VX-152/tezacaftor/ivacaftor for Cystic Fibrosis

VX-152 is a next-generation corrector being developed by Vertex Phamaceuticals. The clinical program, which aims to study the triple combination of VX-152 with tezacaftor (VX-661) and ivacaftor, is currently recruiting people with cystic fibrosis (CF) with at least one copy of the F508del mutation — the most common mutation in this disease.

How VX-152/tezacaftor/ivacaftor works

The transport of water and charged ions (such as chloride) across cell membranes is regulated through the cystic fibrosis transmembrane (CFTR) protein, resulting in the formation of thin mucus, necessary to protect and lubricate internal organs such as the lungs and pancreas, entire body systems (reproductive, for example), or tissues.

Sometimes a mutation such as F508del occurs in the gene that encodes the CFTR protein. This causes the protein to misfold, resulting in a functional deficiency, which affects the chloride ion flux. Instead of thin mucus, sticky, thick mucus is produced and accumulates in vital organs and body systems.

Both VX-152 and tezacaftor are correctors of the cystic fibrosis transmembrane (CFTR) protein, while ivacaftor is a potentiator of that protein. This means that the correctors move the CFTR protein to the correct position on the cell surface, and ivacaftor works by facilitating the opening of the CFTR channel. In this way, the movement of charged ions (chloride or sodium) across cells is not compromised.

The triple combination of these drugs has the potential to benefit a broad range of people with CF with two copies of the F508del mutation (homozygous) and with one copy of F508del mutation and one copy of another mutation that affects CFTR function (heterozygous).

History of VX-152/tezacaftor/ivacaftor

Preclinical tests of the triple combination of VX-152/tezacaftor/ivacaftor were made on human bronchial epithelial (HBE) cells. Some of these cells were homozygous (when a person has two of the same form of a given gene) of the F508del mutation and others were heterozygous (having one each of two different gene forms).

The results of the triple combination showed an increase in the chloride transport, as well as in cilia beat frequency, when compared to the lumacaftor/ivacaftor combination, suggesting an improvement in the CFTR function.

According to Vertex, Phase 1 studies enrolled 100 healthy volunteers. The clinical program aimed to evaluate escalating doses of VX-152 alone and in triple combination with tezacaftor (VX-661) and ivacaftor for 14 days in these participants.

The Phase 2 study (NCT02951195) of VX-152/tezacaftor/ivacaftor started in November 2016 and is currently recruiting CF participants homozygous and heterozygous for the F508del mutation. This clinical program aims to assess the safety and tolerability of the triple combination and expects to enroll 60 participants at several sites in the U.S.

The participants will be randomized with either the triple drug combination or a placebo. The study consists of two parts: one that enrolls CF participants heterozygous for the F508del mutation and the other enrolling CF patients homozygous for the F508del mutation. Other outcomes, such as change in sweat chloride concentration, are expected to be measured. More information is available by visiting the clinical trial website here.

Vertex has submitted an Investigational New Drug application for the VX-152 triple combination regimen to the U.S. Food and Drug Administration (FDA).

Next steps for VX-152/tezacaftor/ivacaftor

Data from a Phase 2 trial of the triple combination of VX-152/tezacaftor/ivacaftor is expected in the second half of 2017. Vertex Phamaceuticals anticipates that these results will support a Phase 2b study or perhaps a registrational program of the triple therapy.

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