Phase 2 study of VX-770 in Cystic Fibrosis Subjectswith G551D

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DESCRIPTION (provided by applicant): This project is a Phase 2 study assessing the safety and tolerability, pharmacokinetics, and pharmacodynamics of VX-770 in cystic fibrosis subjects. VX-770, a small molecule discovered by Vertex Pharmaceuticals Incorporated, is being developed for treatment of cystic fibrosis (CF), one of the most common lethal inherited disorders in Caucasian populations that affects approximately 30,000 children and adults in the United States. Despite adjunctive treatments with nutritional supplements, antibiotics, and mucolytics, the median predicted age of survival for a person with CF is in the mid-30s. Vertex has received FDA fast track and orphan drug designation. The intention of this research is to advance the development of VX-770 for the treatment of patients with cystic fibrosis. CF is caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. VX-770 has been shown to increase chloride ion transport through defective CFTR chloride ion channels in vitro in multiple cellular systems, including human bronchial epithelial (HBE) cells from CF donor airways. Two completed clinical studies with healthy subjects and subjects with CF demonstrated that VX-770 reaches plasma levels that modeling suggests could be clinically relevant. These studies also demonstrated that VX-770 was also generally well tolerated with only one significant adverse event, which was the occurrence of a rash. The present Phase 2 study is entitled "A Phase 2a, Randomized, Double-Blind, Placebo- Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects with Genotype G551D." Primary endpoints will be safety and tolerability. Secondary endpoints will be nasal potential difference (NPD), sweat chloride, forced expiratory volume in 1 second (FEV1), and pharmacokinetic parameters. These parameters will assess the clinical and functional effects of VX-770 in CF subjects characterized by Class III, IV and V CFTR mutations. Based on nonclinical data, CF patients with these defects are the most likely to respond to VX-770's unique mechanism of action. By increasing CFTR channel chloride conductance in bronchiolar epithelia, VX-770 may help restore properties of airway secretions and decrease cycles of mucus plugging, infection and inflammation. These effects may help preserve pulmonary function, decrease morbidity associated with progressive lung impairment/damage, and prolong survival in CF patients.