From McMaster University and St. Joseph's Healthcare, Hamilton, ON, Canada (P.N.); University of Pittsburgh, Pittsburgh (S.W.); LungenClinic Grosshansdorf and Department of Medicine, Airway Research Center North of the German Center for Lung Research, Christian Albrechts University, Kiel, Germany (K.F.R.); Département de Pneumologie et Addictologie, PhyMedExp, University of Montpellier, INSERM Unité 1046, Centre National de la Recherche Scientifique Unité Mixte de Recherche 9214, Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Montpellier, Montpellier, France (A.B.); Duke University Medical Center, Durham, NC (N.L.L.); Barlicki University Hospital, Medical University of Lodz, Lodz, Poland (P.K.); AstraZeneca, Gaithersburg, MD (P.B., S.S., M.G.); and AstraZeneca, Cambridge, United Kingdom (S.P.).
N Engl J Med. 2017 Jun 22;376(25):2448-2458. doi: 10.1056/NEJMoa1703501. Epub 2017 May 22.
Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia.
In a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed.
Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group.
Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255 .).
许多严重哮喘患者依赖口服糖皮质激素来控制疾病。我们研究了一种针对白细胞介素-5 受体的 α 亚单位的单克隆抗体 benralizumab 是否也可作为一种口服糖皮质激素节省疗法，用于治疗依赖口服糖皮质激素治疗与嗜酸性粒细胞增多相关的严重哮喘的患者。
在一项 28 周的随机对照试验中，我们评估了 benralizumab（皮下注射剂量为 30mg，每 4 周或每 8 周一次[前 3 次剂量每 4 周一次]）与安慰剂在维持成人严重哮喘患者哮喘控制的同时，减少口服糖皮质激素剂量的效果。主要终点是从基线到 28 周时口服糖皮质激素剂量的变化百分比。评估了每年哮喘恶化率、肺功能、症状和安全性。
在 369 名入组患者中，220 名患者接受了随机分组并开始接受 benralizumab 或安慰剂治疗。两种 benralizumab 给药方案均使基线时的中位最终口服糖皮质激素剂量显著降低 75%，而安慰剂组的口服糖皮质激素剂量降低 25%（两者比较 P<0.001）。与安慰剂相比，使用 benralizumab 减少口服糖皮质激素剂量的可能性高出 4 倍以上。在次要结局中，每 4 周接受 benralizumab 治疗的患者每年恶化率比安慰剂组低 55%（边际率为 0.83 比 1.83，P=0.003），每 8 周接受 benralizumab 治疗的患者每年恶化率比安慰剂组低 70%（边际率为 0.54 比 1.83，P<0.001）。28 周时，与安慰剂相比，两种 benralizumab 方案对用力呼气量（FEV）均无显著影响。哮喘症状各种测量指标的影响不一，有些指标显示出有利于 benralizumab 的显著变化，而有些指标则没有显示出显著变化。各 benralizumab 组与安慰剂组的不良反应频率相似。
与安慰剂相比，benralizumab 在口服糖皮质激素使用和恶化率方面显示出显著的、有临床意义的益处。这些效果的产生并没有对 FEV 产生持续影响。（由阿斯利康资助；ZONDA 临床试验.gov 编号，NCT02075255）。
