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



 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.