Cystic Fibrosis Transmembrane Conductance Regulator–Modifying Medications: The Future of Cystic Fibrosis Treatment

OBJECTIVE: To review and evaluate cystic fibrosis transmembrane conductance regulator (CFTR) modulators for the treatment of cystic fibrosis (CF). DATA SOURCES: Literature was accessed through MEDLINE (1977-January 2012), the Cochrane Library, and International Pharmaceutical Abstracts (1977-March 2012). Search terms included ivacaftor, VX-770, VX-809, ataluren, PTC 124, CFTR modulator, and cystic fibrosis. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated for inclusion. Clinical trials and relevant review articles were evaluated for each CFTR modulator. DATA SYNTHESIS: CF is caused by a mutation in the gene that encodes for the CFTR protein; mutations can be separated into 5 different classes. Ivacaftor is a new CFTR potentiator that helps the CFTR channel open properly in patients with the CFTR mutation, G551D. Patients in one study had significant decreases in sweat chloride values and increases in pulmonary function tests. Ivacaftor was approved by the Food and Drug Administration (FDA) to be taken orally at a dose of 150 mg twice a day in G551D CF patients older than 6 years. Additional studies are investigating the use of ivacaftor in other gating mutations and in younger patients. VX-809 is a CFTR corrector that modulates the folding and trafficking of CFTR. VX-809 was originally studied alone in patients with F508del mutation but is now being used in combination with ivacaftor in Phase 2 studies. Ataluren allows the read through of premature stop codons, and studies in patients with CF with nonsense mutations show an increase in chloride transportation. Ataluren requires 3 times a day dosing and is currently in a Phase 3 placebo-controlled study. CONCLUSIONS: Three new agents, ivacaftor, VX-809, and ataluren, target the basic defects in CFTR production. Ivacaftor was recently FDA approved, while the other 2 agents are still in clinical trials. Patients with CF will benefit from personalized medicine based on their specific genotype.