Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, Pa.
Allergy and Clinical Immunology, Faculty of Medicine, Transylvania University, Brasov, Romania.
J Allergy Clin Immunol. 2021 Sep;148(3):790-798. doi: 10.1016/j.jaci.2021.03.044. Epub 2021 Apr 16.
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 IgG 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.
This study evaluated astegolimab efficacy and safety in patients with severe asthma.
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.
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.
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.
IL-33/ST2 通路与哮喘易感性有关。引发哮喘加重的吸入性过敏原、污染物和呼吸道病毒会诱导上皮细胞衍生的“警报素”IL-33 的释放。阿替戈利单抗（astegolimab）是一种人源 IgG mAb，可选择性抑制 IL-33 受体 ST2。用于治疗严重哮喘的已获批生物疗法主要使血嗜酸性粒细胞升高（2 型高）的患者受益，但血嗜酸性粒细胞低（2 型低）的患者治疗选择有限。抑制 IL-33 信号传导可能会针对更广泛的哮喘患者的致病途径。
本研究评估了阿替戈利单抗治疗严重哮喘的疗效和安全性。
这项双盲、安慰剂对照、剂量范围研究（ZENYATTA [一项评估 MSTT1041A 在未控制的严重哮喘患者中的疗效和安全性的研究]）将 502 名成年严重哮喘患者随机分配至皮下安慰剂或 70mg、210mg 或 490mg 阿替戈利单抗每 4 周一次。主要终点是第 54 周时的年化哮喘加重率（AER）。每个治疗组的入组上限确保有约 30 名嗜酸性粒细胞高（≥300 个/μL）和约 95 名嗜酸性粒细胞低（＜300 个/μL）患者。
总体而言，与安慰剂相比，490mg、210mg 和 70mg 阿替戈利单抗的调整后 AER 分别降低了 43%（P=0.005）、22%（P=0.18）和 37%（P=0.01）。嗜酸性粒细胞低患者的调整后 AER 降低与总体人群相似：490mg、210mg 和 70mg 阿替戈利单抗的降低分别为 54%（P=0.002）、14%（P=0.48）和 35%（P=0.05）。阿替戈利单抗治疗组和安慰剂治疗组的不良事件相似。
阿替戈利单抗降低了广泛的哮喘患者（包括嗜酸性粒细胞低的患者）的 AER，这些患者患有控制不佳的严重哮喘。阿替戈利单抗安全且耐受良好。
