嗜酸粒细胞性哮喘患者对 CRTH2 拮抗剂 OC000459 的反应增强。

Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459.

机构信息

Atopix Therapeutics Ltd, The Innovation Centre, Abingdon, UK.

出版信息

Allergy. 2014 Sep;69(9):1223-32. doi: 10.1111/all.12451. Epub 2014 Jul 14.

DOI:10.1111/all.12451

PMID:24866478

Abstract

BACKGROUND

The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. A study was conducted to determine the effect of lower once daily doses of OC000459 and to define the phenotype of subjects most responsive to treatment.

METHODS

Adult subjects (percentage of predicted forced expiratory volume in 1 s (FEV1 ) 60-85%) were randomized to OC000459 at three dose levels (25 mg once daily, 200 mg once daily or 100 mg twice daily) or placebo for 12 weeks (n = 117-125 per group, full analysis set). The primary endpoint was the change from baseline in prebronchodilator FEV1 , and secondary endpoints included Asthma Control Questionnaire (ACQ) and Standardised Asthma Quality of Life Questionnaire [AQLQ(S)], and incidence of exacerbations and respiratory tract infections.

RESULTS

OC459 caused a significant improvement in FEV1 compared with placebo at a dose of 25 mg once daily (P = 0.028). A similar increase was observed in the other dose groups, and the mean change in FEV1 in the pooled dose groups at endpoint was 95 ml greater than placebo (P = 0.024). In a post hoc analysis of atopic eosinophilic subjects with uncontrolled asthma, a mean increase in FEV1 of 220 ml was observed compared with placebo (P = 0.005). The mean increase in FEV1 was more marked in younger subjects in this group: for subjects aged ≤40 years, there was a mean increase of 355 ml compared with placebo (P = 0.007). Improvements in ACQ and AQLQ(S) were observed in both the full analysis set and the atopic eosinophilic subgroup. There was a lower incidence of exacerbations and respiratory infections in subjects treated with OC000459. There were no drug-related serious adverse events.

CONCLUSIONS

OC000459 is a safe and effective oral anti-inflammatory agent, which achieved clinically meaningful improvements in lung function and asthma control in allergic asthmatics with an eosinophil-dominant form of the disease. A dose of 25 mg given once daily was as effective as the higher doses studied.

摘要

背景

CRTH2 拮抗剂 OC000459 先前已被证实可减轻中度持续性哮喘的气道炎症并改善肺功能。进行了一项研究，以确定较低的每日一次剂量 OC000459 的效果，并确定对治疗反应最敏感的患者的表型。

方法

成年受试者（预计用力呼气量 1 秒率（FEV1）的百分比为 60-85%）被随机分配至 OC000459 三个剂量水平（每日一次 25mg、每日一次 200mg 或每日两次 100mg）或安慰剂治疗 12 周（每组 117-125 例，全分析集）。主要终点为支气管扩张剂前 FEV1 的基线变化，次要终点包括哮喘控制问卷（ACQ）和标准化哮喘生活质量问卷 [AQLQ(S)]，以及加重和呼吸道感染的发生率。

结果

与安慰剂相比，OC459 每日一次 25mg 剂量可显著改善 FEV1（P=0.028）。在其他剂量组中也观察到类似的增加，并且在终点时，合并剂量组的 FEV1 平均变化比安慰剂组大 95ml（P=0.024）。在对未控制哮喘的特应性嗜酸性粒细胞患者的事后分析中，与安慰剂相比，观察到 FEV1 的平均增加 220ml（P=0.005）。在该组年龄较小的患者中，FEV1 的平均增加更为明显：对于年龄≤40 岁的患者，与安慰剂相比，平均增加 355ml（P=0.007）。在全分析集和特应性嗜酸性粒细胞亚组中均观察到 ACQ 和 AQLQ(S) 的改善。OC000459 治疗的患者中，加重和呼吸道感染的发生率较低。没有与药物相关的严重不良事件。