Astegolimab(抗ST2抗体)在重症哮喘成年患者中的有效性及安全性：一项随机临床试验
2022/01/28
摘要
背景：白介素（IL）-33/ST2通路与哮喘易感性相关。吸入的过敏原、污染物及呼吸道病毒（他们会引发哮喘加重）能诱导IL-33（一种上皮衍生的“警报素”）的释放。Astegolimab（一种人IgG2单克隆抗体）能选择性地抑制IL-33受体（ST2）。获批的针对重症哮喘的生物疗法主要有益于学嗜酸性粒细胞升高（2型炎症-高）的患者，但是血嗜酸性粒细胞较低（2型炎症-低）的患者的选择有限。抑制IL-33信号传导也许能靶向更广泛的哮喘患者的致病通路。
目的：本研究评估astegolimab在重症哮喘患者中的有效性及安全性。
方法：这个双盲、安慰剂对照、剂量探索研究（ZENYATTA）将502名重症哮喘成年患者随机分配到安慰剂组、70mg astegolimab组、210mg astegolimab组及490mg astegolimab组（皮下注射，每4周一次）。主要终点是第54周的年化哮喘恶化率（AER）。招募人数的上限确保每组大约纳入30名高嗜酸性粒细胞（≥300个细胞/ul）的患者及95名低嗜酸性粒细胞（＜300个细胞/ul）患者。
结果：总体而言，490mg astegolimab组、210mg astegolimab组及70mg astegolimab组相对于安慰剂组的校正后的AER降低量分别为43%（P=0.005）、22%（P=0.18）及37%（P=0.01）。低嗜酸性粒细胞患者的校正后的AER降低量与整个人群的降低量相当：490mg astegolimab组、210mg astegolimab组及70mg astegolimab组分别为54%（P=0.002）、14%（P=0.48）及35%（P=0.05）。Astegolimab组与安慰剂治疗组的不良事件相似。
结论：在一个广泛的未得到充分控制的重症哮喘患者人群（包括低嗜酸性粒细胞患者）中，astegolimab降低了AER。Astegolimab是安全的，并且耐受性良好。
Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial
Steven G Kelsen, Ioana O Agache, Weily Soong, Elliot Israel, Geoffrey L Chupp, Dorothy S Cheung, Wiebke Theess, Xiaoying Yang, Tracy L Staton, David F Choy, Alice Fong, Ajit Dash, Michael Dolton, Rajita Pappu, Christopher E Brightling
Abstract
Background: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics.
Objectives: This study evaluated astegolimab efficacy and safety in patients with severe asthma.
Methods: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/μL) and ∼95 patients who were eosinophil-low (<300 cells/μL) per arm.
Results: Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups.
Conclusions: Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.
背景：白介素（IL）-33/ST2通路与哮喘易感性相关。吸入的过敏原、污染物及呼吸道病毒（他们会引发哮喘加重）能诱导IL-33（一种上皮衍生的“警报素”）的释放。Astegolimab（一种人IgG2单克隆抗体）能选择性地抑制IL-33受体（ST2）。获批的针对重症哮喘的生物疗法主要有益于学嗜酸性粒细胞升高（2型炎症-高）的患者，但是血嗜酸性粒细胞较低（2型炎症-低）的患者的选择有限。抑制IL-33信号传导也许能靶向更广泛的哮喘患者的致病通路。
目的：本研究评估astegolimab在重症哮喘患者中的有效性及安全性。
方法：这个双盲、安慰剂对照、剂量探索研究（ZENYATTA）将502名重症哮喘成年患者随机分配到安慰剂组、70mg astegolimab组、210mg astegolimab组及490mg astegolimab组（皮下注射，每4周一次）。主要终点是第54周的年化哮喘恶化率（AER）。招募人数的上限确保每组大约纳入30名高嗜酸性粒细胞（≥300个细胞/ul）的患者及95名低嗜酸性粒细胞（＜300个细胞/ul）患者。
结果：总体而言，490mg astegolimab组、210mg astegolimab组及70mg astegolimab组相对于安慰剂组的校正后的AER降低量分别为43%（P=0.005）、22%（P=0.18）及37%（P=0.01）。低嗜酸性粒细胞患者的校正后的AER降低量与整个人群的降低量相当：490mg astegolimab组、210mg astegolimab组及70mg astegolimab组分别为54%（P=0.002）、14%（P=0.48）及35%（P=0.05）。Astegolimab组与安慰剂治疗组的不良事件相似。
结论：在一个广泛的未得到充分控制的重症哮喘患者人群（包括低嗜酸性粒细胞患者）中，astegolimab降低了AER。Astegolimab是安全的，并且耐受性良好。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(J Allergy Clin Immunol.2021 Sep;148(3):790-798.doi: 10.1016/j.jaci.2021.03.044.Epub 2021 Apr 16.)
(J Allergy Clin Immunol.2021 Sep;148(3):790-798.doi: 10.1016/j.jaci.2021.03.044.Epub 2021 Apr 16.)
Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial
Steven G Kelsen, Ioana O Agache, Weily Soong, Elliot Israel, Geoffrey L Chupp, Dorothy S Cheung, Wiebke Theess, Xiaoying Yang, Tracy L Staton, David F Choy, Alice Fong, Ajit Dash, Michael Dolton, Rajita Pappu, Christopher E Brightling
Abstract
Background: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics.
Objectives: This study evaluated astegolimab efficacy and safety in patients with severe asthma.
Methods: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/μL) and ∼95 patients who were eosinophil-low (<300 cells/μL) per arm.
Results: Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups.
Conclusions: Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.
