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Background We performed post hoc analyses to evaluate the effect of humanized monoclonal antibody mepolizumab in patients with severe eosinophilic asthma previously treated with omalizumab. Methods Data were collected from two randomized double-blind, placebo-controlled studies: MENSA (NCT01691521: 32-week treatment phase) and SIRIUS (NCT01691508: 24-week treatment phase). Active treatment was 75 mg intravenous mepolizumab (MENSA) or 100 mg subcutaneous mepolizumab (MENSA, SIRIUS). Patients had evidence of eosinophilic inflammation ≥150 cells/μl (at screening) or ≥300 cells/μl (during the previous year). Primary outcomes were the rate of exacerbations (MENSA) and the percentage reduction in oral corticosteroid (OCS) dose (SIRIUS). Other outcomes included lung function (forced expiratory volume in 1 s and morning peak expiratory flow), Asthma Control Questionnaire (ACQ-5), St George's Respiratory Questionnaire (SGRQ) scores, and safety. Results Overall, 576 patients were included from MENSA and 135 from SIRIUS, with 13% and 33% previously receiving omalizumab, respectively. In MENSA, mepolizumab reduced the rate of exacerbations by 57% (prior omalizumab) and 47% (no prior omalizumab) vs placebo. In SIRIUS, reductions in OCS use were comparable regardless of prior omalizumab use. Despite reducing chronic OCS use, mepolizumab also resulted in similar reductions in exacerbation rate relative to placebo in both subgroups. Asthma control and quality of life improved with mepolizumab vs placebo in both studies independent of prior omalizumab use, as shown by ACQ-5 and SGRQ scores. Adverse events were also comparable irrespective of prior omalizumab use. Conclusions These post hoc analyses indicate that patients with severe eosinophilic asthma respond positively to mepolizumab regardless of prior use of omalizumab. [ABSTRACT FROM AUTHOR]

Background In severe asthmatics with persistent airway eosinophilia, blockade of interleukin-5 has significant steroid-sparing effects and attenuates blood and sputum eosinophilia. The contribution of local maturational processes of progenitors within the airways relative to the recruitment of mature cells from the peripheral circulation to the development of airway eosinophilia is not known. We hypothesize that local eosinophilopoiesis may be the predominant process that drives persistent airway eosinophilia and corticosteroid requirement in severe asthmatics. Objectives In a cross-sectional study, the number and growth potential of eosinophil-lineage-committed progenitors (EoP) were assayed in 21 severe eosinophilic asthmatics, 19 mild asthmatics, eight COPD patients and eight normal subjects. The effect of anti- IL-5 treatment on mature eosinophils and EoP numbers was made in severe eosinophilic asthmatics who participated in a randomized clinical trial of mepolizumab (substudy of a larger GSK sponsored global phase III trial, MEA115575) where subjects received mepolizumab (100 mg, n = 9) or placebo ( n = 8), as six monthly subcutaneous injections. Results Mature eosinophil and EoP numbers were significantly greater in the sputum of severe asthmatics compared with all other subject groups. In colony-forming assays, EoP from blood of severe asthmatics demonstrated a greater response to IL-5 than mild asthmatics. Treatment of severe asthmatics with mepolizumab significantly attenuated blood eosinophils and increased EoP numbers consistent with blockade of systemic eosinophilopoiesis. There was however no significant treatment effect on mature eosinophils, sputum EoP numbers or the prednisone maintenance dose. Conclusions and Clinical Relevance Patients with severe eosinophilic asthma have an exaggerated eosinophilopoeitic process in their airways. Treatment with 100 mg subcutaneous mepolizumab significantly attenuated systemic differentiation of eosinophils, but did not suppress local airway eosinophil differentiation to mature cells. Targeting IL-5-driven eosinophil differentiation locally within the lung maybe of relevance for optimal control of airway eosinophilia and asthma. [ABSTRACT FROM AUTHOR]