The Food and Drug Administration (FDA) has approved Trikafta (elexacaftor/tezacaftor/ivacaftor; Vertex) for the treatment of patients aged 12 years and older with cystic fibrosis (CF) who have ≥1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Trikafta is a fixed-dose combination containing elexacaftor 100mg, tezacaftor 50mg, and ivacaftor 75mg that is co-packaged with ivacaftor 150mg. 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 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.

The approval was based on data from two phase 3 trials (Trials 1 and 2) that assessed the efficacy of Trikafta in patients aged ≥12 years with CF. Trial 1 was a 24-week, randomized, double-blind, placebo-controlled trial that included 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. Trial 2 was a 4-week, randomized, double-blind, active-controlled trial that compared Trikafta with  tezacaftor/ivacaftor in 107 patients who had 2 identical F508del mutations. 

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Results from Trials 1 and 2 at week 4 demonstrated Trikafta significantly improved the mean absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) by 13.8 percentage points (95% CI: 12.1, 15.4; P <.0001) and 10 percentage points (95% CI: 7.4, 12.6; P <.0001), respectively (primary end point). Moreover, Trial 1 showed a mean absolute change from baseline in ppFEV1 at week 24 of 14.3 percentage points (95% CI: 12.7, 15.8; P <.0001).

Statistically significant improvements were also observed for key secondary end points (rate of pulmonary exacerbations, absolute change from baseline in sweat chloride, BMI, and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain score) in both trials.

With regard to safety, the most common adverse reactions reported were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, increased liver enzymes, nasal congestion, increased blood creatinine phosphokinase, rhinorrhea, influenza, sinusitis, and increased blood bilirubin.

Commenting on the approval FDA Commissioner Ned Sharpless, MD said, “At the FDA, we’re consistently looking for ways to help speed the development of new therapies for complex diseases, while maintaining our high standards of review. Today’s landmark approval is a testament to these efforts, making a novel treatment available to most cystic fibrosis patients, including adolescents, who previously had no options and giving others in the cystic fibrosis community access to an additional effective therapy.” 

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The FDA previously granted Priority Review, Fast Track, Breakthrough Therapy, and Orphan Drug designations to Trikafta. Vertex is currently assessing Trikafta in CF patients aged 6 to 11 with ≥1 F508del mutation in an ongoing phase 3 study and plans to conduct further studies in children less than 6 years of age.

Trikafta is supplied as 4 wallets, with each wallet containing 14 tablets of elexacaftor 100mg, tezacaftor 50mg, ivacaftor 75mg with 7 tablets of ivacaftor 150mg in an 84-count tablet carton. The treatment is expected to be available through specialty pharmacies in the coming weeks.

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This article originally appeared on MPR