Crim Courtney, Watkins Michael L, Bateman Eric D, Feldman Gregory J, Schenkenberger Isabelle, Kerwin Edward M, Crawford Catriona, Pudi Krishna, Ho Shuyen, Baidoo Charlotte, Castro-Santamaria Ramiro
GSK, Research and Development, Research Triangle Park, NC, USA,
Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Int J Chron Obstruct Pulmon Dis. 2019 Mar 8;14:615-629. doi: 10.2147/COPD.S190603. eCollection 2019.
Batefenterol is a novel bifunctional muscarinic antagonist β-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose-response of batefenterol and select a dose for Phase III development.
Patients aged ≥40 years with COPD and FEV ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV over 0-6 hours post-dose and trough FEV, analyzed by Bayesian and maximum likelihood estimation E of dose-response modeling, respectively, on day 42.
In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1-292.8 and 182.2-244.8 mL, respectively), with a relatively flat dose-response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed.
Batefenterol 300 µg may represent the optimal dose for Phase III studies.
巴替芬特罗是一种正在研发用于慢性阻塞性肺疾病（COPD）的新型双功能毒蕈碱拮抗剂β-激动剂。这项随机、双盲、安慰剂对照、活性药物对照的IIb期研究的主要目的是建立巴替芬特罗的剂量反应模型并选择用于III期研发的剂量。
年龄≥40岁、慢性阻塞性肺疾病患者，其第一秒用力呼气容积（FEV）占预计正常值的30%至70%，被随机均分为接受每日一次37.5、75、150、300或600μg巴替芬特罗、安慰剂或62.5/25μg乌美溴铵/维兰特罗（UMEC/VI）治疗的组。主要和次要终点分别是给药后0至6小时的加权平均FEV和谷值FEV，在第42天分别通过贝叶斯分析和剂量反应模型的最大似然估计进行分析。
在意向性治疗人群（N = 323）中，与安慰剂相比，所有巴替芬特罗剂量在主要和次要终点上均显示出从基线水平有统计学意义和临床意义的改善（分别为191.1至292.8和182.2至244.8 mL），剂量反应相对平缓。在对沙丁胺醇可逆的亚组中，巴替芬特罗各剂量之间的差异更大。≥150μg巴替芬特罗的肺功能改善与UMEC/VI相当。巴替芬特罗耐受性良好，未观察到新的安全信号。
300μg巴替芬特罗可能是III期研究的最佳剂量。
