 0.7); some bronchodilator reversibility (post-bronchodilator FEV1 > 20% and ≤ 80% of predicted values); current COPD therapy for at least 3 months prior to enrollment (a high-dose inhaled corticosteroid, ICS, with at least 2 other classes of medications, to obtain “triple therapy”); and a high risk of exacerbations (at least 1 severe [requiring hospitalization] or 2 moderate [treatment with systemic corticosteroids and/or antibiotics] exacerbations in past year).
Notable exclusion criteria were patients with diagnoses of asthma in never-smokers, alpha-1 antitrypsin deficiency, recent exacerbations (in past month), lung volume reduction surgery (in past year), eosinophilic or parasitic diseases, or those with recent monoclonal antibody treatment. Patients with the asthma-COPD overlap syndrome were included only if they had a history of smoking and met the COPD inclusion criteria listed above.
Intervention. The treatment period lasted for a total of 52 weeks, with an additional 8 weeks of follow-up. Patients were randomized 1:1 to placebo or low-dose medication (100 mg) using permuted-block randomization in the METREX study regardless of eosinophil count (but they were stratified for a modified intention-to-treat analysis at screening into either low eosinophilic count [< 150 cells/uL] or high [≥ 150 cells/uL]). In the METREO study, patients were randomized 1:1:1 to placebo, low-dose (100 mg), or high-dose (300 mg) medication only if blood eosinophilia was present (≥ 150 cells/uL at screening or ≥ 300 cells/uL in past 12 months). Investigators and patients were blinded to presence of drug or placebo. Sample size calculations indicated that in order to provide a 90% power to detect a 30% decrease in the rate of exacerbations in METREX and 35% decrease in METREO, a total of 800 patients and 660 patients would need to be enrolled in METREX and METREO respectively. Both studies met their enrollment quota.
Main outcome measures. The primary outcome was the annual rate of exacerbations that were either moderate (requiring systemic corticosteroids and/or antibiotics) or severe (requiring hospitalization). Secondary outcomes included the time to first moderate/severe exacerbation, change from baseline in the COPD Assessment Test (CAT) and St. George’s Respiratory Questionnaire (SGRQ), and change from baseline in blood eosinophil count, FEV1, and FVC. Safety and adverse events endpoints were also assessed.
A modified intention-to-treat analysis was performed overall and in the METREX study stratified on eosinophilic count at screening; all patients who underwent randomization and received at least one dose of medication or placebo were included in that respective group. Multiple comparisons were accounted for using the Benjamini-Hochberg Test, exacerbations were assumed to follow a negative binomial distribution, and Cox proportional-hazards was used to model the relationship between covariates of interest and the primary outcome.
Main results. In the METREX study, 1161 patients were enrolled and 836 underwent randomization and received at least 1 dose of medication or placebo. In METREO, 1071 patients were enrolled and 674 underwent randomization and received at least one dose of medication or placebo. In both studies the patients in the medication and placebo groups were well balanced at baseline across demographics (age, gender, smoking history, duration of COPD) and pulmonary function (FEV1, FVC, FEV1/FVC, CAT, SGRQ). In METREX, a total of 462 (55%) patients had an eosinophilic phenotype and 374 (45%) did not.
There was no difference between groups in the primary endpoint of annual exacerbation rate in METREO (1.49/yr in placebo vs. 1.19/yr in low-dose and 1.27/yr in high-dose mepolizumab, rate ratio of high-dose to placebo 0.86, 95% confidence interval [CI] 0.7–1.05, P = 0.14). There was no difference in the primary outcome in the overall intention-to-treat analysis in the METREX study (1.49/yr in mepolizumab vs. 1.52/yr in placebo, P > 0.99). Only when analyzing the high eosinophilic phenotype in the stratified intention-to-treat METREX group was there a significant difference in the primary outcome (1.41/yr in mepolizumab vs. 1.71/yr in placebo, P = 0.04, rate ratio 0.82, 95% CI 0.68–0.98).
There were no significant differences in any secondary endpoint in the METREO study. In the METREX study, mepolizumab treatment resulted in a significantly longer time to first exacerbation (192 days vs. 141 days, hazard ratio 0.75, 95% CI 0.60–0.94, P = 0.04) but no difference in the change in SGRQ (–2.8 vs. –3.0, P > 0.99) or CAT score (–0.8 vs. 0, P > 0.99). There was no significant difference in any measures of pulmonary function between the treatment and placebo groups (FEV1, FVC, FEV1/FVC). As expected, there was a significant decrease in peripheral blood eosinophil count in both studies in the medication arm. The incidence of adverse events and safety endpoints were similar between the trial groups in METREX and METREO.
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.
Applications for Clinical Practice
In this study, Pavord and colleagues found a potential benefit of mepolizumab treatment for reducing exacerbations in COPD patients with an eosinophilic phenotype. The conflicting results regarding the underlying physiology and the weak treatment effect suggest this medication may not be ready for use in clinical practice without additional supporting evidence. From a practical standpoint, the high cost of medication (~$2500 per month) and marginal benefit of treatment imply that treatment with mepolizumab in COPD patients may not be cost-effective, and even treatment in individual patients on a trial basis should be discouraged until additional supporting data becomes available. Of primary concern are the optimal selection of COPD patients that will achieve benefit with mepolizumab treatment, and the optimal dose of medication to achieve that benefit. The results presented here do not satisfactorily answer these questions, and additional studies are required.
—Arun Jose, MD, The George Washington University, Washington, DC
Study Overview
Objective. To determine the effect of mepolizumab on the annual rate of chronic obstructive pulmonary disease (COPD) exacerbations in high-risk patients.
Design. Two randomized double-blind placebo-controlled parallel trials (METREO and METREX).
Setting and participants. Participants were recruited from over 15 countries in over 100 investigative sites. Inclusion criteria were adults (40 years or older) with a diagnosis of COPD for at least 1 year with: airflow limitation (FEV1/FVC < 0.7); some bronchodilator reversibility (post-bronchodilator FEV1 > 20% and ≤ 80% of predicted values); current COPD therapy for at least 3 months prior to enrollment (a high-dose inhaled corticosteroid, ICS, with at least 2 other classes of medications, to obtain “triple therapy”); and a high risk of exacerbations (at least 1 severe [requiring hospitalization] or 2 moderate [treatment with systemic corticosteroids and/or antibiotics] exacerbations in past year).
Notable exclusion criteria were patients with diagnoses of asthma in never-smokers, alpha-1 antitrypsin deficiency, recent exacerbations (in past month), lung volume reduction surgery (in past year), eosinophilic or parasitic diseases, or those with recent monoclonal antibody treatment. Patients with the asthma-COPD overlap syndrome were included only if they had a history of smoking and met the COPD inclusion criteria listed above.
Intervention. The treatment period lasted for a total of 52 weeks, with an additional 8 weeks of follow-up. Patients were randomized 1:1 to placebo or low-dose medication (100 mg) using permuted-block randomization in the METREX study regardless of eosinophil count (but they were stratified for a modified intention-to-treat analysis at screening into either low eosinophilic count [< 150 cells/uL] or high [≥ 150 cells/uL]). In the METREO study, patients were randomized 1:1:1 to placebo, low-dose (100 mg), or high-dose (300 mg) medication only if blood eosinophilia was present (≥ 150 cells/uL at screening or ≥ 300 cells/uL in past 12 months). Investigators and patients were blinded to presence of drug or placebo. Sample size calculations indicated that in order to provide a 90% power to detect a 30% decrease in the rate of exacerbations in METREX and 35% decrease in METREO, a total of 800 patients and 660 patients would need to be enrolled in METREX and METREO respectively. Both studies met their enrollment quota.
Main outcome measures. The primary outcome was the annual rate of exacerbations that were either moderate (requiring systemic corticosteroids and/or antibiotics) or severe (requiring hospitalization). Secondary outcomes included the time to first moderate/severe exacerbation, change from baseline in the COPD Assessment Test (CAT) and St. George’s Respiratory Questionnaire (SGRQ), and change from baseline in blood eosinophil count, FEV1, and FVC. Safety and adverse events endpoints were also assessed.
A modified intention-to-treat analysis was performed overall and in the METREX study stratified on eosinophilic count at screening; all patients who underwent randomization and received at least one dose of medication or placebo were included in that respective group. Multiple comparisons were accounted for using the Benjamini-Hochberg Test, exacerbations were assumed to follow a negative binomial distribution, and Cox proportional-hazards was used to model the relationship between covariates of interest and the primary outcome.
Main results. In the METREX study, 1161 patients were enrolled and 836 underwent randomization and received at least 1 dose of medication or placebo. In METREO, 1071 patients were enrolled and 674 underwent randomization and received at least one dose of medication or placebo. In both studies the patients in the medication and placebo groups were well balanced at baseline across demographics (age, gender, smoking history, duration of COPD) and pulmonary function (FEV1, FVC, FEV1/FVC, CAT, SGRQ). In METREX, a total of 462 (55%) patients had an eosinophilic phenotype and 374 (45%) did not.
There was no difference between groups in the primary endpoint of annual exacerbation rate in METREO (1.49/yr in placebo vs. 1.19/yr in low-dose and 1.27/yr in high-dose mepolizumab, rate ratio of high-dose to placebo 0.86, 95% confidence interval [CI] 0.7–1.05, P = 0.14). There was no difference in the primary outcome in the overall intention-to-treat analysis in the METREX study (1.49/yr in mepolizumab vs. 1.52/yr in placebo, P > 0.99). Only when analyzing the high eosinophilic phenotype in the stratified intention-to-treat METREX group was there a significant difference in the primary outcome (1.41/yr in mepolizumab vs. 1.71/yr in placebo, P = 0.04, rate ratio 0.82, 95% CI 0.68–0.98).
There were no significant differences in any secondary endpoint in the METREO study. In the METREX study, mepolizumab treatment resulted in a significantly longer time to first exacerbation (192 days vs. 141 days, hazard ratio 0.75, 95% CI 0.60–0.94, P = 0.04) but no difference in the change in SGRQ (–2.8 vs. –3.0, P > 0.99) or CAT score (–0.8 vs. 0, P > 0.99). There was no significant difference in any measures of pulmonary function between the treatment and placebo groups (FEV1, FVC, FEV1/FVC). As expected, there was a significant decrease in peripheral blood eosinophil count in both studies in the medication arm. The incidence of adverse events and safety endpoints were similar between the trial groups in METREX and METREO.
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.
Applications for Clinical Practice
In this study, Pavord and colleagues found a potential benefit of mepolizumab treatment for reducing exacerbations in COPD patients with an eosinophilic phenotype. The conflicting results regarding the underlying physiology and the weak treatment effect suggest this medication may not be ready for use in clinical practice without additional supporting evidence. From a practical standpoint, the high cost of medication (~$2500 per month) and marginal benefit of treatment imply that treatment with mepolizumab in COPD patients may not be cost-effective, and even treatment in individual patients on a trial basis should be discouraged until additional supporting data becomes available. Of primary concern are the optimal selection of COPD patients that will achieve benefit with mepolizumab treatment, and the optimal dose of medication to achieve that benefit. The results presented here do not satisfactorily answer these questions, and additional studies are required.
—Arun Jose, MD, The George Washington University, Washington, DC
1. Pelaia C, Vatrella A, Busceti MT, et al. Severe eosinophilic asthma: from the pathogenic role of interleukin-5 to the therapeutic action of mepolizumab. Drug Des Devel Ther 2017;11:3137–44.
2. Kim VL, Coombs NA, Staples KJ, et al. Impact and associations of eosinophilic inflammation in COPD: analysis of the AERIS cohort. Eur Respir J 2017;50:pii:1700853.
3. Roche N, Chapman KR, Vogelmeier CF, et al. Blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment. Data from the FLAME trial. Am J Respir Crit Care Med 2017;195:1189–97.
4. Halpin DMG, Decramer M, Celli BR, et al. Effect of a single exacerbation on decline in lung function in COPD. Respir Med 2017;128:85–91.
5. Rassouli F, Baty F, Stolz D, et al. Longitudinal change of COPD assessment test (CAT in a telehealthcare cohort is associated with exacerbation risk. Int J COPD 2017;12:3103–9.
6. Gauthier M, Ray A, Wenzel SE. Evolving concepts of asthma. Am J Respir Crit Care Med 2015;192:660–8.
7. Negewo NA, McDonald VM, Baines KJ, et al. Peripheral blood eosinophils: a surrogate marker for airway eosinophilia in stable COPD. Int J COPD 2016;11:1495–504.
1. Pelaia C, Vatrella A, Busceti MT, et al. Severe eosinophilic asthma: from the pathogenic role of interleukin-5 to the therapeutic action of mepolizumab. Drug Des Devel Ther 2017;11:3137–44.
2. Kim VL, Coombs NA, Staples KJ, et al. Impact and associations of eosinophilic inflammation in COPD: analysis of the AERIS cohort. Eur Respir J 2017;50:pii:1700853.
3. Roche N, Chapman KR, Vogelmeier CF, et al. Blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment. Data from the FLAME trial. Am J Respir Crit Care Med 2017;195:1189–97.
4. Halpin DMG, Decramer M, Celli BR, et al. Effect of a single exacerbation on decline in lung function in COPD. Respir Med 2017;128:85–91.
5. Rassouli F, Baty F, Stolz D, et al. Longitudinal change of COPD assessment test (CAT in a telehealthcare cohort is associated with exacerbation risk. Int J COPD 2017;12:3103–9.
6. Gauthier M, Ray A, Wenzel SE. Evolving concepts of asthma. Am J Respir Crit Care Med 2015;192:660–8.
7. Negewo NA, McDonald VM, Baines KJ, et al. Peripheral blood eosinophils: a surrogate marker for airway eosinophilia in stable COPD. Int J COPD 2016;11:1495–504.