GlaxoSmithKline, Research Triangle Park, NC, USA.
GlaxoSmithKline, Stevenage, UK.
Respir Med. 2017 Sep;130:20-26. doi: 10.1016/j.rmed.2017.07.002. Epub 2017 Jul 4.
p38 mitogen-activated protein kinase (MAPK) expression is increased in chronic inflammatory disease. Losmapimod, a p38 MAPK inhibitor, has been developed as a potential anti-inflammatory therapy in COPD.
To evaluate the effect of losmapimod in reducing exacerbations in subjects with moderate-to-severe COPD.
In this double-blind, parallel-group study, subjects at risk of COPD exacerbations and ?2% blood eosinophils at screening, were randomized 1:1 to losmapimod 15 mg or placebo (variable treatment duration: 26-52 weeks). The primary endpoint was the annualized rate of moderate/severe exacerbations. Using a Bayesian framework, treatment success was defined as >90% posterior probability that the true ratio of the losmapimod/placebo exacerbation rate was <1. Lung function and health status (St George's Respiratory Questionnaire (SGRQ)) were also assessed.
A planned interim analysis resulted in early study termination due to the low probability of a successful study outcome; a total of 94 subjects were randomized to placebo and 90 to losmapimod 15 mg, and 14 and 10 subjects respectively completed the study. Losmapimod treatment was not associated with an improvement in the adjusted posterior median annualized exacerbation rate (losmapimod/placebo ratio: 1.04 (95% Cr I: 0.63, 1.73)). The posterior probability for the losmapimod/placebo annualized rate ratio being <1 was 0.44 (success criterion: >0.90). A statistically significant improvement in post-bronchodilator forced expiratory volume in 1 s was seen at Week 26, at the 5% significance level, with losmapimod treatment versus placebo (p = 0.007). Changes from baseline in SGRQ total score were similar in both groups. No new risks or safety signals were identified with losmapimod treatment.
Losmapimod treatment did not reduce the rate of exacerbations in, subjects with COPD at high risk of exacerbation and ?2% blood eosinophils. These data do not support its use as a therapy in COPD in addition to standard of care.
p38 丝裂原活化蛋白激酶（MAPK）在慢性炎症性疾病中的表达增加。洛索洛芬是一种 p38 MAPK 抑制剂，已被开发为 COPD 的潜在抗炎治疗药物。
评估洛索洛芬对降低中重度 COPD 患者急性加重风险的疗效。
这是一项双盲、平行分组研究，筛选时存在 COPD 急性加重风险且血嗜酸性粒细胞计数≥2%的受试者，按 1:1 随机分配至洛索洛芬 15mg 或安慰剂组（可变治疗时间：26-52 周）。主要终点为中重度急性加重的年发生率。采用贝叶斯框架，定义治疗成功为洛索洛芬/安慰剂急性加重率的真实比值大于 90%后验概率<1。还评估了肺功能和健康状况（圣乔治呼吸问卷[SGRQ]）。
由于成功研究结果的可能性较低，计划进行的中期分析导致研究提前终止；共 94 例受试者随机分配至安慰剂组，90 例随机分配至洛索洛芬 15mg 组，分别有 14 例和 10 例受试者完成了研究。洛索洛芬治疗与调整后中位年急性加重发生率的改善无关（洛索洛芬/安慰剂比值：1.04（95%可信区间：0.63，1.73））。洛索洛芬/安慰剂年急性加重率比值<1 的后验概率为 0.44（成功标准：>0.90）。与安慰剂组相比，洛索洛芬治疗在第 26 周时可显著改善支气管扩张剂后用力呼气量 1 秒率（p=0.007，5%显著水平）。两组间 SGRQ 总分的变化从基线开始相似。洛索洛芬治疗未发现新的风险或安全性信号。
洛索洛芬治疗不能降低高急性加重风险且血嗜酸性粒细胞计数≥2%的 COPD 患者的急性加重率。这些数据不支持其作为 COPD 标准治疗之外的治疗药物。
