Study of the Effect of VX-770 on Lung Clearance Index in Subjects With Cystic Fibrosis and the G551D Mutation

Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance
regulator (CFTR) gene. The encoded protein, CFTR, is an epithelial chloride ion channel
responsible for aiding in the regulation of salt and water absorption and secretion in
various tissues. Although the disease affects multiple organs, the leading cause of
mortality is the progressive loss of lung function. Obstruction of airways with thick
mucous, chronic bacterial infection of the airways, and inflammatory response are all
thought to play a role in causing lung damage. Through its function as a chloride channel,
CFTR is believed to be integral in epithelial ion and water transport and hence, maintaining
the normal hydration of lung secretions.

VX-770 is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms
of human CFTR. Based on in vitro studies and pharmacologic, pharmacokinetic (PK), and safety
profiles, VX-770 has been selected for clinical development as a possible treatment for
patients with CF.

Currently, limited objective measures are available to quantify lung function in CF patients
with mild lung disease. Lung clearance index (LCI) derived from inert gas multiple-breath
washout (MBW) testing hold considerable promise to evaluate early lung disease as studies
have detected abnormalities in a high percentage of CF patients with normal spirometry in
both infants and children.