Called a next-generation corrector, it is designed to treat the most common form of CF, caused by the so-called F508del mutation, as part of a triple therapy with tezacaftor (VX-661) and ivacaftor (marketed on its own as Kalydeco), two other Vertex treatments for CF.
What is cystic fibrosis?
CF is a rare genetic disease caused by mutations in the CFTR gene, resulting in the CFTR protein being made incorrectly or not at all. The CFTR protein maintains the salt and fluid balance inside cells. The most common CF-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. In the lungs, this makes breathing difficult and increases the risk of infections and organ damage.
How does elexacaftor work?
Elexacaftor is a CFTR corrector; it increases the amount of mature protein that reaches the cell surface by targeting the processing defect that causes the faulty protein to be degraded.
Elexacaftor in clinical trials
Elexacaftor has only been tested in clinical trials for CF as part of the triple-combination therapy together with tezacaftor and ivacaftor. In these 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 randomized and placebo-controlled Phase 3 trial (NCT03525444) evaluated the triple-combo therapy in 403 CF patients with one F508del and one minimal function mutation. As its name implies, minimal function mutations leave the CFTR protein barely functioning or unable to work at all.
Patients were given either a placebo or 200 mg of elexacaftor, 100 mg of tezacaftor, and 150 mg of ivacaftor as a single tablet in the morning, plus 150 mg of only ivacaftor in the evening, for 24 weeks. Efficacy was assessed 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 disease symptoms.
Another randomized Phase 3 study (NCT03525548) enrolled 107 CF patients with two F508del mutations who were treated with either elexacaftor or a placebo in combination with tezacaftor and ivacaftor for four weeks. Again, those treated received 200 mg of elexacaftor, 100 mg of tezacaftor, and 150 mg of ivacaftor as tablets in the morning, and 150 mg of ivacaftor as a tablet in the evening. The placebo group was given all treatments but elexacaftor.
Some CF patients with two F508del mutations do not benefit fully from current Vertex treatments such as the double combinations Orkambi (lumacaftor/ivacaftor) and Symdeko (tezacaftor/ivacaftor and ivacaftor).
Triple-combo-treated patients in both trials demonstrated significant improvements in lung function, as assessed by percent predicted forced expiratory volume in one second (ppFEV1), each study’s primary goal. ppFEV1 increased by an average of 14.3% in the 24-week trial, and by 10% in the four-week trial.
Data also showed improvements in secondary objectives, including a lower annual rate of pulmonary exacerbations, and reduced levels of chloride in patients’ sweat. The treatment was generally well tolerated.
A separate global, open-label Phase 3 trial (NCT03525574) is examining the long-term (96-week) safety and effectiveness of this oral triple combination — 200 mg of elexacaftor, 100 mg of tezacaftor, and 150 mg of ivacaftor in the morning and ivacaftor again at night — in more than 500 CF patients with one or two copies of the F508del mutation. All enrolled participants have taken part in a previous study of this combination, either in a treatment or placebo group. In the open-label trial, all participants receive the treatment. The trial is expected to finish in July 2021.
Last updated: Oct. 25, 2019
Cystic Fibrosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.