|References on VX-809:
1 . Kim Chiaw P, Eckford PD, Bear CE.Insights into the mechanisms underlying CFTR channel activity, the molecular basis for cystic fibrosis and strategies for therapy.Essays Biochem. 2011 Sep 7;50(1):233-48.
Mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) cause CF (cystic fibrosis), a fatal genetic disease commonly leading to airway obstruction with recurrent airway inflammation and infection. Pulmonary obstruction in CF has been linked to the loss of CFTR function as a regulated Cl- channel on the lumen-facing membrane of the epithelium lining the airways. We have learned much about the molecular basis for nucleotide- and phosphorylation-dependent regulation of channel activity of the normal (wild-type) version of the CFTR protein through electrophysiological studies. The major CF-causing mutation, F508del-CFTR, causes the protein to misfold and be retained in the ER (endoplasmic reticulum). Importantly, recent studies in cell culture have shown that retention in the ER can be 'corrected' through the application of certain small-molecule modulators and, once at the surface, the altered channel function of the major mutant can be 'potentiated', pharmacologically. Importantly, two such small molecules, a 'corrector' (VX-809) and a 'potentiator' (VX-770) compound are undergoing clinical trial for the treatment of CF. In this chapter, we describe recent discoveries regarding the wild-type CFTR and F508del-CFTR protein, in the context of molecular models based on X-ray structures of prokaryotic ABC (ATP-binding cassette) proteins. Finally, we discuss the promise of small-molecule modulators to probe the relationship between structure and function in the wild-type protein, the molecular defects caused by the most common mutation and the structural changes required to correct these defects.
2 . Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA.Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809.Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18843-8. Epub 2011 Oct 5.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC(50), 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.
3 . Lubamba B, Dhooghe B, Noel S, Leal T.Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy.Clin Biochem. 2012 Jun 12.
Cystic fibrosis is the most common life-threatening recessively inherited disease in Caucasians. Due to early provision of care in specialized reference centers and more comprehensive care, survival has improved over time. Despite great advances in supportive care and in our understanding of its pathophysiology, there is still no cure for the disease. Therapeutic strategies aimed at rescuing the abnormal protein are either being sought after or under investigation. This review highlights salient insights into pathophysiology and candidate molecules suitable for CFTR pharmacotherapy. Clinical trials using Ataluren, VX-809 and ivacaftor have provided encouraging data. Preclinical data with inhibitors of phosphodiesterase type 5, such as sildenafil and analogs, have highlighted their potential for CFTR pharmacotherapy. Because sildenafil and analogs are in clinical use for other clinical applications, research on this class of drugs might speed up the development of new therapies for CF.
4 . Pettit RS.Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment.Ann Pharmacother. 2012 Jul;46(7-8):1065-75. Epub 2012 Jun 26.
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.
5 . Clancy JP et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax doi:10.1136
Background VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTRin vitro. Methods A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. Results The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). ...