Chapter Twenty-Four – Case History: Kalydeco® (VX-770, Ivacaftor), a CFTR Potentiator for the Treatment of Patients with Cystic Fibrosis and the G551D-CFTR Mutation

Abstract Cystic fibrosis (CF) is caused by mutations in the CFTR gene of an epithelial ion channel, the CF transmembrane conductance regulator (CFTR). We initiated efforts to discover potentiators of mutated CFTR. Potentiators are small molecules that increase the flow of ions through activated CFTR in the cell membrane. In-house HTS campaigns led to the identification of multiple hits. Extensive medicinal chemistry efforts driven by phenotypic assays led to the discovery of VX-770 (ivacaftor). VX-770 was found to be a potent, selective, orally bioavailable potentiator of G551D -CFTR, displaying excellent pharmacokinetic and safety profiles in rodents and nonrodents. Due to poor aqueous solubility, extensive formulation efforts were required and resulted in a spray-dried dispersion of VX-770 suitable for clinical development. After successful clinical trials, ivacaftor was approved by the FDA in 2012 for the treatment of people with CF who have a G551D mutation in the CFTR gene.