A Pilot Study of the Effect of the CFTR Potentiator Ivacaftor in COPD (P-TOPIC)

 描述(申请人提供)：慢性阻塞性肺疾病(COPD)的治疗需要新的疗法，这种疾病每年的医疗费用超过400亿美元，最近超过中风，成为美国第三大死亡原因。与囊性纤维化(CF)一样，COPD的特征是小气道粘液阻塞，与肺功能加速丧失和高死亡率相关。香烟烟雾在体外和体内对呼吸道上皮细胞功能有多种有害影响，我们的初步数据表明，香烟烟雾还导致CFTR活性显着降低，从而导致粘液纤毛运输显着减少。此外，CFTR功能障碍与慢性支气管炎和呼吸困难独立相关，即使戒烟也可以持续存在，并可以通过激活野生型CFTR在体外被CFTR增强剂iVacaftor(Kalydeco，以前的VX-770)逆转，导致粘液纤毛运输的强劲增加。这些数据再加上使用iVacaftor治疗的CFTR基因突变有反应的慢性阻塞性肺疾病患者的粘液纤毛清除能力得到了前所未有的改善，这些数据表明CFTR是解决慢性支气管炎COPD患者(仅在美国就可能有800多万名患者)粘液淤积的一个可行的治疗目标。在这个项目中，我们将调查假设，在慢性支气管炎的慢性阻塞性肺疾病患者中，iVacaftor可以增强CFTR活性。尽管我们的初步数据令人信服，但关于最具信息量和响应性的终点和剂量选择的问题要求本申请中概述的研究。为了解决这一问题，我们设计了一项创新的第二阶段随机、双盲、安慰剂对照试验，以确定IVacaftor(VX-770)治疗慢性阻塞性肺疾病(试验性课题研究)的安全性和有效性，并将使用最新的分析方法和临床方法解决COPD和呼吸道上皮生物学领域的一些关键问题，以评估CFTR活性、上皮功能、粘液纤毛清除和临床结果。这项主题研究将测试是否可以在患有慢性支气管炎的COPD患者中增强MCC，即使在CFTR基因没有先天性突变的情况下，也能改善人类的疾病。此外，该试验将提供初步的概念验证，评估CFTR增强剂在COPD中的疗效，同时探索剂量范围，提供设计后续研究所需的必要信息，包括最具信息量的生物标志物和结果衡量标准。如果成功，这一结果可能建立一种新的治疗范例来解决COPD的粘液功能障碍，这是一种与死亡率和疾病进展独立相关的发病率的重要原因。

 DESCRIPTION (provided by applicant): New therapies are needed for the treatment of chronic obstructive pulmonary disease (COPD), which accounts for over $40 billion in annual healthcare costs and recently surpassed stroke as the 3rd leading cause of death in the U.S. Like cystic fibrosis (CF), COPD is characterized by small airway mucus obstruction that is associated with accelerated loss of lung function and excess mortality. Cigarette smoke exhibits a variety of deleterious effects on airway epithelial function in vitro and in vivo and our preliminary data suggests it also causes a significant reduction in CFTR activity that leads to a pronounced decrement in mucociliary transport. Furthermore, CFTR dysfunction is independently associated with chronic bronchitis and dyspnea, can persist despite smoking cessation, and can be reversed by the CFTR potentiator ivacaftor (Kalydeco, formerly VX- 770) in vitro by activating wild-type CFTR, resulting in a robust increase in mucociliary transport. Combined with unprecedented clinical improvement via augmented mucociliary clearance observed in CF patients with a responsive CFTR mutation treated with ivacaftor, these data indicate that CFTR represents a viable therapeutic target to address mucus stasis in COPD patients with chronic bronchitis (potentially representing over 8 million patients in the U.S. alone). In this project, we will investigate the hypothesis that ivacaftor can augment CFTR activity in individuals with COPD who exhibit chronic bronchitis. Though our preliminary data are compelling, questions regarding the most informative and responsive endpoints and dose selection mandate the studies outlined in this application. To address this, we have designed an innovative Phase 2, Randomized, Double-blind, Placebo Controlled Pilot Trial to Determine the Safety and Efficacy of Ivacaftor (VX-770) for the Treatment of Chronic Obstructive Pulmonary Disease (The Pilot TOPIC study), and will address a number of key questions to the field of COPD and airway epithelial biology using the latest assays and clinical methods for assessing CFTR activity, epithelial function, mucociliary clearance, and clinical outcomes. The TOPIC study will test whether MCC can be augmented in COPD patients with chronic bronchitis, ameliorating human disease even in the absence of congenital mutations in the CFTR gene. Moreover, the trial will provide an initial proof of concept evaluating the efficacy of CFTR potentiators in COPD while also exploring dose ranging, providing the necessary information needed to design subsequent studies, including the most informative biomarkers and outcome measures. If successful, the results could establish a novel treatment paradigm to address mucus dysfunction in COPD, an important cause of morbidity that is independently associated with mortality and disease progression.