VX-659 is the third next-generation corrector being developed by Vertex Phamaceuticals. Preclinical results of the triple combination of VX-659 with tezacaftor (VX-661) and ivacaftor (Kalydeco) have already shown greater effectiveness and potency in restoring the cystic fibrosis transmembrane (CFTR) function.

How VX-659/tezacaftor/ivacaftor works

CFTR proteins serve as a channel to allow the transport of water and charged ions such as chloride in and out of cells. The transport of chloride is linked to the production of thin mucus that protects and lubricates internal organs like the lungs, body systems (like the reproductive system), or tissues.

Defective CFTR proteins are created when a mutation occurs in the gene that encodes this protein. The most common mutation that affects people with cystic fibrosis (CF) is the F508del mutation, which causes the protein to misfold. Other mutations, such as G551D – known as the “gating” mutation – affects the opening of this protein. The overall result is the production of thick mucus that accumulates in vital organs.

Both VX-659 and tezacaftor (VX-661) are CFTR protein correctors, and ivacaftor (Kalydeco) is a potentiator of this protein. While the mechanism of action of the first two is to move the defective CFTR protein to the correct place on the cell’s surface, ivacaftor aids in the opening of this protein. In this way, the transport of chloride and sodium (salt) across cell membranes is enhanced and thin mucus, which lubricates and protects internal organs and body systems, is produced.

History of VX-659/tezacaftor/ivacaftor

In October 2016, the first preclinical results of the triple combination VX-659/tezacaftor/ivacaftor were announced. The tests, performed on human bronchial epithelial (HBE) cells with different CFTR mutations (including two copies of the F508del mutation and one copy of the F508del mutation and another mutation known to affect the CFTR function) showed that the VX-659/tezacaftor/ivacaftor triple combination has a higher maximal efficacy (as measured by percentage of normal chloride transport) and potency when compared to other next-generation correctors (VX-152 and VX-440) in triple combinations.

Next steps for VX-659/tezacaftor/ivacaftor

A Phase 1 study of VX-659 is not yet open, but the clinical program is expected to begin soon, Vertex announced. According to Vertex, the Phase 1 study expects to enroll healthy volunteers and people with CF with one copy of the F508del mutation and one copy of another mutation known to affect CFTR function. In the first case, single and multiple ascending doses of VX-659 and the triple combination doses will be evaluated.

In the second case, CF patients will receive either the triple combination or a placebo. The results of this study will be the basis of a Phase 2 study, which, according to Vertex, is expected to start in 2017.

The company is also working in on its fourth next-generation correctors. A clinical trial program is expected to start in 2017.

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