Background:

VX-809 is a CFTR corrector that partially restores the function of F508del-CFTR. In Fischer rat thyroid (FRT) cells, it increases F508del-CFTR maturation at EC50 of 0.1 μM, and elevates F508del-CFTR–mediated chloride transport at EC50 of 0.5 μM [1]. It has no effect of other ion channels (hERG), transporter (P-gp) and disease-causing mislocalized proteins (α1-antitrypsin Z mutant) [1]. VX-809 stabilizes N-terminal fragment of CFTR that contain MSD1 by altering its protein conformation [2, 3].

Homozygous F508del-CFTR is the most common mutation in cystic fibrosis (CF) patients, accounting for 66–70% of CF cases worldwide. In cultured human bronchial epithelial cells that are homozygous for F508del, VX-809 restored the CFTR function and improved chloride and fluid Transport [1]. The combination of CFTR potentiators and VX-809 further improved the function of F508del-CFTR [4].

VX-809 has been tested in several clinical trials. Although it had minimal benefit to F508del-CFTR homozygous patients as a monotherapy [4], the result of Phase 2 study of VX-809 and KALYDECO combination showed significant improvements in lung function in CF patients with homozygous F508del-CFTR [5]. VX-809 is currently under investigation in two phase 3 trials.

参考文献:
[1]Van Goor F, Hadida S, Grootenhuis PD et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 2011; 108: 18843-18848.[2] Ren HY, Grove DE, De La Rosa O et al. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell 2013; 24: 3016-3024.[3]Loo TW, Bartlett MC, Clarke DM. Corrector VX-809 stabilizes the first transmembrane domain of CFTR. Biochem Pharmacol 2013; 86: 612-619.[4]Clancy JP, Rowe SM, Accurso FJ 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 2012; 67: 12-18.[5]http://investors.vrtx.com/releasedetail.cfm?releaseid=687394