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Background Severe asthma is associated with a broad range of phenotypes and clinical characteristics. This analysis assessed whether select baseline patient characteristics could prognosticate mepolizumab efficacy in severe eosinophilic asthma. Methods This was a post hoc meta-analysis of data from the Phase III MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862) studies. Patients aged ≥ 12 years with severe eosinophilic asthma and a history of exacerbations were randomised to receive placebo (MENSA/MUSCA), mepolizumab 75 mg intravenously (MENSA) or 100 mg subcutaneously (SC) (MENSA/MUSCA) every 4 weeks for 32 (MENSA) or 24 (MUSCA) weeks. The primary endpoint was the annual rate of clinically significant exacerbations; other outcomes included the proportion of patients with no exacerbations and changes from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ) total score and Asthma Control Questionnaire (ACQ)-5 score. Analyses were performed by baseline age of asthma onset (1 ≤ 60; 60–80; > 80); airway reversibility (reversible [≥ 12% change in FEV1]; non-reversible [1]); perennial and/or seasonal allergen sensitivity (yes/no); asthma control (uncontrolled [ACQ-5 score ≥ 1.5]; partial/complete control [ACQ-5 score Results Overall, 936 patients received mepolizumab 100 mg SC or placebo. Across age at asthma onset, lung function and airway reversibility subgroups, mepolizumab reduced the rate of clinically significant exacerbations by 49–63% versus placebo. Improvements in lung function, SGRQ total score and ACQ-5 score were also seen with mepolizumab versus placebo across most age and lung function subgroups. Clinically significant exacerbations were reduced with mepolizumab versus placebo irrespective of season or allergen sensitivity; SGRQ total and ACQ-5 scores were generally improved across seasons. Conclusions Mepolizumab efficacy was consistent for patients with varying age at asthma onset, lung function, airway reversibility and allergen sensitivities at baseline. Our results indicate that mepolizumab is likely to be beneficial for patients with severe eosinophilic asthma with a broad range of baseline clinical characteristics; large-scale real-world studies are needed to confirm the external validity of these findings. Trial registration Post hoc meta-analysis of data from MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862)

Background Comorbidities can complicate the management of severe asthma; therefore, the presence of comorbid conditions 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 and comorbidities. 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, or 75 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 rate of clinically significant exacerbations; secondary endpoints were Asthma Control Questionnaire-5 score, St George’s Respiratory Questionnaire total score, and pre-bronchodilator forced expiratory volume in 1 s at study end. Subgroups were 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, improved Asthma Control Questionnaire-5 score by 0.27–0.59 points, and improved St George’s Respiratory Questionnaire total score by 5.0–11.6 points. Pre-bronchodilator forced expiratory volume in 1 s was improved by 27.1–286.9 mL in all but one comorbidity subgroup, the diabetes mellitus subgroup. Conclusions Mepolizumab reduces exacerbations, and improves asthma control, health-related quality of life, and lung function in patients with severe eosinophilic asthma despite comorbid conditions, including upper respiratory conditions, psychopathologies, cardiovascular conditions, gastroesophageal reflux disease, diabetes mellitus, and obesity. Trial registration: https://clinicaltrials.gov/ DREAM, MEA112997/NCT01000506; MENSA, MEA115588/NCT01691521; SIRIUS, MEA115575/NCT01842607; MUSCA, 200862/NCT02281318.

Background A pre-specified meta-analysis of individual patient data from the 52-week METREX and METREO trials, which investigated mepolizumab for chronic obstructive pulmonary disease (COPD) in patients with blood eosinophil counts ≥150 cells/µL (screening) or ≥300 cells/µL (prior year) and frequent exacerbations, enables more robust characterization of mepolizumab efficacy in COPD and exploration of the relationship between blood eosinophil count and treatment responses. Methods In METREX (117106/NCT02105948) and METREO (117113/NCT02105961), randomized patients received mepolizumab or placebo added to existing inhaled corticosteroid (ICS)–based triple maintenance therapy. The annual rate of moderate/severe exacerbations (primary endpoint) was compared between subcutaneous (SC) mepolizumab 100 mg versus placebo (primary comparison of interest) and all doses (100 mg and 300 mg SC) versus placebo in patients with blood eosinophil counts ≥150 cells/µL at screening or ≥300 cells/µL in the prior year. Secondary/other endpoints included time to first moderate/severe exacerbation, exacerbations leading to emergency department visit/hospitalization and health-related quality of life (HRQoL). A predictive model of the relationship between screening blood eosinophil counts and exacerbation rates included data from all randomized patients. Results In total, 1510 patients were randomized in METREX and METREO and 1136 patients were included in the pre-specified meta-analysis. From the meta-analysis, mepolizumab 100 mg SC significantly reduced annual moderate/severe exacerbation rates versus placebo by 18% (rate ratio: 0.82; 95% confidence interval: 0.71, 0.95; p=0.006) and delayed time to first moderate/severe exacerbation (hazard ratio: 0.80 [0.68, 0.94]; p=0.006). Mepolizumab 100 mg SC versus placebo numerically reduced exacerbations leading to ED visits/hospitalization and improved HRQoL. A modelling approach demonstrated increasing efficacy for moderate/severe exacerbations with increasing screening blood eosinophil count; this relationship was more pronounced for exacerbations requiring oral corticosteroids (post hoc). The all-doses comparison had similar results. Conclusion Mepolizumab reduces exacerbations in patients with eosinophil-associated COPD. Results suggest that blood eosinophil counts (≥150 cells/µL at screening or ≥300 cells/µL in the prior year) allow for identification of patients with COPD who experience exacerbations while treated with maximal ICS-based triple maintenance therapy who are likely to benefit from mepolizumab., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/YCq1mqQ5Xl4

Background: Anti–IL-5 therapy is a potential treatment for patients with hypereosinophilic syndrome (HES), although its clinical efficacy is unclear. Objective: We sought to investigate the clinical efficacy and safety of mepolizumab versus placebo in patients with HES. Methods: This randomized, multicenter, double-blind, placebo-controlled, phase III trial was conducted across 39 centers in 13 countries. Eligible patients had FIP1L1-PDGFRA-negative HES, experienced 2 or more flares (worsening of HES-related symptoms or blood eosinophil count requiring therapeutic escalation) in the previous 12 months, and had a screening blood eosinophil count greater than or equal to 1000 cells/μL. Patients were randomized (1:1) to subcutaneous mepolizumab (300 mg) or placebo every 4 weeks for 32 weeks, plus existing HES therapy. The primary outcome was the proportion of patients with 1 or more flares (worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue oral corticosteroids) during the study; in addition, patients who withdrew early from the study were counted as having a flare. Safety end points were also assessed. Results: The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P =.002). Logistic regression analysis was consistent with the primary analysis (odds ratio, 0.28; 95% CI, 0.12-0.64; P =.003). Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (48 of 54 [89%] vs 47 of 54 [87%]). Conclusions: Compared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified., SCOPUS: ar.j, info:eu-repo/semantics/published

This study compared the pharmacokinetic (PK) profile of a new liquid formulation of mepolizumab with the established lyophilized formulation. In this open‐label, parallel‐group, single‐dose study (NCT03014674; GSK ID: 204958), healthy participants were randomized (1:1:1) to receive a single mepolizumab dose (100 mg) administered subcutaneously as liquid in a single‐use prefilled syringe or single‐use prefilled autoinjector, or as a lyophilized formulation. Maximum plasma concentration, area under the plasma concentration–time curve from time zero (predose) to time of last quantifiable concentration (AUC0–t), and AUC from time zero to infinity (AUC0–∞) as well as additional PK parameters, safety assessments, and blood eosinophil count were evaluated. In total, 244 participants received study drug. All PK parameters were similar across the 3 groups; 90% confidence intervals for maximum plasma concentration, AUC0–t, and AUC0–∞ treatment ratios (liquid prefilled syringe or autoinjector vs lyophilized formulation) were within conventional bioequivalence bounds (0.80‐1.25), demonstrating statistical PK comparability. On‐treatment adverse event incidence was 29% to 38%. Mepolizumab liquid formulation administered via prefilled syringe or autoinjector had similar PK properties to the lyophilized formulation, with no safety concerns identified.

Objectives There are no published reports for anti‐interleukin‐5 therapy in children

Objective: To assess the effect of asthma exacerbations and mepolizumab treatment on health status of patients with severe asthma using the St George’s Respiratory Questionnaire (SGRQ).Meth...

Background The long-term efficacy and safety of mepolizumab for treatment of severe eosinophilic asthma are well established. Here, we examine the clinical impact of stopping mepolizumab after long-term use. Methods COMET (NCT02555371) was a randomised, double-blind, placebo-controlled, parallel-group, multicentre study. Patients who had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692) and received continuous mepolizumab treatment for ≥3 years were randomised 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg every 4 weeks for 52 weeks. Primary end-point: time to first clinically significant exacerbation; secondary end-points: time to first exacerbation requiring hospitalisation/emergency department visit, time to decrease in asthma control (≥0.5-point increase in Asthma Control Questionnaire-5 score from COMET baseline) and blood eosinophil count ratio to COMET baseline. Safety was assessed. Results Patients stopping (n=151) versus continuing (n=144) mepolizumab had significantly shorter times to first clinically significant exacerbation (hazard ratio 1.61, 95% CI 1.17–2.22; p=0.004) and decrease in asthma control (hazard ratio 1.52, 95% CI 1.13–2.02; p=0.005), and higher blood eosinophil counts at week 52 (270 versus 40 cells·µL−1; ratio (stopping versus continuing) 6.19, 95% CI 4.89–7.83; p, This randomised study demonstrates increased exacerbation risk and a decrease in asthma control in patients with severe eosinophilic asthma who stop mepolizumab treatment after long-term use, when compared with those who continue treatment. https://bit.ly/3fsxGV2

Background: The long-term efficacy and safety of mepolizumab in severe eosinophilic asthma (SEA) have been shown. Aims: To assess the impact of stopping versus continuing long-term mepolizumab on asthma worsening. Methods: COMET (NCT02555371) was a randomised, double-blind, placebo-controlled study. Patients had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692), had continuous mepolizumab for ≥3 years (mean 46.6 months), and stayed on asthma controller therapy. Randomisation was 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg for 52 weeks. Composite endpoint: time to first asthma worsening (defined in Table). Daily eDiary data were analysed using Kaplan–Meier estimates and a Cox proportional hazards model adjusted for covariates. Results: Treatment differences for those who stopped versus continued mepolizumab emerged by Week 4 (8 weeks post last open-label mepolizumab dose). For those who stopped mepolizumab, 51.7% reported asthma worsening by Week 52 versus 35.0% who continued mepolizumab (Table), leading to a significantly shorter time to first asthma worsening in those who stopped mepolizumab. Conclusion: Stopping mepolizumab in patients with SEA led to an increased risk of asthma worsening with a significantly shorter time to first asthma worsening versus those continuing long-term mepolizumab. Funding: GSK [201810/NCT02555371].

The development of mepolizumab, an anti-IL-5 monoclonal antibody for the treatment of severe eosinophilic asthma, is an example of a clinical development program that evolved over time based on sound, basic scientific principles. Initial clinical data on the effects of mepolizumab on lung function in a general asthmatic population were disappointing. However, it became clear that mepolizumab may be more effective against other clinical endpoints, particularly asthma exacerbations, in patients with more severe disease. Furthermore, a developing understanding of asthma disease pathobiology led to the identification of an appropriate target population and predictive biomarker for mepolizumab treatment: patients with severe eosinophilic asthma and blood eosinophil count. Mepolizumab use provides clinically meaningful benefits in this target population, fulfilling an unmet need. This Clinical Commentary Review describes the clinical development of mepolizumab and details of how this program informed the development of other biologic therapies in patients with severe asthma. This account highlights how a personalized approach toward treatment of patients with severe eosinophilic asthma, supported by a large body of scientific evidence, ultimately led to new and effective treatments and improved patient outcomes.

Introduction Previous studies showed that mepolizumab significantly reduces exacerbations and oral corticosteroid use in patients with severe eosinophilic asthma. However, early studies reported inconsistent effects on lung function. This study specifically assessed the onset of clinical effect and the relationship of baseline blood eosinophil count of mepolizumab 100 mg subcutaneous (SC) administration on morning peak expiratory flow (AM PEF). Methods Post hoc analysis of data from two randomized, double-blind, placebo-controlled studies (MENSA, NCT01691521; MUSCA, NCT02281318) of 4-weekly mepolizumab 100 mg versus placebo in patients with severe eosinophilic asthma. Individual study results were generated using a mixed model repeated measures model controlling for multiple covariates and were combined using a fixed effects meta-analysis via inverse-variance weighting. Results Significant improvements in AM PEF after the first dose of mepolizumab 100 mg SC vs. placebo were seen as early as week 1 and continued to improve further with subsequent doses. The mean change in AM PEF was 26 L/min in the mepolizumab group compared to 4 L/min in the placebo group, p

Introduction Improved understanding of genetic effects on response to treatments with novel approaches for COPD with peripheral blood eosinophilia, such as mepolizumab (a humanized monoclonal antibody to IL-5), may improve treatment outcomes. We conducted a study to identify genetic variants associated with efficacy of mepolizumab COPD. Materials and methods Using generalized linear and logistic regression models, genome-wide association analyses were performed to investigate genetic associations with frequency of moderate and/or severe COPD exacerbations in COPD subjects receiving mepolizumab (weeks 0–52). Additional analyses included: (i) frequency of COPD exacerbations requiring hospitalization or emergency department visit (weeks 0–52), (ii) change from baseline mean total St. George's Respiratory Questionnaire (SGRQ) score (week 24), and (iii) SGRQ response defined as achieving a 4 unit or greater decrease of SGRQ score from baseline (week 24). This study included 610 patients with COPD, a subset of the Intent-to-treat (ITT) populations in two phase III double-blind trials assessing the efficacy and safety of mepolizumab, METREX (NCT02105948) and METREO (NCT02105961). All subjects had elevated eosinophil levels (≥150 cells/μL at screening or ≥300 cell/μL in the 12 months prior to study), were treated with mepolizumab, and provided consent for genetic analysis. Results From this post-hoc analysis, no genetic variant was significantly associated with moderate and/or severe COPD exacerbations or any of the other endpoints tested (threshold for statistical significance at the genome-wide level, p = 5 × 10−8). Conclusions In this exploratory study in patients with COPD, with peripheral blood eosinophilia, no genetic effects on mepolizumab-treatment response were identified.

Objectives: Severe asthma comprises several distinct phenotypes. Consequently, patients with severe asthma can be eligible for more than one biologic treatment targeting Th2 inflammation, such as anti-interleukin (IL)-5 and anti-immunoglobulin (Ig) E. The objective of this study was to describe treatment eligibility and overlap in treatment eligibility for mepolizumab (anti-IL-5), omalizumab (anti-IgE) and reslizumab (anti-IL-5) in patients with severe asthma, who were recruited from clinical practice. Methods: This cross-sectional, single-visit, observational study in six countries enrolled patients with severe asthma (defined by American Thoracic Society/European Respiratory Society guidelines). Assessable patients were analysed as a total cohort and a sub-cohort, who were not currently receiving omalizumab. Treatment eligibility was defined according to the local prescribing information or protocol-defined inclusion/exclusion criteria. Patients currently receiving omalizumab were automatically categorised as omalizumab-eligible. Results: The total cohort comprised 670 patients who met the analysis criteria, of whom 20% were eligible for mepolizumab, 31–41% were eligible for omalizumab (depending on eligibility criteria used), and 5% were eligible for reslizumab. In patients not currently receiving omalizumab (n = 502), proportions eligible for each biologic were similar (mepolizumab: 20%, reslizumab 6%) or lower (omalizumab 7–21%) than those for the total cohort. Overlap in treatment eligibility varied; in mepolizumab-eligible patients not currently receiving omalizumab (n = 101), 27–37% were omalizumab-eligible and 18% were reslizumab-eligible. Conclusions: Treatment eligibility for mepolizumab and omalizumab was higher than that for reslizumab. Although there was some overlap in treatment eligibility, the patient groups eligible for treatment with anti-IL-5 or anti-IgE therapies were often distinct, emphasising the different phenotypes and endotypes in severe asthma.

Background Severe asthma is a heterogeneous disease. Patients with both eosinophilic and allergic asthma phenotypes may be eligible for treatment with mepolizumab and omalizumab. Evidence on the relative effectiveness of these treatments in this ‘overlap’ population would be informative for clinical and payer decision making. Methods A systematic literature review and indirect treatment comparison (Bayesian framework) were performed to assess the comparative effectiveness and tolerability of mepolizumab and omalizumab, as add-ons to standard of care. Studies included in the primary analysis were double-blind, randomized controlled trials, ≥12 weeks' duration enrolling patients with severe asthma with a documented exacerbation history and receiving high-dose inhaled corticosteroids plus ≥1 additional controller. Two populations were examined: patients potentially eligible for 1) both treatments (Overlap population) and 2) either treatment (Trial population). Results In the Overlap population, no differences between treatments in clinically significant exacerbations and exacerbations requiring hospitalization were found, although trends favored mepolizumab (rate ratio [RR]:0.66 [95% credible intervals (Crl):0.37,1.19]; 0.19[0.02,2.32], respectively). In the Trial population, mepolizumab treatment produced greater reductions in clinically significant exacerbations (RR:0.63 [95% CrI:0.45,0.89]) but not exacerbations requiring hospitalization compared with omalizumab (RR:0.58 [95% Crl: 0.16,2.13]), although the trend favored mepolizumab. Both treatments had broadly comparable effects on lung function, and similar tolerability profiles. Conclusions Whilst this analysis has limitations due to a restricted evidence base and residual heterogeneity, it showed that in patients with severe asthma, mepolizumab seems to be at least as effective as omalizumab and that the tolerability profiles of the two treatments did not meaningfully differentiate.

Introduction Les patients asthmatiques peuvent etre egalement atteints de polypose nasale (PN) et/ou d’une intolerance a l’aspirine ou a d’autres anti-inflammatoires non steroidiens (AINS). La presence de ces trois symptomes est connue sous le nom de maladie de Widal (MW). Dans les essais cliniques de phase III, le mepolizumab, autorise en traitement additionnel pour l’asthme severe a eosinophiles (ASE), reduisait les exacerbations cliniquement significatives par rapport au placebo. Nous presentons ici les donnees d’efficacite du mepolizumab chez les patients avec un ASE avec PN et/ou une intolerance a l’aspirine/AINS. Methodes Cette etude est une analyse post-hoc des essais controles randomises de phase III, MUSCA et MENSA. Les patients (âge ≥ 12 ans) avec un ASE et ayant eu au moins 2 exacerbations au cours de l’annee precedente, malgre l’utilisation de CSI a fortes doses et de ≥ 1 traitement additionnel, ont recu du mepolizumab 100 mg SC ou un placebo toutes les 4 semaines, pendant 24 (MUSCA) ou 32 semaines (MENSA). Le critere principal etait le taux annuel d’exacerbations cliniquement significatives (aggravation de l’asthme necessitant l’utilisation de corticoides oraux/hospitalisation/visite aux urgences). Les sous-analyses ont ete effectuees en fonction de la presence ou non de PN, d’intolerance a l’aspirine/AINS ou des deux a l’inclusion. Le taux d’exacerbations a ete analyse en sous-groupe par une regression binomiale negative. Resultats Sur 936 patients, 468 ont recu du mepolizumab et 468 ont recu un placebo. Parmi les patients, 18 % souffraient de PN (86 mepolizumab, 80 placebo), 9 % avaient declare une intolerance a l’aspirine/AINS (42 mepolizumab, 45 placebo) et 4 % avaient une MW (20 mepolizumab, 20 placebo). Le mepolizumab a reduit significativement les exacerbations vs placebo chez les patients avec ou sans PN a l’inclusion (ratio des taux [IC95 %] : 0,20[0,11 ; 0,35] et 0,51[0,41 ; 0,64], respectivement), avec ou non une intolerance a l’aspirine/AINS (ratio des taux [IC95 %] : 0,66[0,37 ; 1,18] et 0,43[0,35 ; 0,55] respectivement) et chez ceux souffrant ou non d’une MW (rapport des taux [IC95 %] : 0,66[0,24 ;1,79] et 0,45[0,36 ; 0,56] respectivement, Tableau 1 ). Conclusion Le mepolizumab a permis une diminution significative des exacerbations severes d’asthme vs placebo independamment de la presence d’une intolerance a l’aspirine/AINS ou d’une MW. La presence d’une polypose nasale etait associee a une reduction plus importante des exacerbations d’asthme.

Altres ajuts: This trial was funded by Eli Lilly and Company. There are sparse real-world data on severe asthma exacerbations (SAE) in children. This multinational cohort study assessed the incidence of and risk factors for SAE and the incidence of asthma-related rehospitalization in children with asthma. Asthma patients 5-17 years old with ≥1 year of follow-up were identified in six European electronic databases from the Netherlands, Italy, the UK, Denmark and Spain in 2008-2013. Asthma was defined as ≥1 asthma-specific disease code within 3 months of prescriptions/dispensing of asthma medication. Severe asthma was defined as high-dosed inhaled corticosteroids plus a second controller. SAE was defined by systemic corticosteroids, emergency department visit and/or hospitalization all for reason of asthma. Risk factors for SAE were estimated by Poisson regression analyses. The cohort consisted of 212 060 paediatric asthma patients contributing to 678 625 patient-years (PY). SAE rates ranged between 17 and 198/1000 PY and were higher in severe asthma and highest in severe asthma patients with a history of exacerbations. Prior SAE (incidence rate ratio 3-45) and younger age increased the SAE risk in all countries, whereas obesity, atopy and GERD were a risk factor in some but not all countries. Rehospitalization rates were up to 79% within 1 year. In a real-world setting, SAE rates were highest in children with severe asthma with a history of exacerbations. Many severe asthma patients were rehospitalized within 1 year. Asthma management focusing on prevention of SAE is important to reduce the burden of asthma.

BACKGROUND: In a recent phase III trial (NCT02020889) 53% of mepolizumab-treated versus 19% of placebo-treated patients with eosinophilic granulomatosis with polyangiitis (EGPA) achieved protocol-defined remission. OBJECTIVE: We sought to investigate post hoc the clinical benefit of mepolizumab in patients with EGPA using a comprehensive definition of benefit encompassing remission, oral glucocorticoid (OGC) dose reduction, and EGPA relapses. METHODS: The randomized, placebo-controlled, double-blind, parallel-group trial recruited patients with relapsing/refractory EGPA receiving stable OGCs (prednisolone/prednisone, ≥7.5-50 mg/d) for 4 or more weeks. Patients received 300 mg of subcutaneous mepolizumab or placebo every 4 weeks for 52 weeks. Clinical benefit was defined post hoc as follows: remission at any time (2 definitions used), 50% or greater OGC dose reduction during weeks 48 to 52, or no EGPA relapses. The 2 remission definitions were Birmingham Vasculitis Activity Score of 0 plus OGC dose of 4 mg/d or less (remission 1/clinical benefit 1) or 7.5 mg/d or less (remission 2/clinical benefit 2). Clinical benefit was assessed in all patients and among subgroups with a baseline blood eosinophil count of less than 150 cells/μL, baseline OGC dosage of greater than 20 mg/d, or weight of greater than 85 kg. RESULTS: With mepolizumab versus placebo, 78% versus 32% of patients experienced clinical benefit 1, and 87% versus 53% of patients experienced clinical benefit 2 (both P < .001). Significantly more patients experienced clinical benefit 1 with mepolizumab versus placebo in the blood eosinophil count less than 150 cells/μL subgroup (72% vs 43%, P = .033) and weight greater than 85 kg subgroup (68% vs 23%, P = .005); in the OGC greater than 20 mg/d subgroup, results were not significant but favored mepolizumab (60% vs 36%, P = .395). CONCLUSION: When a comprehensive definition of clinical benefit was applied to data from a randomized controlled trial, 78% to 87% of patients with EGPA experienced benefit with mepolizumab.

Background Data on the risk of death following an asthma exacerbation are scarce. With this multinational cohort study, we assessed all-cause mortality rates, mortality rates following an exacerbation, and patient characteristics associated with all-cause mortality in asthma. Methods Asthma patients aged ≥18 years and with ≥1 year of follow-up were identified in 5 European electronic databases from the Netherlands, Italy, UK, Denmark and Spain during the study period January 1, 2008–December 31, 2013. Patients with asthma-COPD overlap were excluded. Severe asthma was defined as use of high dose ICS + use of a second controller. Severe asthma exacerbations were defined as emergency department visits, hospitalizations or systemic corticosteroid use, all for reason of asthma. Results The cohort consisted of 586,436 asthma patients of which 42,611 patients (7.3%) had severe asthma. The age and sex standardized all-cause mortality rates ranged between databases from 5.2 to 9.5/1000 person-years (PY) in asthma, and between 11.3 and 14.8/1000 PY in severe asthma. The all-cause mortality rate in the first week following a severe asthma exacerbation ranged between 14.1 and 59.9/1000 PY. Mortality rates remained high in the first month following a severe asthma exacerbation and decreased thereafter. Higher age, male gender, comorbidity, smoking, and previous severe asthma exacerbations were associated with mortality. Conclusion All-cause mortality following a severe exacerbation is high, especially in the first month following the event. Smoking cessation, comorbidity-management and asthma-treatment focusing on the prevention of exacerbations might reduce associated mortality.

Objective: A liquid mepolizumab formulation in a single-use prefilled syringe (PFS) is under development. We evaluated the usability of mepolizumab self-injected via PFS by patients with severe eosinophilic asthma (SEA), or their caregivers, in clinic and at home. Methods: This open-label, single-arm, Phase IIIa study included patients with SEA, aged ≥12 years, and receiving mepolizumab (100 mg subcutaneously) every 4 weeks for ≥12 weeks prior to screening. Patients with SEA not receiving mepolizumab at screening who met additional criteria were also included. Patients/caregivers self-administered mepolizumab (100 mg subcutaneously) via PFS every 4 weeks for 12 weeks. The first (Week 0) and third (Week 8) dose were observed in clinic; the second dose (Week 4) was unobserved at home. Primary and secondary endpoints were the proportion of patients who successfully self-administered their third and second doses, respectively. Injection success was determined by investigator/site staff. Patient experience, mepolizumab trough concentrations, blood eosinophil counts, and safety were also assessed. Results: Of the 56 patients/caregivers who self-administered ≥1 dose of mepolizumab, 55 completed the study. All patients were reported to have successfully self-administered their third mepolizumab dose in clinic (N = 55, 100%); this was further evidenced by trough concentrations/blood eosinophil counts. Most patients/caregivers found the PFS easy and convenient to use with 75% (n = 42) expressing little/no anxiety about using the device at home. Incidence of on-treatment drug-related adverse events was low (4%); none were fatal. Conclusions: Patients/caregivers successfully self-administered mepolizumab via the PFS both in clinic and at home, with no new safety concerns identified.

Purpose The goal of this study was to assess the long-term safety and efficacy of mepolizumab in patients with the most severe eosinophilic asthma. Methods This multicenter, open-label, long-term, Phase IIIb study (COSMEX [COSMOS Extension]; 201312/NCT02135692) enrolled patients from the 52-week, open-label extension study COSMOS (A Study to Determine Long-term Safety of Mepolizumab in Asthmatic Subjects) that previously enrolled patients from the double-blinded, placebo-controlled Phase III studies MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) and SIRIUS (Steroid Reduction with Mepolizumab Study). To enter COSMEX, patients had to have life-threatening/seriously debilitating asthma before entering MENSA or SIRIUS and to have completed these previous studies with demonstrated improvement while receiving mepolizumab. In COSMEX, patients received mepolizumab 100 mg subcutaneously every 4 weeks as add-on therapy for up to 172 weeks. Primary endpoints were adverse event frequency and exacerbation rate per year; also assessed were forced expiratory volume in 1 s, Asthma Control Questionnaire-5 score, and daily oral corticosteroid (OCS) use. Findings Of the 340 patients enrolled, 339 received mepolizumab; median treatment duration within this extension study was 2.2 years, equating to 718 patient-years of additional exposure. No new safety signals were identified. Patients receiving mepolizumab throughout this study and previous studies had lasting reductions in exacerbation rate and daily OCS use and improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire-5 score. In COSMEX, the on-treatment exacerbation rate (95% CI) was 0.93 (0.81–1.06) event/year for clinically significant exacerbations, 0.13 (0.10–0.18) event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 (0.05–0.10) event/year for exacerbations requiring hospitalization. In patients requiring systemic/oral corticosteroids with ≥128 weeks of continuous enrollment across SIRIUS, COSMOS, and COSMEX, mepolizumab maintained the median daily OCS dose at 1.3–2.8 mg during COSMEX, with additional patients no longer requiring OCS after extended mepolizumab treatment. Implications This study indicates that long-term mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT02135692.

BackgroundThe long-term efficacy and safety of mepolizumab for treatment of severe eosinophilic asthma are well established. Here, we examine the clinical impact of stopping mepolizumab after long-term use.MethodsCOMET (NCT02555371) was a randomised, double-blind, placebo-controlled, parallel-group, multicentre study. Patients who had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692) and received continuous mepolizumab treatment for ≥3 years were randomised 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg every 4 weeks for 52 weeks. Primary end-point: time to first clinically significant exacerbation; secondary end-points: time to first exacerbation requiring hospitalisation/emergency department visit, time to decrease in asthma control (≥0.5-point increase in Asthma Control Questionnaire-5 score from COMET baseline) and blood eosinophil count ratio to COMET baseline. Safety was assessed.ResultsPatients stopping (n=151) versus continuing (n=144) mepolizumab had significantly shorter times to first clinically significant exacerbation (hazard ratio 1.61, 95% CI 1.17–2.22; p=0.004) and decrease in asthma control (hazard ratio 1.52, 95% CI 1.13–2.02; p=0.005), and higher blood eosinophil counts at week 52 (270 versus 40 cells·µL−1; ratio (stopping versus continuing) 6.19, 95% CI 4.89–7.83; pConclusionPatients who stopped mepolizumab had an increase in exacerbations and reduced asthma control versus those who continued.

Introduction L’efficacite et la tolerance du mepolizumab dans ASE etant bien etablies, COMET a examine les resultats apres la poursuite ou l’arret du mepolizumab a long terme. Methodes COMET etait une etude multicentrique, randomisee, en double aveugle, controle par placebo. Les patients eligibles avaient complete COLUMBA/COSMEX, recu un traitement continu par mepolizumab pendant au moins 3 ans. Les patients ont ete randomises 1 :1 pour continuer mepolizumab 100 mg par voie SC toutes les 4 semaines pendant 52 semaines ou pour arreter mepolizumab. Les patients pouvaient revenir au traitement par mepolizumab en ouvert a la suite d’une exacerbation. Le critere primaire etait la duree jusqu’a la premiere exacerbation cliniquement significative. Les criteres secondaires etaient : la duree jusqu’a la diminution du controle de l’asthme ; la reduction de taux d’eosinophiles sanguins. Les criteres ont ete analyses en utilisant le modele des risques proportionnels de Cox et des modeles repetes de modele mixte ajustes pour les covariables. Resultats Cent quarante-quatre patients ont recu mepolizumab et 151 placebo. Quarante-six pour cent (66/144) patients ayant continue mepolizumab versus 59 % (89/151) patients ayant arrete mepolizumab ont eu une exacerbation. Les patients ayant continue versus ceux ayant arrete mepolizumab ont eu une duree plus longue jusqu’a la premiere exacerbation (HR : 0,62 [(IC)95 % : 0,45 ; 0,86] ; p = 0,004) et une duree significativement plus longue jusqu’a la diminution du controle de l’asthme (HR : 0,66 [0,49 ; 0,88] ; p =0,005), sans difference entre les traitements pour la duree jusqu’a la premiere exacerbation necessitant une venue aux urgences ou une consultation (HR : 1,33 [0,50 ; 3,51]). Les patients continuant mepolizumab ont maintenu leur taux d’eosinophiles entre 40 et 60 cellules/μL, les taux d’eosinophiles ont augmente jusqu’a 270 cellules/μL a la semaine 12 pour les patients ayant arrete mepolizumab (ratio : 0,19 [0,15 ; 0,24] ; p Conclusion Les patients ayant arrete mepolizumab ont presente une augmentation du taux d’eosinophiles sanguins, une augmentation des exacerbations, une duree plus courte jusqu’a la premiere exacerbation, et une reduction du controle de l’asthme compare a ceux ayant continue mepolizumab. Ces resultats montrent que le traitement continu par mepolizumab a des benefices cliniques durables chez la plupart des patients avec ASE.

Introduction Le mepolizumab est approuve pour le traitement de l’asthme severe a eosinophiles (ASE) chez les adultes et, dans certaines regions, chez les adolescents (12–17 ans). En aout 2018, l’Agence europeenne des medicaments a approuve le mepolizumab a 40 mgSC pour les enfants de 6 a 11 ans avec un ASE. L’efficacite et la tolerance du mepolizumab a long terme chez les enfants de 6 a 11 ans n’ont pas ete evaluees. Methodes Il s’agissait d’une etude ouverte, non controlee avec 2 parties A et B, chez les enfants atteint d’ASE. Les patients ayant termine la partie A (semaine 0–20) de l’etude sur la pharmacocinetique et pharmacodynamique etaient eligibles a la partie B de 52 semaines (semaine 20–72) de l’etude pour evaluer la tolerance et la pharmacodynamie a long terme du mepolizumab. Dans la partie B, les patients ont recu 40 mgSC de mepolizumab si 40 kg en plus de leur traitement de fond de depart. La dose de mepolizumab etait augmentee a 100 mgSC si le patient atteignait 40 kg pendant la phase B. Les criteres d’evaluation comprenaient le taux d’exacerbations, le controle de l’asthme et la tolerance. Resultats Trente patients sont entres dans la partie B et 29 ont termine les 52 semaines de traitement. Une amelioration du controle de l’asthme a ete observee via les questionnaires ACQ-7 et ACQ-5, avec respectivement 55 % et 59 % de repondeurs (amelioration ≥ 0,5 points par rapport a l’inclusion) a la visite de fin d’etude (semaine 72). Une augmentation du score ACT pour les enfants a ete egalement observee, qui montre une amelioration du controle de l’asthme et ce independamment du groupe de traitement (sur le poids des patients). Les taux annuels d’exacerbations pendant le traitement etaient inferieurs aux valeurs initiales pour chaque groupe. Dans l’ensemble, 80 % des sujets ont presente une reduction ≥ 50 % du taux d’exacerbations pendant la partie B par rapport a l’annee precedant l’inclusion. Le mepolizumab a ete bien tolere dans la partie B, aucun nouveau probleme de tolerance n’a ete rapporte chez les enfants par rapport au profil de tolerance connu des adultes/adolescents. La bronchite (30 %) etait l’effet indesirable le plus souvent rapporte. Aucun patient n’a eu d’anticorps anti-mepolizumab pendant la partie B ( Tableau 1 ). Conclusion Chez les enfants de 6 a 11 ans, le traitement par mepolizumab a entraine pendant 52 semaines une amelioration du controle de l’asthme et une reduction du taux annuel d’exacerbations par rapport a l’annee precedant l’inclusion. Le mepolizumab a ete bien tolere chez les enfants de 6 a 11 ans.

Background Mepolizumab has demonstrated favorable safety and efficacy profiles in placebo-controlled trials of 12 months' duration or less; however, long-term data are lacking. Objective We sought to evaluate the long-term safety and efficacy of mepolizumab in patients with severe eosinophilic asthma (SEA). Methods COLUMBA (Open-label Long Term Extension Safety Study of Mepolizumab in Asthmatic Subjects, NCT01691859 ) was an open-label extension study in patients with SEA previously enrolled in DREAM (Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma, NCT01000506 ). Patients received 100 mg of subcutaneous mepolizumab every 4 weeks plus standard of care until a protocol-defined stopping criterion was met. Safety end points included frequency of adverse events (AEs), serious AEs, and AEs of special interest. Efficacy end points included annualized exacerbation rates, changes from baseline in Asthma Control Questionnaire 5 scores, and blood eosinophil counts. Immunogenicity was also assessed. Results Overall, 347 patients were enrolled for an average of 3.5 years (maximum, 4.5 years; total exposure, 1201 patient-years). On-treatment AEs were reported in 94% of patients (exposure-adjusted rate, 3688 events/1000 patient-years). The most frequently reported on-treatment AEs were respiratory tract infection, headache, bronchitis, and asthma worsening. Seventy-nine (23%) patients experienced 1 or more on-treatment serious AEs; there were 6 deaths, none of which were assessed as related to mepolizumab. For patients with 156 weeks or greater enrollment, the exacerbation rate was 0.74 events/y (weeks 0–156), a 56% reduction from the off-treatment period between DREAM and COLUMBA. For all patients, at the first postbaseline assessment, the mean Asthma Control Questionnaire 5 score was reduced by 0.47 points, and blood eosinophil counts were reduced by 78%, with similar improvements maintained throughout the study. The immunogenicity profile (8% anti-drug antibodies) was consistent with previous studies. Conclusion These data support the long-term safety and efficacy of mepolizumab in patients with SEA.

Background: Mepolizumab is approved for severe eosinophilic asthma in adults and, in some regions, adolescents (12-17 years old). Efficacy results in children (6-11 years old) have yet to be compared to data from adults and adolescents. Methods: Asthma exacerbation incidence and asthma control questionnaire (ACQ-5) responder rates were taken from adult/adolescents in double-blind, placebo controlled studies (NCT01000506, NCT01691521, NCT02281318, NCT01691508) of mepolizumab 75 mg to 750 mg while children (40 mg SC if Results: Subjects had similar mean exacerbation rates in the year prior to study: 4.0 in children and 2.8-3.6 in adolescents/adults. All subjects reported at least 2 exacerbations in the prior year. The incidence of exacerbations after 12 weeks of mepolizumab treatment was consistent between children and adolescents/adults (Table). The ACQ-5 responder rate (minimal clinically important reduction ≥0.5 points) at 12 weeks was 55% in children, 33-63% in adolescents, and 52-56% in adults. Conclusions: Mepolizumab in children with severe eosinophilic asthma results in similar efficacy (exacerbations and ACQ-5) when compared to adolescents/adults after 12 weeks. Funding: GSK

Background: In METREX and METREO, mepolizumab reduced exacerbation rates in patients (pts) with eosinophilic COPD. In severe asthma, log-transformed screening blood eosinophil count (sBEC) is a strong predictor of mepolizumab efficacy; however, it is not known whether this is true in COPD. Objective: Assess the effect of sBEC on moderate/severe exacerbation rates with mepolizumab vs placebo. Methods: METREX and METREO: Phase 3, placebo-controlled, randomised, double-blind, multicentre trials enrolled pts aged ≥40 years with COPD, ≥2 moderate/≥1 severe exacerbations (prior yr) despite ICS-based triple maintenance therapy. Pts received placebo or mepolizumab SC (100mg [METREX], 100/300mg [METREO]) every 4 wks for 52 wks as add-on therapy to ICS/LABA/LAMA. Log-transformed eosinophil count was a poor fit for predicting exacerbation rates in COPD so fractional polynomial modelling was used in a post hoc analysis; all mepolizumab doses were combined. Results: Predicted exacerbation rates increased with increasing sBEC in the placebo group and were relatively stable for mepolizumab (placebo rate/yr: 1.44, 1.63, 1.77, mepolizumab rate/yr: 1.45, 1.41, 1.38 at 150, 300 and 500 cells/µL respectively). Predicted exacerbation rate reductions with mepolizumab vs placebo increased with higher sBEC: 13% (95%CI 1–24%) at 300 cells/µL and 22% (95%CI 7–35%) at 500 cells/µL. Conclusions: sBEC is a useful predictor of mepolizumab response in COPD. These data support the role of eosinophils in COPD exacerbations and the utility of mitigating eosinophilic inflammation to improve COPD outcomes in frequent exacerbators despite being on optimal ICS-based triple maintenance therapy. Funding: GSK (207577; 117113/NCT02105961; 117106/NCT02105948)

Background: Safety & durability of mepolizumab were limited in pts with the most severe form of SEA. Objective: To assess the long-term safety & durability of mepolizumab in these SEA pts. Methods: COSMEX was an open-label extension of COSMOS (a 52-wk extension of mepolizumab Ph3 trials)*. Pts had life-threatening/seriously debilitating asthma prior to Ph3 trials (≥1 intubation [lifetime]; ≥1 hospitalisation or ≥3 exacerbations [12m prior]; OCS dose ≥10mg [randomisation]; %predFEV1 ≤50% + ACQ-5 score ≥3 or SGRQ score ≥60) & improved on mepolizumab (≥50% reduction in exacerbations/OCS dose & investigator-confirmed improvement) during the previous studies. Coprimary endpoints: frequency of AEs & exacerbation rate; other endpoint: OCS reduction. Results: 339 pts entered COSMEX. Total mepolizumab exposure over COSMEX was 718pt-yr (mean 25m[range 2–39m] & over COSMEX & previous studies was 1202pt-yr [mean 43m (range 14–57m)]). See table for coprimary endpoint results; no new safety signals seen. Exacerbation & OCS reductions achieved in the previous studies were sustained over COSMEX (median OCS dose maintained at 0–5mg/day). Conclusions: In these SEA pts, the safety profile of mepolizumab was similar to previous shorter-term trials, with no new safety signals; long-term treatment provided sustained & consistent exacerbation & OCS reductions for up to 4.5yrs. Funding: GSK [201312/NCT02135692]

BACKGROUNDPatients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5.METHODSWe performed two phase 3, randomized, placebo-controlled, double-blind, parallel-group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid-based triple maintenance therapy. In METREX, unselected patients in the modified intention-to-treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (>= 150 per cubic millimeter at screening or >= 300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed.RESULTSIn METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P = 0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P = 0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P = 0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo.CONCLUSIONSMepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations.