Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: A聽randomized trial

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• 作者：Erika H. De Boever ; PhD^a ; ^{erika.h.deboever@gsk.com" class="auth_mail} ; Claire Ashman ; BSc^b ; Anthony P. Cahn ; MB BS^c ; Nicholas W. Locantore ; PhD^d ; Phil Overend ; BSc (Hons)^e ; Isabelle J. Pouliquen ; PharmD^f ; Adrian P. Serone ; PhD^g ; Tracey J. Wright ; PhD^b ; Mair M. Jenkins ; MB BS^h ; Inderpal S. Panesar ; MRPharmSⁱ ; Sivayogan S. Thiagarajah ; MB ChB^j ; Sally E. Wenzel ; MD^k
• 关键词：IL-13 ; IL13R伪1 ; IL13R伪2 ; efficacy ; safety ; pharmacokinetics ; pharmacodynamics
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：April, 2014
• 年：2014
• 卷：133
• 期：4
• 页码：989-996.e4
• 全文大小：705 K

文摘

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Background

Approximately 5% to 10% of asthmatic patients achieve incomplete symptom control on current therapies. The association of IL-13 with asthma pathology and reduced corticosteroid sensitivity suggests a potential benefit of anti-IL-13 therapy in refractory asthma. GSK679586, a humanized mAb, inhibits IL-13 binding to both IL-13 receptor 伪1 and 伪2.

Objectives

We sought to evaluate the efficacy and safety of GSK679586 in patients with severe asthma refractory to maximally indicated doses of inhaled corticosteroids.

Methods

Patients who remained symptomatic (Asthma Control Questionnaire score 鈮?.5) after uptitration to 1000 渭g/d fluticasone propionate or greater were randomized to 3 once-monthly intravenous infusions of 10 mg/kg GSK679586 (n聽= 99) or placebo (n聽= 99).

Results

Treatment differences in adjusted mean change from baseline over 12 weeks were nonsignificant for Asthma Control Questionnaire symptom scores (the primary end point; GSK679586聽= 鈭?.31, placebo聽= 鈭?.17, P聽= .058) and FEV₁ (GSK679586聽= 鈭?.01, placebo聽= 0.03, P聽= .276). Similar analyses in patients with increased serum IgE levels, blood eosinophil counts, or both were also negative. Incidence of asthma exacerbations was similar between treatments. Most聽adverse events were nonserious and unrelated to聽treatment. Two GSK679586-treated patients had treatment-related serious adverse events (lethargy and supraventricular extrasystoles).

Conclusions

Although well tolerated, GSK679586 did not demonstrate clinically meaningful improvements in asthma control, pulmonary function, or exacerbations in patients with severe asthma. Further studies are needed to determine whether therapies targeting IL-13, the functionally related IL-4 cytokine, or both can provide clinical benefit in patients with severe refractory asthma or a subpopulation of these patients beyond that achievable with high-dose corticosteroids.