VX-440 is a next-generation corrector being developed by Vertex Phamaceuticals. When combined to another CFTR corrector (tezacaftor, VX-661), VX-440 has the potential to enhance the amount of CFTR protein at the cell’s surface. The clinical program aims to study the triple combination of VX-440 with tezacaftor (VX-661) and ivacaftor (Kalydeco).

How VX-440/tezacaftor/ivacaftor works

The cystic fibrosis transmembrane (CFTR) protein plays an import role in the transport of water and charged ions (such as chloride) across cell membranes, which results in the formation of thin mucus necessary to protect and lubricate internal organs like the lungs and pancreas, entire body systems (such as the reproductive system) or tissues.

Defective CFTR proteins are produced when a mutation like F508del occurs in the gene that encodes that protein. This results in a functional deficiency which affects the chloride ion flux. Instead of thin mucus, a thick mucus is produced and accumulates in vital organs and body systems.

The mechanism of action of VX-440/tezacaftor/ivacaftor is similar to that of VX-152/tezacaftor/ivacfator. Both VX-440 and tezacaftor are CFTR correctors, whose purpose is to move CFTR protein to the correct place on the surface of cells. Once there, ivacaftor works by opening the CFTR channel, facilitating the transport of chloride and sodium (salt) in and out of cells.

The triple combination of the next-generation corrector VX-440 with tezacaftor (VX-661) and ivacaftor has the potential to benefit people with CF who are homozygous and heterozygous for the F508del mutation.

History of VX-440/tezacaftor/ivacaftor

In October 2015, preclinical results of the triple combination VX-440/tezacaftor/ivacaftor were announced. The studies involved two sets of human bronchial epithelial (HBE) cells, one with two copies of the F508del mutation (homozygous) and the other with one copy of the F508del mutation and another mutation known to affect CFTR function (heterozygous).

When compared to the lumacaftor/ivacaftor combination, VX-440 as part of a triple combination with tezacaftor (VX-661) and ivacaftor showed a greater chloride transport. The same was observed with the other next-generation corrector, VX-152, suggesting that the triple combination has the potential to improve CFTR function in HBE cells homozygous and heterozygous for F508del mutation.

Phase 1 studies enrolled 100 healthy volunteers. They aimed to evaluate escalating doses of VX-440 alone and in a triple combination with tezacaftor (VX-661) and ivacaftor for 14 days. The safety and drug properties of VX-440 were confirmed.

There is currently a Phase 2 (NCT02951182) study recruiting people with CF homozygous and heterozygous for the F508del mutation. The study aims to assess the safety and tolerability of VX-440 and the absolute change in percent predicted force expiratory volume in one second (ppFEV1). The participants will receive either VX-440 in dual or triple combination with tezacaftor and/or ivacaftor, or a placebo.

The study is divided into three parts: Part A will enroll people with CF heterozygous for the F508del mutation who receive the triple combination or a placebo for four weeks. This part includes two cohorts in which different VX-440 doses are evaluated. The study is also designed to confirm whether the safety and drug property profiles of VX-440 observed in healthy volunteers are similar in people with CF.

Part B will enroll people with CF homozygous for the F508del mutation, who will also receive the triple combination or a placebo for four weeks.

Part C will include people with CF heterozygous for the F508del mutation. The triple combination dose will be assessed for 12 weeks.

Data from Parts A and B are expected in the second half of 2017. More information is available by visiting NCT02951182.

Next steps for VX-440/tezacaftor/ivacaftor

Part C of this study will begin only after data from Part A and Part B are collected. This is expected to run in parallel with a potential Phase 3 study.

The application of VX-440 as an Investigational New Drug has been submitted to the U.S. Food and Drug Administration (FDA), according to Vertex Pharmaceuticals.

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