Elexacaftor/tezacaftor/ivacaftor explained

Type:combo
Component1:Elexacaftor
Class1:Cystic fibrosis transmembrane conductance regulator (CFTR) corrector
Component2:Tezacaftor
Class2:CFTR corrector
Component3:Ivacaftor
Class3:Chloride channel opener
Tradename:Trikafta, Kaftrio
Dailymedid:Elexacaftor, tezacaftor, and ivacaftor
Pregnancy Au:B3
Routes Of Administration:By mouth
Atc Prefix:R07
Atc Suffix:AX32
Legal Au:S4
Legal Au Comment:[1] [2] [3]
Legal Ca:Rx-only
Legal Ca Comment:[4] [5] [6]
Legal Uk:POM
Legal Uk Comment:[7]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[8]
Cas Number:2398469-65-1
Kegg:D11700

Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta and Kaftrio, is a fixed-dose combination medication used to treat cystic fibrosis.[9] Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.

It is approved for use in the United States for people aged two years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene. It is also approved for use in Canada, the European Union, and Australia.[10]

Medical uses

The combination is indicated for the treatment of people aged two years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene.

Side effects

The most common side effects affecting more than 5% of patients are headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increase, nasal congestion, blood creatine phosphokinase increase, aspartate aminotransferase increase, rhinorrhea, rhinitis, influenza, sinusitis, and blood bilirubin increase.

Interactions

Concomitant use with CYP3A inducers is not recommended.[11] Dosage must be adjusted with moderate or strong CYP3A inhibitors.

Other drugs with the potential for interaction include warfarin, digoxin, statins, glyburide, nateglinide, and repaglinide.

Pharmacology

Cystic fibrosis and CFTR

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.[12] [13] The CFTR protein is found in epithelial cells of the lung, liver, pancreas, digestive tract, and reproductive tracts.[14] [15] [16] CFTR has a role in the production of mucus, sweat, and digestive fluids.[17] The thickened mucus can lead to inflammation, respiratory infections, and clogged ducts.[18] [19]

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 correct fluid shifts that are dysregulated in cystic fibrosis.[20] Its effectiveness is dependent on the type of CF mutations the patient has.[21]

CFTR channel potentiator

Ivacaftor is a selective small-molecule potentiator of the CFTR protein that increases the protein's ability to open chloride channels.[22] [23] Its effectiveness is highly dependent on the amount of CFTR protein at the cell surface and the responsiveness of the mutant CFTR protein.[24] Ivacaftor's primary target is to treat class III CFTR gating mutations like G551D as well as other less common mutations.[23] In the crystalline figure is shown ivacaftor, displayed 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.[25]

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.[23] They work by modulating the position of the CFTR protein into the right position on the cell surface. Elexacaftor binds at a different site than tezacaftor.[26]

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.

Pharmacokinetics

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. 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.

History

A phase III trial published in 2019 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.[27] [28]

Society and 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.[29] In December 2020, after an additional clinical trial was completed, and FDA approval was expanded for 177 other cystic fibrosis mutations.[30] FDA approval for children aged 6–11 was added in January 2021, after a third clinical trial was completed.[31] In 2023, approval was extended to children 2–5.[32]

The US Food and Drug Administration (FDA) granted the application priority review, in addition to fast track, breakthrough therapy, and orphan drug designations. The drug's manufacturer Vertex Pharmaceuticals will receive a rare pediatric disease priority review voucher for having developed this therapy.

Australia

In March 2021, health regulators in Australia approved the combination for people aged 12 years and older with at least one copy of the F508del mutation.[33] At the end of April 2022, it was placed on the Pharmaceutical Benefits Scheme, thus reducing the cost from tens of thousands of dollars a month, to tens of dollars a month.[34]

Canada

In June 2020, Health Canada approved the combination for people aged 12 years and older. 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 criteria that have not yet been announced.[35]

European Union

In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended approval of the combination for the treatment of cystic fibrosis.[36] [37] It was approved for medical use in the European Union in August 2020.[38]

Norway

In April 2022, approved the combination for treatment of cystic fibrosis.[39]

New Zealand

In February 2022, Pharmac recommended, with medium priority, funding for people aged 12 years and over.[40] In December 2022, Pharmac announced it had reached a provisional agreement with Vertex funding Trikafta starting on 1 April 2023 for patients aged six or above.[41] [42]

Economics

United States

The list price of a year's treatment in the US is (formerly).[43] 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".[44] [45]

Australia

Following the listing of the combination on the Pharmaceutical Benefits Scheme in 2022, the cost for people aged twelve years of age or older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator gene is $30.00 per month, or $7.30 for concession card holders.[46]

Germany

The initial list price in Germany for one year of therapy in 2020 was 295,000€, and in 2024 it was lowered to 207,000€. Vertex return on sales has been 36%.[47]

Ireland

In March 2023, Ireland's Health Service Executive approved funding for the provision of Kaftrio to people aged six and over with cystic fibrosis.[48] [49]

Spain

In November 2021, the Spanish government approved the reimbursement of the combination for people aged 12 years and older with at least one copy of the F508del mutation.[50]

Controversy

In addition to Trikafta's high list price, Vertex declines to make the combination available in developing countries and works to block generic alternatives. This has led to groups of patients in three countries, namely India, Ukraine and South Africa, to initiate legal and regulatory processes to compel their governments to allow the importation or local production of low-cost generic versions of Trikafta through compulsory licensing.[51] [52] In 2022, the estimated cost of manufacturing a year's supply of Trikafta was US$5,700.[53]

Research

Human studies/trials!Trial!Type!Primary endpoint!Target age!Target mutations!Results!References
Trial 1A placebo-controlled trial in patients heterozygous for the F508del mutation and another specific mutationAbsolute change in ppFEV1 from baseline at Week 4People 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% and 90% at screening
percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks[54] [55]
Trial 2A double-blind, active-controlled, phase 3 studyAbsolute change in ppFEV1 from baseline at Week 4People aged 12 years and olderHomozygous for the F508del mutationElexacaftor/tezacaftor/ivacaftor showed improvements in percent predicted forced expiratory volume (ppFEV1) over patients receiving tezacaftor/ivacaftor[56]
Trial 3Open label study with no placebo controlSafety, pharmacokinetics and efficacyChildren aged 6–11
  • Homozygous for the F508del mutation OR
  • 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
safety and pharmacokinetic profiles were generally consistent with those observed in older patients[57]
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.

Notes and References

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  2. Web site: 8 July 2021 . AusPAR: Elexacaftor/tezacaftor/ivacaftor and ivacaftor . 8 September 2021 . Therapeutic Goods Administration (TGA) . 9 September 2021 . https://web.archive.org/web/20210909050121/https://www.tga.gov.au/auspar/auspar-elexacaftortezacaftorivacaftor-and-ivacaftor . live .
  3. Web site: Trikafta (Vertex Pharmaceuticals Australia Pty LTD) | Therapeutic Goods Administration (TGA) . 18 March 2023 . 18 March 2023 . https://web.archive.org/web/20230318050006/https://www.tga.gov.au/resources/prescription-medicines-registrations/trikafta-vertex-pharmaceuticals-australia-pty-ltd-0 . live .
  4. Web site: 23 October 2014 . Summary Basis of Decision (SBD) for Trikafta . 29 May 2022 . Health Canada . 29 May 2022 . https://web.archive.org/web/20220529224105/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00553&lang=en . live .
  5. Web site: Regulatory Decision Summary for Trikafta . Drug and Health Products Portal . 16 October 2023 . 2 April 2024.
  6. Web site: Health product highlights 2021: Annexes of products approved in 2021 . . 3 August 2022 . 25 March 2024.
  7. Web site: 28 November 2022 . Kaftrio 37.5mg 25 mg 50 mg film-coated tablets - Summary of Product Characteristics (SmPC) . 28 November 2022 . (emc) . 28 November 2022 . https://web.archive.org/web/20221128235301/https://www.medicines.org.uk/emc/product/13216/smpc . live .
  8. Web site: Kaftrio Product information . 3 March 2023 . Union Register of medicinal products . 5 March 2023 . https://web.archive.org/web/20230305063540/https://ec.europa.eu/health/documents/community-register/html/h1468.htm . live .
  9. Web site: 29 January 2020 . Trikafta- elexacaftor, tezacaftor, and ivacaftor kit . 22 August 2020 . DailyMed . 21 July 2020 . https://web.archive.org/web/20200721105004/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f354423a-85c2-41c3-a9db-0f3aee135d8d . live .
  10. Web site: Health Canada Approves Trikafta for Eligible CF Patients, 12 and Up . 8 November 2021 . Wexler M . 22 June 2021 . 8 November 2021 . https://web.archive.org/web/20211108144655/https://cysticfibrosisnewstoday.com/2021/06/22/health-canada-approves-trikafta-patients-12-older-f508del-mutation/ . live .
  11. Web site: elexacaftor/tezacaftor/ivacaftor (Rx) . live . https://web.archive.org/web/20201028170854/https://reference.medscape.com/drug/trikafta-elexacaftor-tezacaftor-ivacaftor-4000016 . 28 October 2020 . 3 October 2021 . Medscape.
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  20. Web site: Tezacaftor . 24 November 2022 . PubChem . 7 April 2023 . https://web.archive.org/web/20230407041530/https://pubchem.ncbi.nlm.nih.gov/compound/46199646 . live .
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  22. Web site: Ivacaftor pathway, pharmacokinetics/pharmacodynamics . 9 December 2021 . PharmGKB . 9 December 2021 . https://web.archive.org/web/20211209011544/https://www.pharmgkb.org/pathway/PA166153178 . live .
  23. Zaher A, ElSaygh J, Elsori D, ElSaygh H, Sanni A . July 2021 . A Review of Trikafta: Triple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Therapy . Cureus . 13 . 7 . e16144 . 10.7759/cureus.16144 . free . 8266292 . 34268058.
  24. Web site: Ivacaftor . 7 November 2021 . PubChem . 7 November 2021 . https://web.archive.org/web/20211107202713/https://pubchem.ncbi.nlm.nih.gov/compound/16220172 . live .
  25. Liu F, Zhang Z, Levit A, Levring J, Touhara KK, Shoichet BK, Chen J . June 2019 . Structural identification of a hotspot on CFTR for potentiation . Science . 364 . 6446 . 1184–1188 . 2019Sci...364.1184L . 10.1126/science.aaw7611 . 7184887 . 31221859.
  26. Ridley K, Condren M . Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy . The Journal of Pediatric Pharmacology and Therapeutics . 25 . 3 . 192–197 . 2020 . 32265602 . 7134581 . 10.5863/1551-6776-25.3.192 .
  27. Middleton PG, Mall MA, Dřevínek P, Lands LC, McKone EF, Polineni D, Ramsey BW, Taylor-Cousar JL, Tullis E, Vermeulen F, Marigowda G, McKee CM, Moskowitz SM, Nair N, Savage J, Simard C, Tian S, Waltz D, Xuan F, Rowe SM, Jain R . November 2019 . Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele . The New England Journal of Medicine . 381 . 19 . 1809–1819 . 10.1056/NEJMoa1908639 . 7282384 . 31697873 . free . doi . VX17-445-102 Study Group.
  28. Taylor-Cousar JL, Mall MA, Ramsey BW, McKone EF, Tullis E, Marigowda G, McKee CM, Waltz D, Moskowitz SM, Savage J, Xuan F, Rowe SM . April 2019 . Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles . ERJ Open Research . 5 . 2 . 00082–2019 . 10.1183/23120541.00082-2019 . 6571452 . 31218221.
  29. FDA approves new breakthrough therapy for cystic fibrosis . 21 October 2019 . 13 November 2019 . live . https://web.archive.org/web/20191113165814/https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis . 13 November 2019 . U.S. Food and Drug Administration (FDA).
  30. Web site: FDA Approves Expansion of Modulators for People With Certain Rare Mutations . 3 October 2021 . Cystic Fibrosis Foundation . 21 December 2020 . 3 October 2021 . https://web.archive.org/web/20211003191030/https://www.cff.org/News/News-Archive/2020/FDA-Approves-Expansion-of-Modulators-for-People-With-Certain-Rare-Mutations/ . live .
  31. Web site: FDA Accepts Vertex Application for Expansion of Trikafta to Include Children ages 6-11 . 3 October 2021 . Cystic Fibrosis Foundation . 26 January 2021 . 3 October 2021 . https://web.archive.org/web/20211003191028/https://www.cff.org/News/News-Archive/2021/FDA-Accepts-Vertex-Application-for-Expansion-of-Trikafta-to-Include-Children-ages-6-11/ . live .
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  33. Web site: Trikafta Approved in Australia for CF Patients Starting at Age 12 . 28 November 2021 . Maia M . 30 March 2021 . 28 November 2021 . https://web.archive.org/web/20211128222713/https://cysticfibrosisnewstoday.com/2021/03/30/trikafta-vertex-approved-australia-ages-12-and-up-f508del-mutation/ . live .
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This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Elexacaftor/tezacaftor/ivacaftor".

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