VX-661

VX-661, one of vertex derivatives, corrects F508del-CFTR trafficking and increases F508del-CFTR protein activity in vitro [1].

VX-661 treated alone or in combination with ivacaftor have shown to enhance F508del-CFTR trafficking to the cell surface. VX-661 has been at phase 2 study [1].

References:
[1] S. Donaldson, J. Pilewski, M. Griese, Q. Dong, P.-S. Lee, for the VX11–661-101 Study Group. WS7.3 VX-661, an investigational CFTR corrector, in combination with ivacaftor, a CFTR potentiator, in patients with CF and homozygous for the F508Del-CFTR mutation: Interim analysis. Journal of Cystic Fibrosis, Volume 12, Supplement 1, June 2013, Page S14

Novel picolinamide-based cystic fibrosis transmembrane regulator modulators: evaluation of WO2013038373, WO2013038376, WO2013038381, WO2013038386 and WO2013038390.[Pubmed:24392786]

Expert Opin Ther Pat. 2014 Jul;24(7):829-37.

Cystic fibrosis (CF) is a genetic disease caused by defects in the CF transmembrane regulator (CFTR) gene, which encodes an epithelial chloride channel. The most common mutation, Delta508CFTR, produces a protein that is misfolded and does not reach the cell membrane. The discovery that partial chloride channel function could be restored by exposure to exogenous chemical stimuli led to the search for selective CFTR modulators. Vertex has led the way in developing N-aryl-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide derivatives such as lumacaftor and VX-661, which correct trafficking of Delta508CFTR and partially restore chloride channel activity. Novartis had identified similar activity in a series of picolinamide derivatives such as 3-amino-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5,6-bis(trifluoromethyl )pyridine-2-carboxamide. A series of five filings from Novartis has expanded on the activity of compounds based on this scaffold and provided compounds with nanomolar potency in cellular assays.

Some gating potentiators, including VX-770, diminish DeltaF508-CFTR functional expression.[Pubmed:25101887]

Sci Transl Med. 2014 Jul 23;6(246):246ra97.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the DeltaF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous DeltaF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of DeltaF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface DeltaF508-CFTR density and function. VX-770-induced destabilization of DeltaF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of DeltaF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF.