Anti-Interleukin-5 (IL5) Monoclonal Antibody (MAb) in Prednisone-dependent Eosinophilic Asthma

Summary

The steroid sparing effect of anti interleukin (IL-5) monoclonal antibody has been proven, but the effectiveness of subcutaneous (SC) compared to intravenous (IV) administration of these drugs to suppress airway eosinophilia is still under debate. As part of a previous study, 100mg of mepolizumab were administered subcutaneously to a group of subjects with prednisone-dependent eosinophilic asthma. Despite this intervention, 50% of the subjects (15 patients participated in this study) had persistently elevated sputum eosinophil counts. The same 15 patients will be invited to participate in the current study, and if they provide their informed consent, will receive 2 monthly doses of placebo, followed by 4 monthly doses of IV reslizumab. The primary outcomes are blood and sputum eosinophils, and the secondary outcomes include sputum and blood Innate lymphoid cell-2 (ILC2) cells, cluster of differentiation 4 (CD4+) cells, cluster of differentiation-8 (CD8+) cells, cluster of differentiation-34 (CD34+), Eosinophil-Basophil cluster cells (Eo/B progenitor cells), forced expired volume in 1 second (FEV1), asthma control questionnaire (ACQ) and number of eosinophilic exacerbations. Measurements of the outcomes will be done before placebo, after placebo and after IV reslizumab. This study design will determine whether IV reslizumab is effective in suppressing airway eosinophilia in prednisone-dependent patients.

Timeline

Start

2015-10

Primary completion

2017-04

Completion

2017-08

Publications

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• Background Bousquet J, Mantzouranis E, Cruz AA, Ait-Khaled N, Baena-Cagnani CE, Bleecker ER, Brightling CE, Burney P, Bush A, Busse WW, Casale TB, Chan-Yeung M, Chen R, Chowdhury B, Chung KF, Dahl R, Drazen JM, Fabbri LM, Holgate ST, Kauffmann F, Haahtela T, Khaltaev N, Kiley JP, Masjedi MR, Mohammad Y, O'Byrne P, Partridge MR, Rabe KF, Togias A, van Weel C, Wenzel S, Zhong N, Zuberbier T. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010 Nov;126(5):926-38. doi: 10.1016/j.jaci.2010.07.019.
• Background Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002 Nov 30;360(9347):1715-21. doi: 10.1016/S0140-6736(02)11679-5.
• Background Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, Cartier A, Hussack P, Goldsmith CH, Laviolette M, Parameswaran K, Hargreave FE. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006 Mar;27(3):483-94. doi: 10.1183/09031936.06.00137704.
• Background Nissim Ben Efraim AH, Levi-Schaffer F. Tissue remodeling and angiogenesis in asthma: the role of the eosinophil. Ther Adv Respir Dis. 2008 Jun;2(3):163-71. doi: 10.1177/1753465808092281.
• Background Zhang J, Kuvelkar R, Murgolo NJ, Taremi SS, Chou CC, Wang P, Billah MM, Egan RW. Mapping and characterization of the epitope(s) of Sch 55700, a humanized mAb, that inhibits human IL-5. Int Immunol. 1999 Dec;11(12):1935-44. doi: 10.1093/intimm/11.12.1935.
• Background Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009 Mar 5;360(10):973-84. doi: 10.1056/NEJMoa0808991.
• Background Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012 Aug 18;380(9842):651-9. doi: 10.1016/S0140-6736(12)60988-X.
• Background Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1198-207. doi: 10.1056/NEJMoa1403290. Epub 2014 Sep 8.
• Background Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, Wilkins HJ, Henkel T, Nair P; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011 Nov 15;184(10):1125-32. doi: 10.1164/rccm.201103-0396OC. Epub 2011 Aug 18.
• Background Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1189-97. doi: 10.1056/NEJMoa1403291. Epub 2014 Sep 8.
• Background Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O'Byrne PM. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009 Mar 5;360(10):985-93. doi: 10.1056/NEJMoa0805435.
• Background Nair P. Anti-interleukin-5 monoclonal antibody to treat severe eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1249-51. doi: 10.1056/NEJMe1408614. Epub 2014 Sep 8. No abstract available.
• Background McKenzie AN. Type-2 innate lymphoid cells in asthma and allergy. Ann Am Thorac Soc. 2014 Dec;11 Suppl 5(Suppl 5):S263-70. doi: 10.1513/AnnalsATS.201403-097AW.
• Background Hogan SP, Rosenberg HF, Moqbel R, Phipps S, Foster PS, Lacy P, Kay AB, Rothenberg ME. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy. 2008 May;38(5):709-50. doi: 10.1111/j.1365-2222.2008.02958.x. Epub 2008 Apr 1.
• Background Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria JP, O'Byrne PM, Gauvreau GM, Boulet LP, Lemiere C, Martin J, Nair P, Sehmi R. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016 Jan;137(1):75-86.e8. doi: 10.1016/j.jaci.2015.05.037. Epub 2015 Jul 17.
• Background Kabata H, Moro K, Fukunaga K, Suzuki Y, Miyata J, Masaki K, Betsuyaku T, Koyasu S, Asano K. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat Commun. 2013;4:2675. doi: 10.1038/ncomms3675.
• Mukherjee M, Aleman Paramo F, Kjarsgaard M, Salter B, Nair G, LaVigne N, Radford K, Sehmi R, Nair P. Weight-adjusted Intravenous Reslizumab in Severe Asthma with Inadequate Response to Fixed-Dose Subcutaneous Mepolizumab. Am J Respir Crit Care Med. 2018 Jan 1;197(1):38-46. doi: 10.1164/rccm.201707-1323OC.

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Indications