Called a “next-generation” corrector, it is designed to treat the most common form of cystic fibrosis, caused by the so-called F508del mutation, as part of triple therapy with tezacaftor (VX-661) and Kalydeco (ivacaftor), two other Vertex treatments for cystic fibrosis.
How Elexacaftor works
Cystic fibrosis is a rare genetic disease caused by mutations in the CFTR gene, which leads to the CFTR protein to be made incorrectly or not at all. The CFTR protein maintains the salt and fluid balance inside 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. In the lungs, this makes breathing difficult and increases the risk of infections and organ damage.
Elexacaftor and tezacaftor, both correctors, 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, a potentiator, is designed to increase the function of the protein once it reaches the cell surface. The combination of the three should improve the flow of salt and water into and out of cells.
Elexacaftor in clinical trials
The triple combination therapy of elexacaftor, tezacaftor, and ivacaftor 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 randomized and placebo-controlled Phase 3 clinical trial (NCT03525444) evaluated the effectiveness of elexacaftor in combination with tezacaftor and ivacaftor in 403 cystic fibrosis 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 just 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 cystic fibrosis 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 but elexacaftor.
Some cystic fibrosis patients with two F508del mutations do not benefit fully from current Vertex treatments, 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 endpoint or 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 endpoints, including a lower annual rate of pulmonary exacerbations, and reduced levels of chloride in patients’ sweat. The treatment was generally well-tolerated.
Based on these findings, Vertex submitted an application to the U.S. Food and Drug Administration (FDA) in July 2019, asking for priority approval of this new combination therapy.
A separate global and open-label Phase 3 trial (NCT03525574) is looking at 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 cystic fibrosis patients with one or two copies of the F508del mutation. All enrolled had taken part in a previous study of this combination, either in a treatment or placebo group. In the open-label trial, all are given treatment. The trial is expected to finish in July 2021.
The new drug application that Vertex submitted to the FDA in July was given with a request for priority review, meaning that the agency’s decision could come sometime in March 2020 rather than one year later.
Triple combinations are being developed to treat the 40% of cystic fibrosis patients whose underlying mutations do not respond or respond fully to other Vertex treatments developed for this disease.
Last updated: July 23, 2019
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