Jackson David J, Wechsler Michael E, Jackson Daniel J, Bernstein David, Korn Stephanie, Pfeffer Paul E, Chen Ruchong, Saito Junpei, de Luíz Martinez Gustavo, Dymek Lucyna, Jacques Loretta, Bird Nicholas, Schalkwijk Stein, Smith Douglas, Howarth Peter, Pavord Ian D
From Guy's Severe Asthma Centre, Guy's and St. Thomas' NHS Foundation Trust, and the School of Immunology and Microbial Sciences, King's College London (David J. Jackson), Barts Health NHS Trust (P.E.P.), and GSK (L.J., N.B., S.S., P.H.), London, and the Oxford Respiratory NIHR Biomedical Research Centre, Nuffield Department of Clinical Medicine, University of Oxford, Oxford (I.D.P.) - all in the United Kingdom; National Jewish Health, Denver (M.E.W.); the University of Wisconsin-Madison, Madison (Daniel J. Jackson); the University of Cincinnati College of Medicine and Bernstein Clinical Research Center, Cincinnati (D.B.); Clinical Research Center, Respiratory Medicine, IKF Pneumologie Mainz, Mainz, and Thoraxklinik Heidelberg, Heidelberg - both in Germany (S.K.); State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Joint International Research Laboratory of Respiratory Health, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (R.C.); Fukushima Medical University, Fukushima, Japan (J.S.); Hospital Vithas Xanit Internacional, Málaga, Spain (G.L.M.); Centrum Medyczne Lucyna Andrzej Dymek, Strzelce Opolskie, Poland (L.D.); and GSK, Collegeville, PA (D.S.).
N Engl J Med. 2024 Dec 19;391(24):2337-2349. doi: 10.1056/NEJMoa2406673. Epub 2024 Sep 9.
Depemokimab is an ultra-long-acting biologic therapy with enhanced binding affinity for interleukin-5 that may enable effective 6-month dosing intervals.
In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the efficacy and safety of depemokimab in patients with severe asthma and an eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per microliter in the previous 12 months or ≥150 cells per microliter at screening) and a history of exacerbations despite the receipt of medium- or high-dose inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus standard care. The primary end point was the annualized rate of exacerbations at 52 weeks. Secondary end points, which were analyzed in a hierarchical manner to adjust for multiplicity, included the change from baseline in the score on the St. George's Respiratory Questionnaire (SGRQ), the forced expiratory volume in 1 second, and asthma symptom reports at 52 weeks.
Across the two trials, 792 patients underwent randomization and 762 were included in the full analysis; 502 were assigned to receive depemokimab and 260 to receive placebo. The annualized rate of exacerbations was 0.46 (95% confidence interval [CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and 0.56 (95% CI, 0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41) with placebo (rate ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2. No significant between-group difference in the change from baseline in the SGRQ score was observed in either trial, so no statistical inference was drawn on subsequent secondary end points. The proportion of patients with any adverse event was similar in the two groups in both trials.
Depemokimab reduced the annualized rate of exacerbations among patients with severe asthma with an eosinophilic phenotype. (Funded by GSK; SWIFT-1 and SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and NCT04718103.).
地培莫单抗是一种超长效生物疗法，对白细胞介素-5具有增强的结合亲和力，这可能使每6个月给药一次成为有效给药间隔。
在这些3A期随机、安慰剂对照重复试验中，我们评估了地培莫单抗对重度哮喘且具有嗜酸性粒细胞表型患者的疗效和安全性，这些患者的特征为嗜酸性粒细胞计数高（在之前12个月内≥300个细胞/微升或筛查时≥150个细胞/微升）且尽管接受了中或高剂量吸入性糖皮质激素治疗仍有急性加重病史。患者按2:1的比例随机分组，在第0周和第26周接受地培莫单抗（皮下注射剂量为100 mg）或安慰剂治疗，同时接受标准治疗。主要终点是52周时的年化急性加重率。次要终点以分层方式进行分析以调整多重性，包括圣乔治呼吸问卷（SGRQ）评分相对于基线的变化、第1秒用力呼气量以及52周时的哮喘症状报告。
在两项试验中，792例患者进行了随机分组，762例纳入全分析；502例被分配接受地培莫单抗治疗，260例接受安慰剂治疗。在SWIFT - 1试验中，地培莫单抗组的年化急性加重率为0.46（95%置信区间[CI]，0.36至0.58），安慰剂组为1.11（95%CI，0.86至1.43）（率比为0.42；95%CI，0.30至0.59；P<0.001）；在SWIFT - 2试验中，地培莫单抗组为0.56（95%CI，0.44至0.70），安慰剂组为1.08（95%CI，0.83至1.41）（率比为0.52；95%CI，0.36至0.73；P<0.001）。在两项试验中，两组间SGRQ评分相对于基线的变化均未观察到显著差异，因此未对后续次要终点进行统计推断。在两项试验中，两组中发生任何不良事件的患者比例相似。
地培莫单抗降低了具有嗜酸性粒细胞表型的重度哮喘患者的年化急性加重率。（由葛兰素史克公司资助；SWIFT - 1和SWIFT - 2的ClinicalTrials.gov编号分别为NCT04719832和NCT04718103。）
