VX-445 is an experimental treatment for cystic fibrosis being developed by Vertex Pharmaceuticals. It is designed to treat the most common form of cystic fibrosis, caused by a mutation called F508del, as part of a triple therapy with tezacaftor (VX-661) and Kalydeco (ivacaftor), two other cystic fibrosis treatments.

How VX-455 works

Cystic fibrosis is a rare genetic disease caused by mutations in the CFTR gene, which cause the CFTR protein to be made incorrectly or not at all. The CFTR protein maintains the salt and fluid balance in cells. The most common cystic fibrosis-causing mutation is the F508del mutation, resulting in the production of a misfolded CFTR protein, which is degraded before it can reach the cell surface. Without CFTR, the mucus covering the cells becomes thick and viscous. This makes breathing difficult and increases the risk of infections and lung damage.

VX-455 and tezacaftor increase the amount of mature protein that reaches the cell surface by targeting the processing defect that causes the faulty protein to be degraded. Ivacaftor is designed to increase the function of the protein once it reaches the cell surface. The combination of the three treatments should improve the flow of salt and water into and out of the cells.

VX-455 in clinical trials

The triple combination therapy of VX-455, tezacaftor, and Kalydeco has been tested in Phase 1 and 2 clinical trials. Improvements were observed in lung function measured by forced expiratory volume in one second (FEV1), which measures the total amount of air exhaled in one second, and sweat chloride content, a measure of disease severity.

A Phase 3 clinical trial (NCT03525444) is currently recruiting 360 cystic fibrosis patients at 35 locations across the U.S. The study will evaluate the effectiveness of VX-445 in combination with tezacaftor and Kalydeco in cystic fibrosis patients who have one copy of F508del and a minimally functional CFTR protein.

Patients will either receive a placebo or 200 mg of VX-445, 100 mg of tezacaftor, and 150 mg of Kalydeco as a single tablet in the morning, plus 150 mg of just Kalydeco in the evening, for 24 weeks. They will be evaluated using FEV1, sweat chloride content, and the Cystic Fibrosis Questionnaire Revised (CFQ-R), which measures the impact of the disease on overall health, daily life, perceived well-being, and symptoms.

There are two additional Phase 3 clinical trials not yet recruiting participants. Patients in these studies will also be evaluated using FEV1, sweat chloride content, and CFQ-R before and throughout the study.

The first of these trials (NCT03525548), which is randomized, aims to recruit 100 cystic fibrosis patients who have two copies of the F508del mutation, and will evaluate the effectiveness of VX-445 in combination with tezacaftor and Kalydeco for 16 weeks. Fifty patients will receive 200 mg of VX-445, 100 mg of tezacaftor, and 150 mg of Kalydeco as tablets in the morning, and 150 mg of Kalydeco as a tablet in the evening. The remaining 50 patients will receive 100 mg of tezacaftor and 150 mg of Kalydeco in the morning, and 150 mg of Kalydeco in the evening, but no VX-445.

The second Phase 3 trial (NCT03525574) aims to recruit 460 cystic fibrosis patients who have one or two copies of the F508del mutation, and will evaluate the long-term safety and tolerability of VX-445 in combination with tezacaftor and Kalydeco for up to 96 weeks. In the open-label trial, patients will receive 200 mg of VX-445, 100 mg of tezacaftor, and 150 mg of Kalydeco as a tablet in the morning, and 150 mg of Kalydeco as a tablet in the evening.

Both trials are expected to begin recruiting participants later in 2018. The study locations have not yet been announced.

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