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Objective: Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) generally involves intranasal corticosteroids (INCS) and saline irrigation, followed by short courses of systemic corticosteroids (SCS) or surgery with postoperative medical therapy for patients who do not respond to INCS. However, both SCS use and surgery are associated with a range of adverse effects or complications, have a high recurrence rate, and are unsuitable for some patients. Biologics targeting the underlying pathophysiology are promising treatment alternatives for these patients. Dupilumab, omalizumab, and mepolizumab are approved for use in patients with severe, uncontrolled CRSwNP. However, the lack of a consistent definition of severe CRSwNP makes the decision to initiate biologic treatment particularly complex. Furthermore, the position of each biologic in the overall management of CRSwNP remains to be clarified. Data Sources: Publications reporting results of phase III trials of dupilumab, omalizumab, mepolizumab, and benralizumab in the treatment of CRSwNP. Study Selections: Randomized, controlled phase III trials of biologics approved for CRSwNP. Results: These trials all used different enrollment criteria. We discuss the complexities of assessing CRSwNP disease severity and highlight how these impact comparisons of the populations and outcomes of the phase III biologic trials. Conclusion: To position biologic agents appropriately within the existing CRSwNP treatment paradigm, future trials will need to include comparable patient populations and standardized outcome measures. Such trials will help to ensure that biologic treatment is targeted appropriately to support optimal clinical outcomes.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is generally associated with eosinophilic tissue infiltration linked to type 2 inflammation and characterized by elevated levels of interleukin (IL)-5 and other type 2 inflammatory mediators. Although distinct and overlapping contributions of eosinophils and IL-5 to CRSwNP pathology are still being explored, they are both known to play an important role in NP inflammation. Eosinophils secrete numerous type 2 inflammatory mediators including granule proteins, enzymes, cytokines, chemokines, growth factors, lipids, and oxidative products. IL-5 is critical for the differentiation, migration, activation, and survival of eosinophils but is also implicated in the biological functions of mast cells, basophils, innate lymphoid cells, B cells, and epithelial cells. Results from clinical trials of therapeutics that target type 2 inflammatory mediators (including but not limited to anti-IL-5, anti-immunoglobulin-E, and anti-IL-4/13) may provide further evidence of how eosinophils and IL-5 contribute to CRSwNP. Finally, the association between eosinophilia/elevated IL-5 and greater rates of NP recurrence after endoscopic sinus surgery (ESS) suggests that these mediators may have utility as biomarkers of NP recurrence in diagnosing and assessing the severity of CRSwNP. This review provides an overview of eosinophil and IL-5 biology and explores the literature regarding the role of these mediators in CRSwNP pathogenesis and NP recurrence following ESS. Based on current published evidence, we suggest that although eosinophils play a key role in CRSwNP pathophysiology, IL-5, a cytokine that activates these cells, also represents a pertinent and effective treatment target in patients with CRSwNP.

Background: Chronic rhinosinusitis with nasal polyps affects approximately 2–4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps. Methods: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49–52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797. Findings: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians −0·73, 95% CI −1·11 to −0·34; p

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 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/aims The efficacy and safety of mepolizumab in patients with severe eosinophilic asthma has been evaluated in a global clinical trial programme. This post hoc analysis assesses the efficacy and safety of mepolizumab in Korean patients. Methods Data from Korean patients in the Phase III, placebo-controlled, randomised DREAM (MEA112997/NCT01000506) and MENSA (MEA115588/ NCT01691521) studies were included. Patients ≥ 12 years old with severe eosinophilic asthma received mepolizumab (DREAM: 75, 250 or 750 mg intravenously [IV]; MENSA: 75 mg IV or 100 mg subcutaneously [SC]), or placebo every 4 weeks for 52 weeks (DREAM) or 32 weeks (MENSA). The primary outcome was the rate of clinically significant asthma exacerbations. Secondary outcomes included forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire (ACQ) and St George's Respiratory Questionnaire (SGRQ) scores (MENSA only). Blood eosinophil counts (BEC) and safety were assessed throughout. Results Reductions in the rate of clinically significant asthma exacerbations were observed with the approved (100 mg SC) and bioequivalent (75 mg IV) doses of mepolizumab in Korean patients who participated in DREAM and MENSA. In MENSA, trends for improvements from baseline at week 32 in pre-bronchodilator FEV1 (75 mg IV group), ACQ-5 and SGRQ scores (in both treatment groups) were seen versus placebo in Korean patients. Incidence of on-treatment adverse events was similar in Korean patients versus non-Korean patients as were observed reductions from baseline in BEC. Conclusions Mepolizumab treatment provided clinical benefits for Korean patients with severe eosinophilic asthma; the safety profile is consistent with the overall population.

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

Background Mepolizumab (100 mg delivered s.c. every 4 weeks) is indicated for add-on maintenance treatment for patients with severe eosinophilic asthma. Mepolizumab has been shown to reduce exacerbations and the requirement for daily oral corticosteroids, and improve asthma control and symptoms. However, data on the durability of the response to mepolizumab during dosing periods are limited. The aim of this study was to investigate the efficacy profile in patients with severe eosinophilic asthma over the 4-weekly dosing period for various fixed mepolizumab doses. Methods This was a post hoc analysis of data from the phase IIb/III DREAM study. Patients ≥12 years of age with severe eosinophilic asthma were randomised (1:1:1:1) to receive intravenous mepolizumab 75 mg (equivalent to 100 mg s.c.), 250 mg, 750 mg or placebo, plus standard of care, every 4 weeks for 52 weeks. The number of exacerbations and eDiary data (peak expiratory flow, rescue medication use and symptom scores) from two periods in each 4-weekly dosing interval (days 1–14 and 15–28) over the 52-week treatment period were analysed. Findings eDiary data and the proportion of patients experiencing ≥1 exacerbation were similar during the first and second 2 weeks of a dosing period across all mepolizumab doses. Interpretation These results demonstrate that the response to mepolizumab is sustained over the 4-weekly dosing period with no differences across a 10-fold dose range and supports the use of the current mepolizumab dosing regimen in patients with severe eosinophilic asthma., Post hoc analysis of data from DREAM demonstrated a sustained response to mepolizumab across the 4-weekly dosing period, suggesting therapeutic benefit is maintained between each mepolizumab dose following long-term treatment https://bit.ly/3843lH6

Treatment of patients with the rare disease eosinophilic granulomatosis with polyangiitis (EGPA) with mepolizumab, a monoclonal antibody to interleukin-5 (IL-5) that reduces blood eosinophil counts, as an add-on therapy to glucocorticoid treatment, results in more accrued weeks in remission, reductions in glucocorticoid use and reductions in relapse rate. However, treatment response varies across a continuum. Therefore, to investigate if large genetic effects could identify responders, the impact of genetic variants on efficacy in EGPA subjects taking mepolizumab and glucocorticoids was assessed in this post hoc study. Using linear regression and a negative binomial model, genetic variant association with three endpoints (accrued duration of remission, average oral glucocorticoid dose, and frequency of relapse) was tested in 61 EGPA subjects dosed with mepolizumab from MIRRA, a phase 3 trial. Candidate gene and genome-wide approaches were used. The candidate gene analysis was designed to investigate drug target effects with eight gene regions selected that were focused on the intersection of the glucocorticoid response (steroidal response) and IL-5 response mechanisms and recognizing potential overlap between EGPA and severe eosinophilic asthma diseases for which mepolizumab is used. The sample size was insufficient to enable testing of rare variants for effects. No genetic variant from either the candidate gene analysis or the GWAS associated with any endpoint. Thresholds to declare significance were p

Asthma worsening and symptom control are clinically important health outcomes in patients with severe eosinophilic asthma. This analysis of COMET evaluated whether stopping versus continuing long-term mepolizumab therapy impacted these outcomes. Patients with severe eosinophilic asthma with ≥3 years continuous mepolizumab treatment (via COLUMBA (NCT01691859) or COSMEX (NCT02135692) open-label studies) were eligible to enter COMET (NCT02555371), a randomised, double-blind, placebo-controlled study. Patients were randomised 1:1 to continue mepolizumab 100 mg subcutaneous every 4 weeks or to stop mepolizumab, plus standard of care asthma treatment. Patients could switch to open-label mepolizumab following an exacerbation. Health outcome endpoints included time to first asthma worsening (composite endpoint: rescue use, symptoms, awakening at night and morning peak expiratory flow (PEF)), patient and clinician assessed global rating of asthma severity and overall perception of response to therapy, and unscheduled healthcare resource utilisation. Patients who stopped mepolizumab showed increased risk of and shorter time to first asthma worsening compared with those who continued mepolizumab (hazard ratio (HR) 1.71; 95% CI 1.17–2.52; p=0.006), including reduced asthma control (increased risk of first worsening in rescue use (HR 1.36; 95% CI 1.00–1.84; p=0.047) and morning PEF (HR 1.77; 95% CI 1.21–2.59; p=0.003). There was a higher probability of any unscheduled healthcare resource use (HR 1.81; 95% CI 1.31–2.49; p, The COMET study investigated whether stopping long-term mepolizumab had an impact on health outcomes in patients with severe eosinophilic asthma; data suggest those who continue long-term mepolizumab treatment sustain clinically important improvements https://bit.ly/3A0bvwu

BackgroundCurrent standard-of-care treatments for hypereosinophilic syndrome (HES) include oral corticosteroids (OCS) and immunosuppressive/cytotoxic (IS/CT) therapies. The anti-IL-5 monoclonal antibody mepolizumab has also recently been approved for patients with this disease. The objective of this analysis was to assess the relationship between baseline therapy and flare reduction in patients with HES treated with mepolizumab, using data from the Phase III 200622 study (NCT02836496).MethodsIn the double-blind, parallel-group 200622 study, eligible patients were ≥12 years old and had HES for ≥6 months, ≥2 flares in the previous 12 months, blood eosinophils ≥1000 cells/μL at screening and ≥4 weeks’ stable HES therapy. Patients were randomised (1:1) to receive mepolizumab 300 mg subcutaneously or placebo every 4 weeks for 32 weeks plus their existing HES therapy. This post hoc, descriptive analysis assessed the effect of baseline HES therapy [IS/CT (± OCS), OCS No IS/CT, and No IS/CT/OCS] on the proportion of patients with ≥1 flare during the study period, the annualised rate of flares, time to first flare, and the proportion of patients with ≥1 flare during Weeks 20─32, with mepolizumab versus placebo.ResultsMepolizumab treatment was associated with a decrease in the proportion of patients who experienced ≥1 flare during the study period in all baseline therapy groups versus placebo (32–96% reduction). Similarly, the probability of a flare was lower with mepolizumab (14.3–31.4%) than placebo (35.7–74.1%) in all baseline therapy groups, as was the annualised flare rate (0.22–0.68 vs 1.14–1.62). The proportion of patients who experienced ≥1 flare during Weeks 20–32 was reduced with mepolizumab versus placebo for all baseline therapy groups (55–85% reduction). For all endpoints, the greatest effect of mepolizumab treatment was seen in the IS/CT (± OCS) group.ConclusionsPatients with poorly controlled HES are likely to achieve clinical benefit with mepolizumab in terms of flare reduction, regardless of their baseline therapy.Clinical Trial Registration(https://clinicaltrials.gov/ct2/show/NCT02836496).

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

Aims GSK3511294 is a humanized anti-interleukin (IL)-5 monoclonal antibody (mAb) engineered for extended half-life and improved IL-5 affinity versus other anti-IL-5 mAbs. This study examined its safety, tolerability, pharmacokinetics (PK) and effect on blood eosinophil counts. Methods This was a double-blind, parallel-group, single-ascending-dose, multicenter, Phase 1 study (205722;NCT03287310) in patients with asthma and a blood eosinophil count ≥200 cells μL-1 . Patients were randomized 3:1 within dose cohorts to receive a single subcutaneous dose of GSK3511294 (2, 10, 30, 100 or 300 mg) or placebo and followed for up to 40 weeks to assess safety (primary endpoint), ratio to baseline in blood eosinophil count, plasma PK parameters and frequency/titers of binding antidrug antibodies (all secondary). Results Forty-eight patients received study drug and completed the study. Adverse events (AEs) occurred in 92% of placebo-treated and 81% of GSK3511294-treated patients. There were no AEs leading to study withdrawal or serious AEs; hypersensitivity (one event in one patient) and injection-site reaction (three events in two patients) occurred infrequently. Marked reductions (>48%) in blood eosinophil count were seen from 24 hours post-dose with all GSK3511294 doses but not placebo; suppression was maintained for longer with increasing dose (82% and 83% adjusted reductions vs placebo with 100 and 300 mg, respectively, at Week 26). PK were linear and dose proportional over the dose range; terminal half-life was 38-53 days. Conclusions GSK3511294 was well tolerated, with linear and dose proportional PK, extended half-life and blood eosinophil count reduction, supporting less frequent dosing versus other anti-IL-5 mAbs.

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.

Background A double-blind, placebo-controlled, phase III study (200622) showed that mepolizumab reduces disease flares for patients with uncontrolled FIP1-like-1-platelet-derived growth factor receptor α–negative hypereosinophilic syndrome (HES) and two or more flares in the previous year. Objective To further characterize the safety, clinical benefit, and pharmacodynamics of mepolizumab. Methods Eligible patients from both treatment arms of the double-blind study could enter an open-label extension study (205203; NCT03306043) to receive 4-weekly mepolizumab (300 mg subcutaneously) plus background therapy for 20 weeks. Primary end points were safety-based; other end points included flare rates and changes from baseline in mean daily oral corticosteroid (OCS) dose and blood eosinophil count. Results Of 104 patients who completed the double-blind study, 98% (previous placebo, n = 52; previous mepolizumab, n = 50) enrolled in the open-label extension. Overall, 66 of patients reported adverse events (AEs) (65%), 15 reported treatment-related AEs (15%), and nine reported serious AEs (9%). No events were fatal. The annualized flare rate (95% confidence interval) in the previous placebo and previous mepolizumab groups was 0.37 (0.16-0.86) and 0.14 (0.04-0.49) events/y, respectively. Of 72 patients receiving OCS during weeks 0 to 4, 20 (28%; previous placebo, n = 14; previous mepolizumab, n = 6) achieved 50% or greater reductions in mean daily dose during weeks 16 to 20. At week 20, blood eosinophil count was reduced by 89% in patients previously receiving placebo and remained reduced for those previously receiving mepolizumab. Conclusions Extended mepolizumab treatment was associated with a positive benefit–risk profile. Continued control of disease flares and blood eosinophil counts, plus reductions in OCS use, were observed with mepolizumab in patients with FIP1-like-1-platelet-derived growth factor receptor α–negative HES.

Introduction Le traitement par mepolizumab, un anticorps monoclonal humanise anti-interleukine 5, est associe a une reduction des poussees chez les patients atteints de syndrome hypereosinophilique (SHE). Ici, nous caracterisons les symptomes de ces poussees et mesurons l’impact de mepolizumab sur leur duree. Patients et methodes Cette etude de phase III en double aveugle, en groupe parallele versus placebo a recrute des patients ≥ 12 ans avec un SHE de plus de 6 mois, ayant eu ≥ 2 poussees lors des 12 mois precedant et ayant une eosinophilie plasmatique ≥ 1000 cellules/μL a l’inclusion. Les patients ont maintenu pendant ≥ 4 semaines un traitement stable de leur SHE avant d’etre randomises (1 :1) vers mepolizumab (300 mg) ou placebo sous-cutane, conservant leur traitement initial, pour une duree de 32 semaines. Pour ces analyses, seules les poussees de type A ont ete retenues ; definies par une augmentation de ≥ 10 mg/j de corticosteroides oraux ou l’ajout/augmentation d’un traitement cytotoxique/immunosuppresseur, en reponse a une evolution clinique des symptomes. La duree de la poussee etait la date de l’escalade therapeutique ; les poussees espacees de moins de 14 jours ont ete analysees comme 1 seul evenement. Les verbatims decrivant les poussees enregistres par les investigateurs ont ete categorises post-hoc en 7 groupes de symptomes (general, dermatologique, gastrointestinal, respiratoire, nasal, neurologique, autre) et resumes ; les donnees concernant la duree des poussees ont egalement ete evaluees. Resultats Durant l’etude, 15 poussees ont ete rapportees chez 12/54 patients recavant mepolizumab ; 35 poussees ont ete rapportees chez 12/54 patients recevant le placebo. Au total, les symptomes les plus rapportes etaient generaux (94 %, n = 47/50), dermatologiques (82 %, n = 41/50) et respiratoires (72 %, n = 36/50). Parmi les symptomes generaux, la fatigue (n = 43/47) et la douleur (n = 37/47) sont les plus rapportes. Les symptomes generaux sont les plus rapportees dans les deux groupes de traitement (mepolizumab : 100 %, n = 15/15 ; placebo : 91 %, n = 32/35). Pour les poussees intervenues chez les patients recevant mepolizumab, les symptomes nasaux et respiratoires ont ete rapportes plus frequemment que pour les poussees intervenues chez les patients sous placebo (87 %, n = 13/15 et 80 %, n = 12/15 vs 60 %, n = 21/35 et 69 %, n = 24/35, respectivement). Les symptomes dermatologiques et neurologiques etaient les plus courant chez les patients sous placebo (86 %, n = 30/35 et 60 % n = 21/35) que chez les patients sous mepolizumab (73 %, n = 11/15 et 40 %, n = 6/15). Le traitement par mepolizumab a egalement ete associe a une reduction de la duree des poussees versus placebo (mediane [etendue] jours : 10,0 [4–126] vs 26,0 [1–154]). Conclusion Chez les patients atteints de SHE, les poussees sont associees a des symptomes touchant de nombreux systemes d’organes, dermatologiques et respiratoires inclus. Pour un petit nombre de poussees reportees par les patients sous mepolizumab, il y avait une difference d’organes affectes, et les poussees ont ete divisees par 2 au moins en duree et en nombre compare au placebo.

Purpose Improved understanding of characteristics that may influence treatment response across phenotypes may help guide treatment decisions. Patients and Methods This was a post hoc analysis of MENSA, a multicenter, randomized, double-blind, placebo-controlled trial (NCT01691521). Patients aged ≥12 years with severe eosinophilic asthma received mepolizumab (75 mg intravenously or 100 mg subcutaneously) or placebo, plus standard of care, every 4 weeks for 32 weeks. Outcomes assessed were the annualized rate of clinically significant exacerbations and change from baseline in Asthma Control Questionnaire (ACQ)-5 score. Subgroup analyses were performed by baseline blood eosinophil count (17.5 kU/L]), and by house dust mite (HDM) sensitivity. Results Of 576 patients analyzed, 272 were non-atopic, 181 were atopic and 94 were strongly atopic; 29 had missing atopy data. In patients with blood eosinophil counts ≥300 cells/µL, mepolizumab versus placebo reduced clinically significant exacerbations by 74%, 43% and 25% in the non-atopic, atopic and strongly atopic subgroups. Similar reductions were observed in all atopic subgroups in other blood eosinophil count categories where there were sufficient patient numbers for analysis, except for non-atopic patients with baseline blood eosinophil counts of, 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/l92s5nzD3OI

Background: Patients with severe eosinophilic asthma (SEA) often have heterogenous phenotypes with periods of asthma worsening, making it difficult to assess mepolizumab treatment response. Aims: To define patient level variables for mepolizumab treatment response. Methods: In this post-hoc analysis we examined mepolizumab response in patients with SEA (≥2 exacerbations in prior year) in the 32-week, randomised, placebo-controlled MENSA study and the following 52-week, open-label COSMOS study. Patients who completed both studies and received mepolizumab throughout were included (n=311). Results: In MENSA, 67% and 21% of patients had 0 or 1 exacerbations, respectively, and were considered responders; 12% (n=37) with ≥2 exacerbations were considered non-responders and assessed against four variables of clinical benefit. Of these non-responders, 89% (n=33) had evidence of response when other variables were assessed (Table). Of the 37 non-responders in MENSA, 38% (n=14) responded in COSMOS, having either 0 (n=3) or 1 (n=11) exacerbations. Conclusions: These data highlight the difficulty in defining individual response to mepolizumab treatment. Responder classification should ideally take into account several clinical measures of improvement beyond exacerbation reduction. The relative importance of each of these measures may differ between patients, therefore doctors should set realistic treatment goals with each patient. Funding: GSK[NCT01691521/NCT01842607]

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.

Background The MENSA trial assessed the efficacy and safety of mepolizumab in patients with severe eosinophilic asthma. This report describes the efficacy and safety of mepolizumab in Japanese patients from MENSA. Methods A post hoc analysis of the Japanese subgroup from the randomized, double-blind, placebo-controlled, double-dummy, Phase III MENSA trial (NCT01691521). Patients ≥12 years with severe eosinophilic asthma received mepolizumab 75 mg intravenously (IV), 100 mg subcutaneously (SC), or placebo, every 4 weeks for 32 weeks. The primary endpoint was the annualized rate of exacerbations. Secondary and other endpoints included annualized rate of exacerbations requiring emergency department (ED) visit/hospitalization, morning peak expiratory flow (PEF), St George's Respiratory Questionnaire (SGRQ) score and eosinophil counts. Adverse events (AEs) were monitored. Results In the Japanese subgroup ( N = 50), the rate of clinically significant exacerbations was reduced by 90% (rate ratio [RR]: 0.10; 95% confidence interval [CI]: 0.02–0.57; P = 0.010) with mepolizumab IV and 62% (RR: 0.38; 95% CI: 0.12–1.18; P = 0.094) with mepolizumab SC, versus placebo. No exacerbations requiring ED visit/hospitalization were reported with mepolizumab IV; exacerbations were reduced by 73% (RR: 0.27; 95% CI: 0.06–1.29; P = 0.102) with mepolizumab SC versus placebo. Compared with placebo, mepolizumab IV and SC numerically increased morning PEF from baseline by 40 L/min and 13 L/min, improved quality of life by greater than the minimal clinically important difference (SGRQ: 9.5 [ P = 0.083] and 7.9 [ P = 0.171] points) and reduced eosinophil counts. AE incidence was similar between treatments. Results were broadly consistent with the overall population. Conclusions Mepolizumab was efficacious and well tolerated in Japanese patients with severe eosinophilic asthma, producing similar responses to the overall MENSA population.

Purpose Limited data exist on the quantitative validity of the St George's Respiratory Questionnaire (SGRQ) in asthma populations. This study evaluated the psychometric properties of the SGRQ in patients with severe asthma. Methods This was a post-hoc analysis of pooled data from MENSA (N = 576; NCT01691508) and SIRIUS (N = 135; NCT01691521), two randomized, placebo controlled trials of mepolizumab in patients with severe asthma. Patients completed the SGRQ at Baseline and Exit (MENSA Week 32; SIRIUS Week 24). Distributional characteristics, internal consistency reliability, test-retest reliability, convergent and discriminant validity, known-groups validity and responsiveness were assessed. Results Internal consistency reliability was acceptable for the total and domain scores at Baseline and Exit (Cronbach's α was 0.92 and 0.94 at Baseline and Exit, respectively, for the Total score). Test-retest reliability was demonstrated (intraclass correlation coefficients >0.7) for Total score and the Activity and Impacts domains. Convergent and discriminant validity were demonstrated with measures associated or not associated with respiratory-related health status. Known groups validity based on baseline FEV 1 % predicted, Asthma Control Questionnaire (ACQ)-5 score, exacerbations and eosinophil counts was demonstrated for the SGRQ total and domain scores. Responses to therapy based on clinician-rated response, patient-rated response, ACQ-5 change score and exacerbations generally correlated with improvements in SGRQ scores. Conclusions This analysis demonstrated that the SGRQ has acceptable psychometric properties in patients with severe asthma, exceeding the thresholds for adequate reliability, validity and responsiveness. The SGRQ appears to be a good instrument for identifying response to therapy in patients with severe asthma.

Purpose Content validity is the extent to which a patient-reported outcome measure evaluates the concepts most relevant to a patient's condition and treatment. The St George's Respiratory Questionnaire (SGRQ) has been validated in a range of respiratory conditions. This study evaluated the content validity of the SGRQ in patients with severe asthma. Methods A qualitative study, guided by a protocol, which included concept elicitation and cognitive debriefing of the SGRQ, was conducted in patients aged ≥18 years with history of severe asthma and blood eosinophil counts of ≥150/μL (past month) or ≥300/μL (past 12 months). Patients were recruited until saturation for concept elicitation was achieved (i.e. no additional concepts identified). Concepts identified by the patients were then mapped to the SGRQ. Results 18 patient interviews provided concept saturation. Concept elicitation confirmed that the SGRQ includes the commonly reported asthma symptoms and their impact on daily life. In total, 89–100% of patients routinely experienced cough, nighttime awakenings, shortness of breath, chest tightness, sleep difficulty, phlegm/mucus, and wheezing. Patients reported asthma impacting daily and physical activities, mood and sleep. Cognitive interviewing confirmed that patients understood the instructions, items and response options in the SGRQ. Nearly half of the concepts in the SGRQ were endorsed by ≥12 patients; of the 17 items with scoring weights ≥85, 11 were mentioned by ≥12 patients. Conclusions This study demonstrates that the SGRQ is a relevant, comprehensive and content-valid instrument to assess health status in patients with severe asthma.

Severe eosinophilic asthma patients are at risk of exacerbations, which are associated with substantial costs. Mepolizumab lowers eosinophil levels and reduces exacerbation risk in severe eosinophilic asthma. We evaluated asthma-related exacerbation costs in mepolizumab-treated patients (versus placebo).A within-trial economic analysis of the Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA) trial. Objectives were to quantify the incremental: (1) medical costs of asthma-related exacerbation; (2) asthma-related exacerbation emergency department visit/hospitalization costs; and (3) asthma-related total healthcare resource utilization.Mean medical costs of asthma-related exacerbations at 8 months were $969, $852, and $1692 in the mepolizumab 75 mg intravenous (IV), mepolizumab 100 mg subcutaneous (SC), and placebo groups, respectively (p = 0.16). Mean medical costs from emergency department visits or hospitalizations due to asthma-related exacerbations were $901, $795, and $1557 in the mepolizumab 75 mg IV, mepolizumab 100 mg SC, and placebo groups (p = 0.020). Asthma-related healthcare resource utilization (all services) was lower for the mepolizumab groups versus placebo.Adding mepolizumab to standard-of-care treatment for severe eosinophilic asthma lowered asthma exacerbation-related medical costs/healthcare resource utilization; although the cost savings ranged from $723-$840 per patient, differences were not statistically significant.

Background: Mepolizumab (100 mg delivered subcutaneously every 4 weeks) is approved for use in patients with severe eosinophilic asthma (SEA) and has been shown to reduce exacerbations and improve asthma symptoms vs placebo. There are limited data on the durability of the response to mepolizumab between doses. Aim: To investigate the efficacy profile in patients with SEA over the 4-week dosing period for various fixed doses of mepolizumab. Methods: This was a post hoc analysis of data from the Phase IIb DREAM trial. Patients with SEA ≥12 years of age were randomised (1:1:1:1) to receive mepolizumab 75 mg (equivalent to 100 mg SC), 250 mg or 750 mg, or placebo intravenously (IV) every 4 weeks for 52 weeks. Mean daily peak expiratory flow (PEF) and symptom scores recorded as diary data were compared between days 1–14 and 15–28 days (periods 1 and 2, respectively) in each successive 4-weekly dosing period. Results: All three doses of mepolizumab showed a similar effect on PEF and symptoms during periods 1 and 2. The number of patients whose symptoms increased by ≥1 point in period 2 vs period 1 was similar to placebo. Conclusions: These results demonstrate the durability of the response to mepolizumab between doses and that mepolizumab 75 mg IV has a similar efficacy profile over the 4-weekly dosing period compared with higher doses. Further analysis is needed to determine whether other outcomes show a similar trend. Funding: GSK [MEA112997;NCT01000506].

Background: There are limited data that describe the association between markers of asthma control and depressive symptoms in severe asthma. Objective: To evaluate the association between depressive symptoms and markers of asthma control in patients with uncontrolled severe eosinophilic asthma. Methods: Baseline data from the MENSA and SIRIUS studies (N = 681) of mepolizumab intervention in severe eosinophilic asthma was used. We analyzed the relationships between depressive symptom severity by using the Beck Depression Inventory (BDI-II) and quality of life by using the St. George's Respiratory Questionnaire (SGRQ), asthma control questionnaire-5 (ACQ-5), polypharmacy, and sleep symptoms. Results: When compared with patients with less severe depressive symptoms, patients with more severe depressive symptoms were predominantly female (81% versus 54%), had a higher mean body mass index (30.56 versus 27.67 kg/m²), were more likely to have a blood eosinophil count of ≥300 cells/uL within the previous 12 months (81% versus 68%), and to have experienced a near-fatal asthma event (16% versus 7%). The mean SGRQ score was higher in the severe BDI-II category compared with the minimal depressive symptoms category, which indicated a worse quality of life (71.6 versus 41.4, p www.clinicaltrials.gov .

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.