Cystic Fibrosis (CF) is an autosomal recessive disorder affecting ~70,000 patients worldwide. CF is caused by defects in the cystic fibrosis conductance regulator (CFTR) protein that result from mutations in the CFTR gene. Defects in the CFTR protein lead to reduced chloride transport resulting in thick, sticky mucus that causes abnormalities in multiple organs. In the lungs, this excess mucus can lead to progressive loss of lung function and premature death. Currently, over 1900 CFTR mutations are known. The G551D mutation is a gating mutation that is present in 4-5% of CF patients. High throughput screening was used to identify pharmacological agents with the ability to modulate CFTR protein activity for improved chloride transport. One of the scaffolds identified in the screen was characterized as appropriate for further exploration; extensive medicinal chemistry and formulation efforts resulted in the identification and development of ivacaftor (VX-770) for clinical evaluation. Clinical studies in patients aged 6 years and older with CF and the G551D mutation demonstrated that treatment with ivacaftor led to significant improvements in lung function and other clinical endpoints. Ivacaftor is now approved for treatment of CF patients aged 6 years and older who have the G551Dmutation.

Discovery of VX-770 (Ivacaftor), a CFTR potentiator for the treatment of cystic fibrosis in G551D patients

247th National Meeting (2014)

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