Hector G Ortega1, Mark C Liu, Ian D Pavord, Guy G Brusselle, J Mark FitzGerald, Alfredo Chetta, Marc Humbert, Lynn E Katz, Oliver N Keene, Steven W Yancey, Pascal Chanez. 1. From the Respiratory Therapeutic Area Unit, GlaxoSmithKline, Research Triangle Park, NC (H.G.O., L.E.K., S.W.Y.); Johns Hopkins Asthma and Allergy Center, Baltimore (M.C.L.); Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford (I.D.P.), and Clinical Statistics, GlaxoSmithKline, Stockley Park, Middlesex (O.N.K.) - both in the United Kingdom; the Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium (G.G.B.); the Lung Centre, Institute for Heart and Lung Health, Vancouver, BC, Canada (J.M.F.); the Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy (A.C.); and Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, and INSERM Unité Mixte de Recherche 999, Le Kremlin-Bicêtre (M.H.), and Unités Mixtes de Recherche INSERM Unité 1067 Centre Nationale de la Recherche Scientifique 7733, Aix-Marseille Université, Department of Respiratory Diseases and Clinical Investigation Center, Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Marseille (P.C.) - both in France.
Abstract
BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).
BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).
Authors: Gaëtane C Michaud; Colleen L Channick; Chad R Marion; Robert M Tighe; James A Town; Andrew M Luks; Jeremy B Richards; Sucharita Kher; Prerna Mota; Gina Hong; Natalie E West; Craig Rackley; Luke Neilans; Josanna Rodriguez-Lopez; Hilary DuBrock; Cassie C Kennedy; Diana J Kelm; Carey C Thomson Journal: Ann Am Thorac Soc Date: 2015-09
Authors: Michael E Wechsler; Praveen Akuthota; David Jayne; Paneez Khoury; Amy Klion; Carol A Langford; Peter A Merkel; Frank Moosig; Ulrich Specks; Maria C Cid; Raashid Luqmani; Judith Brown; Stephen Mallett; Richard Philipson; Steve W Yancey; Jonathan Steinfeld; Peter F Weller; Gerald J Gleich Journal: N Engl J Med Date: 2017-05-18 Impact factor: 91.245
Authors: Elizabeth A Kelly; Stephane Esnault; Lin Ying Liu; Michael D Evans; Mats W Johansson; Sameer Mathur; Deane F Mosher; Loren C Denlinger; Nizar N Jarjour Journal: Am J Respir Crit Care Med Date: 2017-12-01 Impact factor: 21.405