Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Division of Pulmonary & Critical Care Medicine, University of Michigan, Ann Arbor, MI.
Chest. 2022 Aug;162(2):297-308. doi: 10.1016/j.chest.2022.02.038. Epub 2022 Mar 3.
Prostaglandin D receptor 2 (DP) antagonists inhibit prostaglandin D-induced effects, including recruitment and activation of cells driving asthma pathogenesis. However, challenges identifying target population and end points persist.
What is the effect of the DP antagonist GB001 on asthma worsening in patients with moderate to severe eosinophilic asthma?
In this phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter study, GB001 or placebo was added to standard-of-care treatment in patients with moderate to severe asthma with a blood eosinophil count ≥ 250 cells/μL. Patients aged ≥ 18 years to < 75 years received one of four once-daily treatments (GB001 20 mg, 40 mg, or 60 mg or placebo). The primary end point was the proportion of patients who experienced asthma worsening by 24 weeks. Efficacy analyses were performed for the intention-to-treat population and safety analyses for patients who received at least one dose of study treatment.
A total of 480 patients were treated. The ORs for asthma worsening for GB001 20 mg, 40 mg, and 60 mg vs placebo were 0.674 (95% CI, 0.398-1.142), 0.677 (95% CI, 0.399-1.149), and 0.651 (95% CI, 0.385-1.100), respectively. Analysis according to baseline blood eosinophil levels and/or fractional exhaled nitric oxide did not show greater treatment effects with higher values. Elevated liver aminotransferase levels and adverse events leading to discontinuation were more frequent for GB001 60 mg than with placebo, GB001 20 mg, and GB001 40 mg.
Although GB001 did not significantly reduce the odds of asthma worsening, reductions favoring GB001 were observed. Treatment effects were consistent regardless of high/low type 2 phenotype. The overall safety profile was acceptable, although GB001 60 mg was associated with risk of liver injury.
ClinicalTrials.gov; No.: NCT03683576; URL: www.
gov.
前列腺素 D 受体 2（DP）拮抗剂抑制前列腺素 D 诱导的作用，包括招募和激活驱动哮喘发病机制的细胞。然而，确定目标人群和终点的挑战仍然存在。
DP 拮抗剂 GB001 对中重度嗜酸性粒细胞性哮喘患者的哮喘恶化有何影响？
在这项 IIb 期、随机、双盲、安慰剂对照、剂量范围、平行组、多中心研究中，将中重度哮喘患者（血液嗜酸性粒细胞计数≥250 个/μL）的标准治疗方案中加入 DP 拮抗剂 GB001 或安慰剂。年龄在 18 岁至 75 岁之间的患者接受四种每日一次治疗方案之一（GB001 20mg、40mg 或 60mg 或安慰剂）。主要终点是 24 周时哮喘恶化的患者比例。疗效分析针对意向治疗人群进行，安全性分析针对至少接受一剂研究治疗的患者进行。
共 480 例患者接受了治疗。GB001 20mg、40mg 和 60mg 与安慰剂相比，哮喘恶化的 OR 分别为 0.674（95%CI，0.398-1.142）、0.677（95%CI，0.399-1.149）和 0.651（95%CI，0.385-1.100）。根据基线血液嗜酸性粒细胞水平和/或呼出的一氧化氮分数的分析并未显示出更高的治疗效果。与安慰剂、GB001 20mg 和 GB001 40mg 相比，GB001 60mg 导致肝氨基转移酶水平升高和导致停药的不良事件更为频繁。
尽管 GB001 并未显著降低哮喘恶化的几率，但观察到对 GB001 的治疗效果有利。无论 2 型表型高/低，治疗效果都是一致的。总体安全性状况可以接受，尽管 GB001 60mg 与肝损伤风险相关。
ClinicalTrials.gov；编号：NCT03683576；网址：www.clinicaltrials.gov。
ClinicalTrials.gov。
