Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta (US) and Kaftrio (Europe), is a
fixed-dose combination medication used with adults and children older than age 6 that have
cystic fibrosis with a
f508del mutation or other mutations.[1] Patients with cystic fibrosis have thicker mucus secretions due to genetic mutations in the
cystic fibrosis transmembrane conductance regulator (CFTR) protein which inhibits the transfer of chloride and sodium ions from cells. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of
ivacaftor, a chloride channel opener, and
elexacaftor and
tezacaftor, CFTR modulators.[1]
It is approved use in the United States for people aged 6 years of age or older with with the f508del mutation or 177 other cystic fibrosis mutations.[2] It is also approved for use in Canada, the European Union and Australia.[3][4][5]
Cystic fibrosis is an autosomal recessive genetic disorder of the CFTR protein which reduces chloride and sodium ion transport through the cell membrane, causing thicker than normal mucus secretions.[10][11] The CFTR protein is found in epithelial cells of the lung, liver, pancreas, digestive tract, and reproductive tracts.[12][13][14] CFTR has a role in the production of mucus, sweat, and digestive fluids.[15] The thickened mucus can lead to inflammation, respiratory infections, and clogged ducts.[16][17][18]
Pharmacology
Effects
A
phase III trial showed people treated with elexacaftor/tezacaftor/ivacaftor improved in
FEV1 at four weeks with sustained improvement at 24 weeks. Rate of pulmonary exacerbation was 63% lower and sweat chloride concentration was 41.8 mmol/L lower.[19][20][21] It's effectiveness is dependent on the type of CF mutations the patient has.[22]
Mechanism of Action
Elexacaftor/tezacaftor/ivacaftor is a tridrug treatment in which the medications work together to increase the transport of chloride and sodium ions, and reducing thick mucus production.[23]
CFTR Channel Potentiator
Ivacaftor is a selective small-molecule potentiator of the
CFTR protein that increases the protein's ability to open chloride channels.[24][25] Its effectiveness is highly dependent on the amount of CFTR protein at the cell surface and the responsiveness of the mutant CFTR protein.[26] Ivacaftor's primary target is to treat class III CFTR gating mutations like G551D as well as other less common mutations.[25] In the crystalline figure, you can see ivacaftor, shown as a gray ball and stick model on the bottom-right, bound to CFTR docked in a cleft formed by transmembrane helices at the protein-lipid interface.[27]
CFTR Correctors
Elexacaftor and
Tezacaftor act as CFTR correctors to repair F508del processing by binding to the CFTR protein to increase the availability of CFTR protein on the cell surface.[25] They work by modulating the position of the CFTR protein into the right position on the cell surface.[28]
The combination of increased CFTR protein in the correct position on the cell surface with ivacaftor's potentiation of chloride channel opening results in increased transport of chloride and thinned mucus secretions.[25]
Formulations
Trikafta utilizes a combination tablet containing 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of ivacaftor, and a separate tablet containing 150mg of ivacaftor.[29]
Recommended Dosage
The morning dose is two combination tablets containing elexacaftor 100 mg, tezacaftor 50 mg and ivacaftor 75 mg. The evening dose is one ivacaftor 150mg tablet.[30]
Elexacaftor/tezacaftor/ivacaftor is primarily metabolized by
CYP3A4/5. This medication should be taken with a high fat meal to improve absorption through the gut. [35] It is excreted as metabolites or unchanged mainly through feces and to a smaller extent urine. The mean effective half-life of elexacaftor, tezacaftor, and ivacaftor is 27.4 hours, 25.1 hours, and 15 hours, respectively. [31]
Research
Human Studies/Trials
Trial
Type
Primary Endpoint
Target age
Target Mutations
Results
References
Trial 1
A placebo-controlled trial in patients heterozygous for the F508del mutation and another specific mutation
• Absolute change in ppFEV1 from baseline at Week 4
People aged 12 years and older
• Heterozygous for the F508del mutation and one of ~200 other mutations in the CFTR gene that resulted in either: - No CFTR protein - A CFTR protein that lacks baseline activity and is not responsive to ivacaftor and tezacaftor/ivacaftor • ppFEV1 between 40% to 90% at screening
percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks
CFTR mutations that are responsive to elexacaftor/tezacaftor/ivacaftor were determined by an in-vitro study of Fischer Rat Thyroid (FRT) cells that expressed mutant CFTR. Elexacaftor/tezacaftor/ivacaftor showed effectiveness with mutations where the CFTR protein was being successfully delivered to the cell surface.[1]
Society & Culture
Legal Status
United States
The combination was approved for use in the United States in 2019 for people twelve years and older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population.[40] In December 2020, after an additional clinical trial was completed, and FDA approval was expanded for 177 other cystic fibrosis mutations.[2] FDA approval for children aged 6-11 was added in January 2021 after third clinical trial was completed.[41]
On March 30, 2021 health regulators in Australia approved trikafta for patients aged 12 years and older with at least one copy of the F508del mutation.[43]
Canada
In June of 2020,
Health Canada approved Trikafta for patients ages 12 and up.[44] In September 2021, the provinces
Alberta and
Saskatchewan announced they will join
Ontario in funding the medication. They will determine coverage on a case-by-case basis using a criteria that has not yet been announced.[45]
The list price of a year's treatment in the US is US$311,000.[48] However, a 2020 report by
Institute for Clinical and Economic Review found that the price has made the treatment not cost effective and that "an appropriate health-benefit price would range from $67,900–$85,500 per year".[49][50]
Spain
On November 19, 2021 the Spanish government approved the reimbursement of KAFTRIO (ivacaftor/tezacaftor/elexacaftor) for patients ages 12 and older with at least one copy of the F508del mutation.[51]
^Sharma S, Hanukoglu I (April 2019). "Mapping the sites of localization of epithelial sodium channel (ENaC) and CFTR in segments of the mammalian epididymis". Journal of Molecular Histology. 50 (2): 141–154.
doi:
10.1007/s10735-019-09813-3.
PMID30659401.
S2CID58026884.
^Sharma S, Hanukoglu A, Hanukoglu I (April 2018). "Localization of epithelial sodium channel (ENaC) and CFTR in the germinal epithelium of the testis, Sertoli cells, and spermatozoa". Journal of Molecular Histology. 49 (2): 195–208.
doi:
10.1007/s10735-018-9759-2.
PMID29453757.
S2CID3761720.
^Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A (March 2012). "Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways". Histochemistry and Cell Biology. 137 (3): 339–53.
doi:
10.1007/s00418-011-0904-1.
PMID22207244.
S2CID15178940.
^Clinical trial number NCT03525444 for "A Phase 3 Study of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)" at
ClinicalTrials.gov