From Royal Brompton Hospital, London (A.M.-G.), Leicester National Institute for Health Research Biomedical Research Centre, University of Leicester, Leicester (C.E.B.), and Late-stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge (S.P.) - all in the United Kingdom; the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (J.C.), and Global Development, Amgen, Thousand Oaks (P.K.) - both in California; Physiologie et Médecine Expérimentale du Cœur et des Muscles, Université de Montpellier, Centre National de la Recherche Scientifique, INSERM, Centre Hospitalier Universitaire de Montpellier, Montpellier, France (A.B.); the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT (G. Chupp); the Division of Pulmonary and Critical Care Medicine and Allergy and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston (E.I.); National Jewish Health, Denver (M.E.W.); Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (J.M.G.), and Biometrics (K.B.), Late-stage Development, Respiratory and Immunology (G. Colice), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD; and Biometrics (Å.H.), Late-stage Development, Respiratory and Immunology (G.A.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
N Engl J Med. 2021 May 13;384(19):1800-1809. doi: 10.1056/NEJMoa2034975.
BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell-derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV) and scores on the Asthma Control Questionnaire-6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]). RESULTS: Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P<0.001). In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 (95% CI, 0.84 to 1.23) with tezepelumab and 1.73 (95% CI, 1.46 to 2.05) with placebo (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P<0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV (0.23 vs. 0.09 liters; difference, 0.13 liters; 95% CI, 0.08 to 0.18; P<0.001) and scores on the ACQ-6 (-1.55 vs. -1.22; difference, -0.33; 95% CI, -0.46 to -0.20; P<0.001), AQLQ (1.49 vs. 1.15; difference, 0.34; 95% CI, 0.20 to 0.47; P<0.001), and ASD (-0.71 vs. -0.59; difference, -0.12; 95% CI, -0.19 to -0.04; P = 0.002). The frequencies and types of adverse events did not differ meaningfully between the two groups. CONCLUSIONS: Patients with severe, uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo. (Funded by AstraZeneca and Amgen; NAVIGATOR ClinicalTrials.gov number, NCT03347279.).
背景：特泽佩鲁单抗是一种人源单克隆抗体，可阻断胸腺基质淋巴细胞生成素，这是一种上皮细胞衍生的细胞因子，与哮喘的发病机制有关。特泽佩鲁单抗在严重、未控制的哮喘患者中的疗效和安全性需要进一步评估。
方法：我们进行了一项 3 期、多中心、随机、双盲、安慰剂对照试验。患者（12 至 80 岁）被随机分配接受特泽佩鲁单抗（210mg）或安慰剂每 4 周皮下注射一次，共 52 周。主要终点是 52 周期间哮喘恶化的年化率。该终点也在基线血嗜酸性粒细胞计数小于 300 个细胞/微升的患者中进行评估。次要终点包括用力呼气量（FEV）和哮喘控制问卷-6（ACQ-6；范围，0[无损伤]至 6[最大损伤]）、哮喘生活质量问卷（AQLQ；范围，1[最大损伤]至 7[无损伤]）和哮喘症状日记（ASD；范围，0[无症状]至 4[最严重症状]）的评分。
结果：总体而言，1061 名患者接受了随机分组（529 名接受特泽佩鲁单抗治疗，532 名接受安慰剂治疗）。特泽佩鲁单抗组的哮喘恶化年化率为 0.93（95%置信区间[CI]，0.80 至 1.07），安慰剂组为 2.10（95%CI，1.84 至 2.39）（比率，0.44；95%CI，0.37 至 0.53；P<0.001）。在血嗜酸性粒细胞计数小于 300 个细胞/微升的患者中，特泽佩鲁单抗组的年化率为 1.02（95%CI，0.84 至 1.23），安慰剂组为 1.73（95%CI，1.46 至 2.05）（比率，0.59；95%CI，0.46 至 0.75；P<0.001）。在第 52 周时，与安慰剂相比，特泽佩鲁单抗在治疗前支气管扩张剂后 FEV 方面有更大的改善（0.23 与 0.09 升；差异 0.13 升；95%CI，0.08 至 0.18；P<0.001），以及在 ACQ-6 评分（-1.55 与-1.22；差异-0.33；95%CI，-0.46 至 -0.20；P<0.001）、AQLQ（1.49 与 1.15；差异 0.34；95%CI，0.20 至 0.47；P<0.001）和 ASD（-0.71 与-0.59；差异-0.12；95%CI，-0.19 至 -0.04；P=0.002）方面的改善更大。两组之间不良事件的频率和类型没有显著差异。
结论：与安慰剂相比，接受特泽佩鲁单抗治疗的严重、未控制的哮喘患者的恶化次数更少，肺功能、哮喘控制和健康相关生活质量更好。（由阿斯利康和安进公司资助；NAVIGATOR 临床试验.gov 编号，NCT03347279。）
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