一项评估IL-33单克隆抗体托扎单抗治疗慢性阻塞性肺疾病患者的2a期试验：FRONTIER-4。
A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4.
作者信息
Singh Dave, Guller Patricia, Reid Fred, Doffman Sarah, Seppälä Ulla, Psallidas Ioannis, Moate Rachel, Smith Rebecca, Kiraga Joanna, Jimenez Eulalia, Brooks Dennis, Kelly Aoife, Nordenmark Lars H, Sadiq Muhammad Waqas, Caballero Luis Mateos, Kell Chris, Belvisi Maria G, Pandya Hitesh
机构信息
Medicines Evaluation Unit, Manchester University NHS Foundation Trust, University of Manchester, Manchester, UK.
Clinical Development, Research and Early Development, Respiratory and Immunology, AstraZeneca, Gothenburg, Sweden.
出版信息
Eur Respir J. 2025 Jul 14;66(1). doi: 10.1183/13993003.02231-2024. Print 2025 Jul.
BACKGROUND
Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-interleukin-33 monoclonal antibody) in patients with moderate-to-severe COPD with chronic bronchitis receiving dual or triple inhaled therapy.
METHODS
FRONTIER-4 was a phase 2a, randomised, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary end‑point was change in pre-bronchodilator forced expiratory volume in 1 s (FEV) from baseline to week 12. Secondary outcomes included post-bronchodilator FEV, time-to-first COPD composite exacerbation event and safety.
RESULTS
The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase, although nonsignificant, from baseline in pre-bronchodilator FEV (least-squares mean difference (LSMD) 24 mL, 80% confidence interval (CI) -15-63 mL, p=0.216) and a significantly greater increase in post-bronchodilator FEV (LSMD 67 mL, 80% CI 17-116 mL, p=0.044) when compared with placebo. At week 12 in a prespecified subgroup of patients with at least two prior exacerbations, tozorakimab also showed improvements placebo in change from baseline in pre-bronchodilator FEV (LSMD 69 mL, 80% CI 9-130 mL, p=0.072) and post-bronchodilator FEV (LSMD 124 mL, 80% CI 47-201 mL, p=0.020). Tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57-1.11, p=0.186) in the intent-to-treat population, although there were greater effects in patients with at least two prior exacerbations (hazard ratio 0.61, 80% CI 0.37-1.00). Results were similar in former and current smokers. Tozorakimab was well tolerated.
CONCLUSION
Although the primary end-point was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals placebo in a subgroup of patients with COPD with a high risk of exacerbations.
背景
白细胞介素-33可能在慢性阻塞性肺疾病（COPD）的病理生物学中发挥作用。FRONTIER-4（NCT04631016）研究了托佐拉单抗（一种抗白细胞介素-33单克隆抗体）在接受双联或三联吸入治疗的中度至重度慢性支气管炎COPD患者中的疗效。
方法
FRONTIER-4是一项2a期随机双盲安慰剂对照研究。患者每4周皮下注射600mg托佐拉单抗或安慰剂，共24周。主要终点是从基线到第12周支气管扩张剂使用前1秒用力呼气容积（FEV）的变化。次要结局包括支气管扩张剂使用后FEV、首次发生COPD复合急性加重事件的时间和安全性。
结果
意向性治疗人群包括135例患者（托佐拉单抗组67例，安慰剂组68例）。在意向性治疗人群中，第12周时，与安慰剂相比，托佐拉单抗在支气管扩张剂使用前FEV方面，虽从基线的增加无统计学意义（最小二乘均值差[LSMD]24mL，80%置信区间[CI]-15至63mL，p=0.216），但支气管扩张剂使用后FEV有显著更大的增加（LSMD67mL，80%CI17至116mL，p=0.044）。在预先指定的至少有两次既往急性加重的患者亚组中，第12周时，托佐拉单抗在支气管扩张剂使用前FEV（LSMD69mL，80%CI9至130mL，p=0.072）和支气管扩张剂使用后FEV（LSMD124mL，80%CI47至201mL，p=0.020）从基线的变化方面也显示出优于安慰剂。托佐拉单抗在意向性治疗人群中未显著降低COPD复合急性加重事件的风险（风险比0.79，80%CI0.57至1.11，p=0.186），尽管在至少有两次既往急性加重的患者中有更大的效果（风险比0.61，80%CI0.37至1.00）。既往吸烟者和当前吸烟者的结果相似。托佐拉单抗耐受性良好。
结论
尽管在意向性治疗人群中未达到主要终点，但托佐拉单抗在COPD急性加重风险高的患者亚组中显示出优于安慰剂的积极疗效信号。
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