Cystic Fibrosis Transmembrane Conductance Regulator–Modifying Medications

The Future of Cystic Fibrosis Treatment

Rebecca S Pettit


The Annals of Pharmacotherapy. 2012;46(7):1065-1075. 

In This Article

Abstract and Introduction


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.


Cystic fibrosis (CF) is the most common autosomal recessive genetic disease in the white population. CF occurs in 1 of every 3000 live births among whites;[1] patients with CF have an average life expectancy of 37 years.[2] The CF gene (CFTR) is located on chromosome 7 and was discovered in 1989.[3] Mutation in this gene causes a reduction or elimination of CF transmembrane conductance regulator (CFTR) protein production. This protein primarily functions as a chloride channel and is expressed on epithelial cells throughout the body.

CFTR dysfunction leads to multiorgan CF manifestations, including pulmonary disease, gastrointestinal abnormalities, hepatic dysfunction, pancreatic disease, and reproductive abnormalities. Typical CF treatment requires numerous chronic medications, including pancreatic enzymes, dornase alfa, hypertonic saline, albuterol, and inhaled antibiotics, to control symptoms.[4] All of these treatments help to ameliorate symptoms but do not address the basic defect of the disease, that is, CFTR dysfunction.

Three drugs—ivacaftor (Kalydeco [VX-770], Vertex Pharmaceuticals Inc.), VX-809 (Vertex Pharmaceuticals Inc.), and ataluren (PTC 124, PTC Therapeutics Inc.)—modulate CFTR function, thus influencing the basic CF defect. Another CFTR corrector, VX-661, was discovered, and recruitment for this study began in late 2011.[5] VX-661 is not reviewed in this article, given the lack of published data. This article reviews CFTR mutation classes and the 3 CFTR modulating drugs. Relevant articles were identified through MEDLINE (1977-March 2012), the Cochrane Library, and International Pharmaceutical Abstracts (1977-January 2012). Search terms included ivacaftor, VX-770, VX-809, ataluren, PTC124, CFTR modulator, and cystic fibrosis. Search results were reviewed for relevance, and selected article references were reviewed. Articles included were primary studies and, when appropriate, review articles addressing primary evaluative studies.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.