托佐拉奇单抗预防慢性阻塞性肺疾病急性加重
完整摘要 · 中文译文
背景：许多接受标准吸入性维持治疗的慢性阻塞性肺疾病（COPD）患者仍会出现急性加重。白细胞介素-33信号通路失调与COPD的发病机制有关。Tozorakimab是一种抑制白细胞介素-33活性的单克隆抗体。 方法：在两项重复的3期试验（OBERON和TITANIA）中，我们纳入了患有COPD的成人，这些患者为当前或既往吸烟者，并且在接受稳定的标准吸入性维持治疗的情况下，既往一年内仍有急性加重史。入选标准未对血嗜酸性粒细胞计数设限。患者被随机分配接受附加的皮下注射tozorakimab（300 mg）或安慰剂，每4周一次，持续52周。主要终点是既往吸烟者在52周期间发生中度或重度急性加重的年化率，第一个关键次要终点是总体人群中发生中度或重度急性加重的年化率。同时评估了安全性。 结果：在OBERON研究中，总体人群包括托佐拉奇单抗组446名患者和安慰剂组431名患者；在TITANIA研究中，包括托佐拉奇单抗组438名患者和安慰剂组435名患者。在既往吸烟者中，中重度急性加重的年化发生率在OBERON研究中，托佐拉奇单抗组为1.34次，安慰剂组为1.90次（发生率比，0.71；95%置信区间[CI]，0.57至0.88；P=0.002）；在TITANIA研究中，分别为1.37次和2.07次（发生率比，0.66；95% CI，0.55至0.80；P<0.001）。在总体人群中，中重度急性加重的年化发生率在OBERON研究中，托佐拉奇单抗组为1.41次，安慰剂组为2.00次（发生率比，0.70；95% CI，0.58至0.85；P<0.001）；在TITANIA研究中，分别为1.44次和2.03次（发生率比，0.71；95% CI，0.59至0.84；P<0.001）。不良事件在OBERON研究中发生于托佐拉奇单抗组70.4%的患者和安慰剂组77.2%的患者；在TITANIA研究中，分别发生于80.1%和79.8%的患者。 结论：在COPD患者中，与安慰剂相比，托佐拉奇单抗治疗在既往吸烟者队列以及当前和既往吸烟者的总体人群中均显著降低了中重度急性加重的发生率。（资助方：阿斯利康；OBERON ClinicalTrials.gov编号，NCT05166889；TITANIA ClinicalTrials.gov编号，NCT05158387。）
完整摘要 · 英文原文
BACKGROUND: Many patients with chronic obstructive pulmonary disease (COPD) have exacerbations despite receiving standard-of-care inhaled maintenance therapy. Dysregulated interleukin-33 signaling is implicated in the pathogenesis of COPD. Tozorakimab is a monoclonal antibody that inhibits the activity of interleukin-33. METHODS: In two replicate phase 3 trials (OBERON and TITANIA), we enrolled adults with COPD who were current or former smokers and had a history of exacerbations in the previous year despite receiving stable standard-of-care inhaled maintenance therapy. There were no eligibility criteria related to blood eosinophil count. Patients were randomly assigned to receive add-on subcutaneous tozorakimab (300 mg) or placebo every 4 weeks for 52 weeks. The primary end point was the annualized rate of moderate or severe exacerbations that occurred over a 52-week period among former smokers, and the first key secondary end point was the annualized rate of moderate or severe exacerbations in the overall population. Safety was also assessed. RESULTS: The overall population in OBERON included 446 patients in the tozorakimab group and 431 in the placebo group, and in TITANIA included 438 in the tozorakimab group and 435 in the placebo group. The annualized rate of moderate or severe exacerbations among former smokers was 1.34 events in the tozorakimab group and 1.90 events in the placebo group (rate ratio, 0.71; 95% confidence interval [CI], 0.57 to 0.88; P = 0.002) in OBERON, and 1.37 events and 2.07 events, respectively (rate ratio, 0.66; 95% CI, 0.55 to 0.80; P<0.001), in TITANIA. In the overall population, the annualized rate of moderate or severe exacerbations was 1.41 events in the tozorakimab group and 2.00 events in the placebo group (rate ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001) in OBERON, and 1.44 events and 2.03 events, respectively (rate ratio, 0.71; 95% CI, 0.59 to 0.84; P<0.001), in TITANIA. Adverse events occurred in 70.4% of the patients in the tozorakimab group and in 77.2% of those in the placebo group in OBERON, and in 80.1% and 79.8%, respectively, in TITANIA. CONCLUSIONS: Among patients with COPD, treatment with tozorakimab resulted in a significantly lower rate of moderate or severe exacerbations than placebo in the cohort of former smokers and in the overall population of current and former smokers. (Funded by AstraZeneca; OBERON ClinicalTrials.gov number, NCT05166889; TITANIA ClinicalTrials.gov number, NCT05158387.).