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Empire-CF study: A phase 2 clinical trial of leukotriene A4 hydrolase inhibitor acebilustat in adult subjects with cystic fibrosis
Journal of Cystic Fibrosis ( IF 5.2 ) Pub Date : 2021-09-17 , DOI: 10.1016/j.jcf.2021.08.007
J Stuart Elborn 1 , Michael W Konstan 2 , Jennifer L Taylor-Cousar 3 , Isabelle Fajac 4 , Alexander Horsley 5 , Sivagurunathan Sutharsan 6 , Shawn D Aaron 7 , Cori L Daines 8 , Ahmet Uluer 9 , Damian G Downey 10 , Vincenzina V Lucidi 11 , Sanjeev Ahuja 12 , Eric Springman 12 , John Mershon 12 , Ralph Grosswald 12 , Steven M Rowe 13 ,
Affiliation  

Background

Cystic fibrosis (CF) is characterized by neutrophilic inflammation in the airways. Leukotriene B4 (LTB4) is a neutrophil chemoattractant and has been implicated in CF pathogenesis. Acebilustat, a novel, synthetic, small-molecule leukotriene A4 hydrolase inhibitor, reduces LTB4 production. We report findings from a randomized placebo-controlled trial of acebilustat in adult subjects with mild-to-moderate lung disease.

Methods

Subjects were randomized (1:1:1) to once-daily acebilustat 50 mg, 100 mg or placebo for 48 weeks, concomitantly with their current therapeutic regimen. Subjects were stratified by use of concomitant CF transmembrane conductance regulator (CFTR) modulators, baseline percent predicted forced expiratory volume in 1 second (ppFEV1) 50-75 and >75, and number of pulmonary exacerbations in the past year (1 or >1). Primary endpoints were the change from baseline in ppFEV1 and safety. Secondary endpoints included the rate of pulmonary exacerbations.

Results

Overall, 199 subjects were randomized and dosed (acebilustat 50 mg, n=67; acebilustat 100 mg, n=66; placebo, n=66). Baseline demographics and disease profile were well balanced among treatment groups. Acebilustat had no statistically significant effect on the primary endpoint of change in ppFEV1 at week 48 or the secondary endpoint pulmonary exacerbations. There was a trend towards reduced pulmonary exacerbations in subjects receiving acebilustat in pre-specified populations with ppFEV1>75 (35% rate reduction) and those on concomitant CFTR modulator therapy (20% rate reduction). Acebilustat was well tolerated.

Conclusions

Acebilustat did not improve lung function. A trend towards reduced pulmonary exacerbations in subjects with an earlier stage of lung disease suggests a potential effect in this population.



中文翻译:

Empire-CF 研究:白三烯 A4 水解酶抑制剂 acebilustat 在成人囊性纤维化受试者中的 2 期临床试验

背景

囊性纤维化 (CF) 的特征是气道中的中性粒细胞炎症。白三烯 B4 (LTB 4 ) 是一种中性粒细胞趋化剂,与 CF 发病机制有关。Acebilustat 是一种新型的合成小分子白三烯 A4 水解酶抑制剂,可减少 LTB 4的产生。我们报告了一项在患有轻度至中度肺病的成人受试者中进行的 acebilustat 随机安慰剂对照试验的结果。

方法

受试者随机(1:1:1)接受每日一次的 acebilusat 50 mg、100 mg 或安慰剂治疗 48 周,同时采用他们目前的治疗方案。通过使用伴随的 CF 跨膜电导调节器 (CFTR) 调节剂对受试者进行分层,基线百分比预测的 1 秒内用力呼气量 (ppFEV 1 ) 50-75 和 >75,以及过去一年的肺部恶化次数(1 或 >1 )。主要终点是 ppFEV 1和安全性从基线的变化。次要终点包括肺部恶化率。

结果

总体而言,199 名受试者被随机分配和给药(阿司匹林 50 mg,n=67;阿司匹司他 100 mg,n=66;安慰剂,n=66)。治疗组之间的基线人口统计学和疾病状况很好地平衡。Acebilustat 对第 48 周时 ppFEV 1变化的主要终点或次要终点肺部恶化没有统计学上的显着影响。在 ppFEV 1 >75(35% 发生率降低)和同时接受 CFTR 调节剂治疗(20% 发生率降低)的预先指定人群中,接受 acebilustat 的受试者的肺部恶化有减少的趋势。Acebilustat 耐受性良好。

结论

阿司匹司他没有改善肺功能。早期肺病患者肺部恶化的趋势减少表明该人群有潜在的影响。

更新日期:2021-09-17
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