(2021) 22:171Gibson et al. Respir Reshttps://doi.org/10.1186/s12931-021-01746-4Open AccessRESEARCHMepolizumab improves clinical outcomesin patients with severe asthma and comorbidconditionsPeter G. Gibson1, Charlene M. Prazma2,7* , Geoffrey L. Chupp3, Eric S. Bradford4, Mark Forshag2,Stephen A. Mallett5, Steve W. Yancey4, Steven G. Smith4 and Elisabeth H. Bel6AbstractBackground: Comorbidities can complicate the management of severe asthma; therefore, the presence of comorbidconditions or traits often need to be considered when considering treatment options for patients with severe asthma.The aim of this analysis is to investigate the efficacy of mepolizumab in patients with severe eosinophilic asthma andcomorbidities.Methods: This was a post hoc analysis (GSK ID:209140) of data from the Phase IIb/III studies DREAM, MENSA, SIRIUS,and MUSCA. Patients aged 12 years with severe eosinophilic asthma were randomized to: mepolizumab 750, 250, or75 mg intravenously or placebo (DREAM); mepolizumab 75 mg intravenously or 100 mg subcutaneously or placebo(MENSA); or mepolizumab 100 mg subcutaneously or placebo (SIRIUS and MUSCA) every 4 weeks for 24 weeks in SIRIUS and MUSCA, 32 weeks in MENSA or 52 weeks in DREAM. In this analysis the primary endpoint was the annual rateof clinically significant exacerbations; secondary endpoints were Asthma Control Questionnaire-5 score, St George’sRespiratory Questionnaire total score, and pre-bronchodilator forced expiratory volume in 1 s at study end. Subgroupswere based on comorbidities at baseline.Results: Overall, 1878 patients received placebo (n 689) or mepolizumab (n 1189). Across all comorbidity subgroups mepolizumab reduced the rate of clinically significant exacerbations by 44–68% versus placebo, improvedAsthma Control Questionnaire-5 score by 0.27–0.59 points, and improved St George’s Respiratory Questionnaire totalscore by 5.0–11.6 points. Pre-bronchodilator forced expiratory volume in 1 s was improved by 27.1–286.9 mL in all butone comorbidity subgroup, the diabetes mellitus subgroup.Conclusions: Mepolizumab reduces exacerbations, and improves asthma control, health-related quality of life, andlung function in patients with severe eosinophilic asthma despite comorbid conditions, including upper respiratoryconditions, psychopathologies, cardiovascular conditions, gastroesophageal reflux disease, diabetes mellitus, andobesity.Trial registration: https:// clini caltr ials. gov/ DREAM, MEA112997/NCT01000506; MENSA, MEA115588/NCT01691521;SIRIUS, MEA115575/NCT01842607; MUSCA, 200862/NCT02281318.*Correspondence: [email protected], 5 Moore Drive, PO Box 13398, Research Triangle Park, NC27709‑3398, USAEric S. Bradford and Mark Forshag were affiliated with RespiratoryTherapeutic Area and Respiratory Medical Franchise, GSK, respectively, atthe time of the study.Full list of author information is available at the end of the article The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, whichpermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit lineto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Gibson et al. Respir Res(2021) 22:171Page 2 of 12Keywords: Mepolizumab, Severe eosinophilic asthma, Comorbidities, Upper respiratory, Cardiovascular, TreatabletraitsIntroductionSevere asthma, thought to affect 5–10% of the asthmapopulation, is characterized by poor symptom control,frequent exacerbations, and airflow limitation, despitethe regular use of maintenance therapies including multiple controllers [1, 2]. Patients with severeasthma frequently exhibit comorbid conditions ortraits, which add to the burden of respiratory symptoms [3–7]. These may include primary airway conditions such as allergic rhinitis, which occurs in 55–68%of patients with severe asthma, chronic rhinosinusitiswith or without nasal polyposis, occurring in 45–50%of patients with severe asthma, and vocal cord dysfunction, which affects 19–50% of the severe asthma population . Other comorbid conditions are also commonand include gastroesophageal reflux disease (GERD),which affects 46–63% of patients with severe asthma,obesity, which occurs in 21–48% of patients with severeasthma, obstructive sleep apnea, seen in up to 88–96%of patients with severe asthma, and anxiety or depression, affecting 81% and 31% of the severe asthma population, respectively .Comorbidities can complicate the management ofsevere asthma. Some, such as vocal cord dysfunction, coexist with or mimic asthma , while others,such as upper airway conditions, contribute to poordisease control by aggravating symptoms [10, 11]. Assuch, the presence of comorbid conditions may leadto under- or overtreatment with anti-asthmatic medications . Additionally, comorbidities could resultas adverse effects of asthma treatment, such as iatrogenic comorbidities, including obesity, osteoporosis,depression, and GERD, that are typically related to theuse of systemic corticosteroids . Furthermore, thepresence of comorbid conditions, whether frequentlyassociated with severe asthma, or simply common withaging, has the potential to alter the response to asthmatherapy, either due to a change in asthma phenotype oran increased or less responsive airway inflammationor resultant anatomical changes (e.g. obesity) impacting mechanical functioning of the pleural cavity .As the focus of severe asthma management movesincreasingly towards personalized care, the role andimportance of comorbid conditions is more often beingrecognized .Severe eosinophilic airway inflammation in asthma is aclinically valid endotype associated with increased exacerbation risk . It has been described as a treatabletrait, since it is identifiable, measurable and treatable,allowing for targeted therapy to improve outcomes forindividual patients . Elevated blood eosinophil levelsand a high number of severe exacerbations in the previous year are predictors of good response to anti-interleukin-5 and anti-interleukin-5 receptor α monoclonalantibodies .Mepolizumab is a humanized monoclonal antibodythat selectively targets interleukin-5 and is approvedas an add-on treatment for patients with severe eosinophilic asthma [17, 18]. During the mepolizumab clinicaldevelopment program, patients with severe eosinophilicasthma treated with mepolizumab showed consistentreductions in both clinically significant exacerbationsand the need for systemic corticosteroids; improvementswere also observed in lung function parameters, asthmasymptom control, and health-related quality of life, compared with placebo [19–22]. Additionally, in patientswith recurrent chronic rhinosinusitis with nasal polyps,mepolizumab treatment reduces the need for surgeryand reduces symptom severity compared with placebo, and in patients with severe eosinophilic asthma andnasal polyps, mepolizumab has been shown to reducethe rate of clinically significant exacerbations comparedwith placebo [19–22]. Given that some comorbiditiescan aggravate symptoms and increase the risk of asthmaexacerbations  or render asthma control more difficult to achieve, detailed data on the effect of mepolizumab in patients with other comorbidities are neededto determine whether the effect of mepolizumab is sensitive to presence or absence of these conditions. The aimof this post hoc meta-analysis of data from four PhaseIIb/III clinical trials was to investigate the impact ofmepolizumab versus placebo on clinically significantexacerbations, asthma control, and health-related quality of life in patients with severe eosinophilic asthma andcomorbidities, including airway-related, airway-unrelated, and iatrogenic conditions, as determined by medical history.MethodsStudy design and treatmentThis was a post hoc meta-analysis (GSK ID: 209140) ofdata from the Phase IIb/III, placebo-controlled, randomized, double-blind, parallel-group, multicenter studies, DREAM (NCT01000506), MENSA (NCT01691521),SIRIUS (NCT01691508), and MUSCA (NCT02281318),which assessed mepolizumab treatment in patients with
Gibson et al. Respir Res(2021) 22:171severe eosinophilic asthma. Full details of these studies have been published previously [19–22]. In brief,patients enrolled in DREAM were randomized (1:1:1:1)to receive mepolizumab 750, 250, or 75 mg intravenouslyor placebo, plus standard of care (high-dose inhaled corticosteroids and another controller), every 4 weeks for52 weeks. Patients enrolled in MENSA were randomized(1:1:1) to receive mepolizumab 75 mg intravenously,mepolizumab 100 mg subcutaneously or placebo, plusstandard of care, every 4 weeks for 32 weeks. Patientsenrolled in SIRIUS or MUSCA were randomized (1:1)to receive mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 24 weeks.All four studies were conducted in accordance with theethical principles of the Declaration of Helsinki, International Conference on Harmonisation Good ClinicalPractice Guidelines, and applicable country-specific regulatory requirements [19–22].PatientsThe four trials enrolled patients who were 12 years ofage with severe eosinophilic asthma, defined as bloodeosinophil count 150 cells/µL at baseline or 300 cells/µL in the prior year (or alternatively in DREAM as oneof the following: a sputum eosinophil count of 3%, anexhaled nitric oxide concentration of 50 ppb, or promptdeterioration of asthma control after 25% reductionin regular maintenance inhaled or oral corticosteroids[OCS]). Additional criteria included a history of 2exacerbations requiring systemic corticosteroids in theyear prior to enrolment despite regular treatment withhigh-dose inhaled corticosteroids in the 12 months priorto screening, plus additional controller medication(s)for 3 months, and evidence of airflow obstruction. TheSIRIUS study did not require a history of 2 exacerbations but did require a 6-month history of maintenancetreatment with systemic corticosteroids (Additionalfile 1: Table 1).Endpoints and assessmentsThe primary endpoint of this meta-analysis was theannual rate of clinically significant exacerbations, definedas a worsening of asthma that required the use of systemic corticosteroids and/or hospitalization/emergencyroom visits. Exacerbations separated by less than 7 dayswere treated as a continuation of the same exacerbation.Secondary endpoints included changes from baselinein pre-bronchodilator forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ)total score, and Asthma Control Questionnaire (ACQ)-5score at study end.Page 3 of 12Patient subgroups were created based on the selfreported presence of current medical conditions at thescreening visit of each study. Information on these conditions was captured in the electronic case report form(eCRF), which included pre-defined medical conditioncategories that were subsequently grouped into comorbid condition subgroups. These subgroups were upperrespiratory (allergic rhinitis/hay fever, sinusitis, nasalpolyps), psychopathologies (anxiety, depression, moodchanges, sleep disorders), cardiovascular (arrythmia,cardiac failure, cardiomyopathy, coronary artery disease,hypertension, hyperglycemia, cerebrovascular disorder,thrombophlebitic event), GERD, diabetes mellitus, andobesity (body mass index 30).A separate post hoc analysis of conditions potentiallyassociated with long-term OCS use was conducted inpatients who were OCS-dependent, defined as patientswith evidence of long-term OCS usage (treatment withOCS for 50% of the year or medium-dose [6–12 mg/day]or high-dose [ 12 mg/day] OCS use for 6 months priorto baseline visit) who were receiving OCS at baseline.Data from these patients were analyzed according tothe presence of the following OCS-related conditions atscreening, which were adrenal-related (adrenal suppression, Cushing’s syndrome, moon face), psychopathologies (anxiety, depression, mood changes, sleep disorders),eye-related (glaucoma, cataract), osteoporosis/bone fractures (bone fractures, osteoporosis), bruising, and weightgain.Statistical analysisAll analyses were conducted in the intent-to-treat population, which included all randomized patients whoreceived 1 dose of study medication. Patients were analyzed based on the treatment received. For the purposesof the analysis, all doses of mepolizumab used duringthe four studies were combined into a single treatmentgroup.The rate of clinically significant exacerbations wasanalyzed using a negative binomial generalized linearmodel with a log-link function, including log of time ontreatment as an offset variable. Change from baseline inSGRQ total score was analyzed using analysis of covariance. Change from baseline in ACQ-5 score and changefrom baseline in pre-bronchodilator F EV1 were analyzed using a mixed model repeated measures (MMRM)analysis. All model-based analyses included study ID,treatment group, region (European Union [EU], Europe[non-EU], South America, United States, rest of world),number of exacerbations in the prior year (0, 1, or 2 vs3 vs 4), baseline maintenance OCS therapy (OCS