Vertex Pharmaceuticals developed the triple-combination therapy, which was approved by the U.S. Food and Drug Administration (FDA) in October 2019 to treat CF patients, ages 12 and older, with at least one F508del mutation. The F508del mutation is the most common CF-causing genetic defect, seen in about 90% of all people with cystic fibrosis.
What is CF?
CF is a rare genetic disease caused by mutations in the CFTR gene. This gene provides instructions for cells to make the CFTR protein, which is a transporter protein that controls the movement of charged ions across cell membranes.
Mutations in CFTR mean that salts cannot cross cell membranes normally. This leads to the build-up of thick, sticky mucus in different tissues and organs, especially the lungs and the digestive tract. In the lungs, this mucus can interfere with breathing, and make patients more susceptible to respiratory infections.
The F508del mutation is the most common CF-causing mutation. It results in a premature stop signal in the genetic code, causing cells to make a truncated or shorter-than-normal CFTR protein. The cells cannot shuttle this truncated protein to the surface as efficiently as normal CFTR, resulting in abnormal ion transport.
How does Trikafta work?
Trikafta is a CFTR modulator. It helps defective CFTR proteins work more effectively. Elexacaftor and tezacaftor work as correctors. They bind to the faulty CFTR protein and help it fold correctly. This way, cells can shuttle more of it to the membrane instead of degrading it. Ivacaftor (also marketed independently as Kalydeco) is a potentiator: it binds to the CFTR protein and holds the channel open so that more salt can pass through it.
With this combination of all three therapies, more CFTR protein reaches the cell membrane, and these proteins are more active and functional.
Trikafta in clinical trials
Before Trikafta’s FDA approval, researchers had already assessed two components of the therapy in CF patients. The two components were approved by the FDA either as a monotherapy or as a dual combination therapy. Kalydeco was approved in 2012, while Orkambi — a combination of lumacaftor and ivacaftor — received approved in 2015. Symdeko, a combination of tezacaftor and ivacaftor and called Symkevi in the E.U., was approved in 2018.
The FDA approved Trikafta based on the results of two Phase 3 clinical trials: AURORA F/MF (NCT03525444) and AURORA F/F (NCT03525548). The first trial enrolled 403 CF patients with one F508del mutation and one minimal function mutation (F/MF). It tested the effect of Trikafta against a placebo for 24 weeks.
The second trial included 107 patients with two F508del mutations (F/F) who received either Trikafta or Symdeko for four weeks. The primary outcome measure was the change in percent predicted forced expiratory volume in one second (ppFEV1, a measure of lung function). The secondary measure was the number of pulmonary exacerbations, or periods of worsening respiratory symptoms.
Data from both studies showed significant improvements in lung function in Trikafta-treated patients, with ppFEV1 improving by an average of 14.3% for this group in AURORA F/MF, and by 10% for those in AURORA F/F. Patients generally tolerated the treatment well.
Vertex announced positive results from another Phase 3 trial (NCT03691779) in September 2020. The trial investigated the pharmacokinetics (movement in the body), pharmacodynamics (effect on the body), safety, tolerability, and efficacy of Trikafta in children ages 6-11. The study recruited 66 children with either F/F or F/MF mutations for 24 weeks of treatment. Results showed that the children tolerated Trikafta well. They also showed improvements in ppFEV1, sweat chloride, and a number of other metrics. Using these results, Vertex plans to file a supplemental new drug application to the FDA to expand the age of approval for Trikafta.
In Europe, the Committee for Medicinal Products for Human Use issued a positive opinion in June 2020 for Kaftrio — Trikafta as it is known in Europe — to be used in combination with Kalydeco as a treatment for CF patients ages 12 and older who have either two F508del mutations or one F508del mutation and one minimal function mutation in the CFTR gene.
Last updated: Oct. 2, 2020
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