General Information

Trikafta is a combination of ivacaftor - a CFTR potentiator and tezacaftor and elexacaftor- both of which bind to different sites on the CFTR protein.

Trikafta is specifically indicated for the treatment of cystic fibrosis (CF) in the following patient populatins:

• patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
• patients who are 12 years and older with at least one of 177 newly-approved mutations that are responsive to Trikafta based on in vitro data
• patients ages 6 through 11 years who have at least one F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive to Trikafta based on in vitro data. 

Trikafta is supplied as a tablet for oral administration. The recommended dose is two tablets (each containing elexacaftor 100 mg, tezacaftor 50 mg and ivacaftor 75 mg) taken in the morning and one ivacaftor tablet (containing ivacaftor 150 mg) taken in the evening, approximately 12 hours apart. Trikafta tablets should be swallowed whole. Trikafta should be taken with fat-containing food. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats.
 
If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. 

If more than 6 hours have passed since: 1) the missed morning dose, the patient should take the missed dose as soon as possible and should not take the evening dose. The next scheduled morning dose should be taken at the usual time. 2) the missed evening dose, the patient should not take the missed dose. The next scheduled morning dose should be taken at the usual time.  Morning and evening doses should not be taken at the same time.

Clinical Results

The FDA approval of Trikafta was based on two trials. The first trial was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients who had an F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or tezacaftor/ivacaftor alone. The second trial was a four-week, randomized, double-blind, active-controlled trial in 107 patients who had two identical F508del mutations. In each trial, the primary analysis looked at increases in the percent predicted forced expiratory volume in one second, known as ppFEV1, which is an established marker of cystic fibrosis lung disease progression. Trikafta increased the ppFEV1 in both trials. In the first trial, it increased mean ppFEV1 13.8% from baseline compared to placebo. In the second trial, it increased mean ppFEV1 10% from baseline compared to tezacaftor/ivacaftor. In the first trial, treatment with Trikafta also resulted in improvements in sweat chloride, number of pulmonary exacerbations (worsening respiratory symptoms and lung function), and body mass index (weight-to-height ratio) compared to placebo.

Side Effects

Adverse effects associated with the use of Trikafta may include, but are not limited to, the following:

• headache
• upper respiratory tract infection
• abdominal pain
• diarrhea
• rash
• alanine aminotransferase increased
• nasal congestion
• blood creatine phosphokinase increased
• aspartate aminotransferase increased
• rhinorrhea
• rhinitis
• influenza
• sinusitis
• blood bilirubin increased

Mechanism of Action

Trikafta is a combination of ivacaftor, a CFTR potentiator, tezacaftor, and elexacaftor. Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.  The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of F508del-CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport.