Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia - 30/10/13
, David L. Gossage, MD b, ∗, Gail Gauvreau, PhD c, Richard Leigh, MD, PhD d, Ron Olivenstein, MD e, Rohit Katial, MD f, William W. Busse, MD g, Sally Wenzel, MD h, Yanping Wu, PhD b, Vivekananda Datta, MD, PhD b, Roland Kolbeck, PhD b, Nestor A. Molfino, MD, MSc b, ‡Abstract |
Background |
Many asthmatic patients exhibit sputum eosinophilia associated with exacerbations. Benralizumab targets eosinophils by binding IL-5 receptor α, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity.
Objectives |
We sought to evaluate the safety of benralizumab in adults with eosinophilic asthma and its effects on eosinophil counts in airway mucosal/submucosal biopsy specimens, sputum, bone marrow, and peripheral blood.
Methods |
In this multicenter, double-blind, placebo-controlled phase I study, 13 subjects were randomized to single-dose intravenous placebo or 1 mg/kg benralizumab (day 0; cohort 1), and 14 subjects were randomized to 3 monthly subcutaneous doses of placebo or 100 or 200 mg of benralizumab (days 0, 28, and 56; cohort 2). Cohorts 1 and 2 were consecutive.
Results |
The incidence of adverse events was similar between groups. No serious adverse events related to benralizumab occurred. In cohort 1 intravenous benralizumab produced a median decrease from baseline of 61.9% in airway mucosal eosinophil counts (day 28; placebo: +19.6%; P = .28), as well as an 18.7% decrease (day 21) in sputum and a 100% decrease (day 28) in blood counts. Eosinophils were not detectable in bone marrow of benralizumab-treated subjects (day 28, n = 4). In cohort 2 subcutaneous benralizumab demonstrated a combined (100 + 200 mg) median reduction of 95.8% in airway eosinophil counts (day 84; placebo, 46.7%; P = .06), as well as an 89.9% decrease (day 28) in sputum and a 100% decrease (day 84) in blood counts.
Conclusion |
Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood. The safety profile supports further development. Additional studies are needed to assess the clinical benefit in asthmatic patients.
Le texte complet de cet article est disponible en PDF.Key words : Eosinophils, IL-5, IL-5 receptors, asthma, antibody-dependent cell-mediated cytotoxicity
Abbreviations used : ADCC, AE, ATP, CPK, CRP, H&E, ICS, IL-5R, IQR, SABA
Plan
| Supported by MedImmune, LLC. |
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| Disclosure of potential conflict of interest: D. L. Gossage is a former employee of MedImmune and is currently employed by Gilead Science. G. Gauvreau, R. Leigh, and R. Katial have received research support from MedImmune. W. W. Busse is a member of the advisory board for Merck; has consultant arrangements with Amgen, Novartis, GlaxoSmithKline, MedImmune, and Genentech; and receives research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute. S. Wenzel has consultant arrangements with TEVA and has received research support from GlaxoSmithKline and MedImmune. Y. Wu is employed by MedImmune and has stock in AstraZeneca. V. Datta is employed by MedImmune and has stock in AstraZeneca. N. A. Molfino is a former employee of MedImmune and is currently employed by KaloBios Pharmaceuticals. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 132 - N° 5
P. 1086 - novembre 2013 Retour au numéro
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