Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma
Pranabashis Haldar, M.R.C.P., Christopher E. Brightling, Ph.D., F.R.C.P., Beverley Hargadon, R.G.N., Sumit Gupta, M.R.C.P., William Monteiro, M.Sc., Ana Sousa, Ph.D., Richard P. Marshall, Ph.D., M.R.C.P., Peter Bradding, D.M., F.R.C.P., Ruth H. Green, M.D., F.R.C.P., Andrew J. Wardlaw, Ph.D., F.R.C.P., and Ian D. Pavord, D.M., F.R.C.P.
Background Exacerbations of asthma are associated with substantialmorbidity and mortality and with considerable use of healthcare resources. Preventing exacerbations remains an importantgoal of therapy. There is evidence that eosinophilic inflammationof the airway is associated with the risk of exacerbations.
Methods We conducted a randomized, double-blind, placebo-controlled,parallel-group study of 61 subjects who had refractory eosinophilicasthma and a history of recurrent severe exacerbations. Subjectsreceived infusions of either mepolizumab, an anti–interleukin-5monoclonal antibody (29 subjects), or placebo (32) at monthlyintervals for 1 year. The primary outcome measure was the numberof severe exacerbations per subject during the 50-week treatmentphase. Secondary outcomes included a change in asthma symptoms,scores on the Asthma Quality of Life Questionnaire (AQLQ, inwhich scores range from 1 to 7, with lower values indicatingmore severe impairment and a change of 0.5 unit considered tobe clinically important), forced expiratory volume in 1 second(FEV1) after use of a bronchodilator, airway hyperresponsiveness,and eosinophil counts in the blood and sputum.
Results Mepolizumab was associated with significantly fewersevere exacerbations than placebo over the course of 50 weeks(2.0 vs. 3.4 mean exacerbations per subject; relative risk,0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) andwith a significant improvement in the score on the AQLQ (meanincrease from baseline, 0.55 vs. 0.19; mean difference betweengroups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantlylowered eosinophil counts in the blood (P<0.001) and sputum(P=0.002). There were no significant differences between thegroups with respect to symptoms, FEV1 after bronchodilator use,or airway hyperresponsiveness. The only serious adverse eventsreported were hospitalizations for acute severe asthma.
Conclusions Mepolizumab therapy reduces exacerbations and improvesAQLQ scores in patients with refractory eosinophilic asthma.The results of our study suggest that eosinophils have a roleas important effector cells in the pathogenesis of severe exacerbationsof asthma in this patient population. (Current Controlled Trialsnumber, ISRCTN75169762
[controlled-trials.com]
.)
Source Information
From the Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester National Health Service Trust, Leicester (P.H., C.E.B., B.H., S.G., W.M., P.B., R.H.G., A.J.W., I.D.P.); and Exploratory Medical Science, Discovery Medicine, Respiratory and Inflammation Center of Excellence for Drug Discovery, GlaxoSmithKline, Stevenage (A.S., R.P.M.) — all in the United Kingdom.
Address reprint requests to Dr. Pavord at the Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester National Health Service Trust, Groby Rd., Leicester LE3 9QP, United Kingdom, or at ian.pavord{at}uhl-tr.nhs.uk.
Finkelman, F. D., Hogan, S. P., Hershey, G. K. K., Rothenberg, M. E., Wills-Karp, M.
(2010). Importance of Cytokines in Murine Allergic Airway Disease and Human Asthma. J. Immunol.
184: 1663-1674
[Abstract][Full Text]
Chapman, K. R., McIvor, A.
(2010). Asthma that is unresponsive to usual care. CMAJ
182: 45-52
[Full Text]
Straumann, A, Conus, S, Grzonka, P, Kita, H, Kephart, G, Bussmann, C, Beglinger, C, Smith, D A, Patel, J, Byrne, M, Simon, H-U
(2010). Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut
59: 21-30
[Abstract][Full Text]
Bush, A., Menzies-Gow, A.
(2009). Phenotypic Differences between Pediatric and Adult Asthma. Proc Am Thorac Soc
6: 712-719
[Abstract][Full Text]
Barnes, P. J.
(2009). The Cytokine Network in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Cell Mol. Bio.
41: 631-638
[Abstract][Full Text]
Kouro, T., Takatsu, K.
(2009). IL-5- and eosinophil-mediated inflammation: from discovery to therapy. Int Immunol
21: 1303-1309
[Abstract][Full Text]
Kottyan, L. C., Collier, A. R., Cao, K. H., Niese, K. A., Hedgebeth, M., Radu, C. G., Witte, O. N., Khurana Hershey, G. K., Rothenberg, M. E., Zimmermann, N.
(2009). Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner. Blood
114: 2774-2782
[Abstract][Full Text]
Dyer, K. D., Percopo, C. M., Fischer, E. R., Gabryszewski, S. J., Rosenberg, H. F.
(2009). Pneumoviruses infect eosinophils and elicit MyD88-dependent release of chemoattractant cytokines and interleukin-6. Blood
114: 2649-2656
[Abstract][Full Text]
Flaherty, K. R.
(2009). Clinical Year in Review IV: Pediatric Pulmonary and Critical Care, Cystic Fibrosis, Asthma, and Pleural Disease. Proc Am Thorac Soc
6: 506-511
[Full Text]
Siddiqui, S., Brightling, C.
(2009). Magic Bullets: The New Goal for Asthma. Am. J. Respir. Crit. Care Med.
180: 383-384
[Full Text]
Woodruff, P. G., Modrek, B., Choy, D. F., Jia, G., Abbas, A. R., Ellwanger, A., Arron, J. R., Koth, L. L., Fahy, J. V.
(2009). T-helper Type 2-driven Inflammation Defines Major Subphenotypes of Asthma. Am. J. Respir. Crit. Care Med.
180: 388-395
[Abstract][Full Text]
Hercus, T. R., Thomas, D., Guthridge, M. A., Ekert, P. G., King-Scott, J., Parker, M. W., Lopez, A. F.
(2009). The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood
114: 1289-1298
[Abstract][Full Text]
Verbout, N. G., Jacoby, D. B., Gleich, G. J., Fryer, A. D.
(2009). Atropine-enhanced, antigen challenge-induced airway hyperreactivity in guinea pigs is mediated by eosinophils and nerve growth factor. Am. J. Physiol. Lung Cell. Mol. Physiol.
297: L228-L237
[Abstract][Full Text]
Zarogiannis, S., Gourgoulianis, K. I., Kostikas, K., Szczeklik, A., Gleich, G. J., Pavord, I. D., Wardlaw, A. J., Haldar, P., Nair, P., Hargreave, F. E., O'Byrne, P., Wenzel, S. E.
(2009). Anti-Interleukin-5 Therapy and Severe Asthma. NEJM
360: 2576-2578
[Full Text]
Humbert, M.
(2009). Biologics in severe difficult-to-treat asthma: find the right niche!. ERR
18: 51-53
[Full Text]
Gaga, M., Zervas, E., Chanez, P.
(2009). Update on severe asthma: what we know and what we need. ERR
18: 58-65
[Full Text]
(2009). All you need to read in the other general journals. BMJ
338: b963-b963
[Full Text]
Wenzel, S. E.
(2009). Eosinophils in Asthma -- Closing the Loop or Opening the Door?. NEJM
360: 1026-1028
[Full Text]
Previous
