Elexacaftor/tezacaftor/ivacaftor

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.

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.

Concomitant use with CYP3A inducers is not recommended.{{Cite web |title=elexacaftor/tezacaftor/ivacaftor (Rx) |url=https://reference.medscape.com/drug/trikafta-elexacaftor-tezacaftor-ivacaftor-4000016 |url-status=live |archive-url=https://web.archive.org/web/20201028170854/https://reference.medscape.com/drug/trikafta-elexacaftor-tezacaftor-ivacaftor-4000016 |archive-date=28 October 2020 |access-date=3 October 2021 |website=Medscape}} 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.

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.{{Cite journal |vauthors=O'Sullivan BP, Freedman SD |date=May 2009 |title=Cystic fibrosis |journal=Lancet |volume=373 |issue=9678 |pages=1891–1904 |doi=10.1016/s0140-6736(09)60327-5 |pmid=19403164 |s2cid=46011502}}{{Cite book |url=https://books.google.com/books?id=9x_cBQAAQBAJ&pg=PA3 |title=Cystic Fibrosis |publisher=Hodder Arnold |year=2012 |isbn=978-1-4441-1369-3 |veditors=Hodson M, Geddes D, Bush A |edition=3rd |location=London |pages=3 |archive-url=https://web.archive.org/web/20170908140759/https://books.google.com/books?id=9x_cBQAAQBAJ&pg=PA3 |archive-date=8 September 2017 |url-status=live}} The CFTR protein is found in epithelial cells of the lung, liver, pancreas, digestive tract, and reproductive tracts.{{Cite journal |vauthors=Sharma S, Hanukoglu I |date=April 2019 |title=Mapping the sites of localization of epithelial sodium channel (ENaC) and CFTR in segments of the mammalian epididymis |journal=Journal of Molecular Histology |volume=50 |issue=2 |pages=141–154 |doi=10.1007/s10735-019-09813-3 |pmid=30659401 |s2cid=58026884}}{{Cite journal |vauthors=Sharma S, Hanukoglu A, Hanukoglu I |date=April 2018 |title=Localization of epithelial sodium channel (ENaC) and CFTR in the germinal epithelium of the testis, Sertoli cells, and spermatozoa |journal=Journal of Molecular Histology |volume=49 |issue=2 |pages=195–208 |doi=10.1007/s10735-018-9759-2 |pmid=29453757 |s2cid=3761720}}{{Cite journal |vauthors=Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A |date=March 2012 |title=Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways |journal=Histochemistry and Cell Biology |volume=137 |issue=3 |pages=339–353 |doi=10.1007/s00418-011-0904-1 |pmid=22207244 |s2cid=15178940}} CFTR has a role in the production of mucus, sweat, and digestive fluids.{{Cite book |url=https://books.google.com/books?id=1cTZAAAAQBAJ&pg=PA351 |title=Molecular Diagnostics: Fundamentals, Methods and Clinical Applications |vauthors=Buckingham L |publisher=F.A. Davis Co. |year=2012 |isbn=978-0-8036-2975-2 |edition=2nd |location=Philadelphia |pages=351 |archive-url=https://web.archive.org/web/20170908140759/https://books.google.com/books?id=1cTZAAAAQBAJ&pg=PA351 |archive-date=8 September 2017 |url-status=live}} The thickened mucus can lead to inflammation, respiratory infections, and clogged ducts.{{Cite journal |vauthors=Flume PA, Mogayzel PJ, Robinson KA, Rosenblatt RL, Quittell L, Marshall BC |date=August 2010 |title=Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax |journal=American Journal of Respiratory and Critical Care Medicine |volume=182 |issue=3 |pages=298–306 |doi=10.1164/rccm.201002-0157OC |pmid=20675678}}{{Cite book |url=https://books.google.com/books?id=-keXQ6LaXVIC |title=Robbins Basic Pathology |vauthors=Mitchell RS, Kumar V, Robbins SL, Abbas AK, Fausto N |publisher=Saunders/Elsevier |year=2007 |isbn=978-1-4160-2973-1 |page=[https://books.google.com/books?id=-keXQ6LaXVIC&pg=PT1253 1253], [https://books.google.com/books?id=-keXQ6LaXVIC&pg=PT1254 1254] |access-date=11 December 2021 |archive-date=29 April 2023 |archive-url=https://web.archive.org/web/20230429045544/https://books.google.com/books?id=-keXQ6LaXVIC |url-status=live }}

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.{{Cite web |title=Tezacaftor |url=https://pubchem.ncbi.nlm.nih.gov/compound/46199646 |access-date=24 November 2022 |website=PubChem |archive-date=7 April 2023 |archive-url=https://web.archive.org/web/20230407041530/https://pubchem.ncbi.nlm.nih.gov/compound/46199646 |url-status=live }} Its effectiveness is dependent on the type of CF mutations the patient has.{{Cite journal |vauthors=Tice JA, Kuntz KM, Wherry K, Seidner M, Rind DM, Pearson SD |date=February 2021 |title=The effectiveness and value of novel treatments for cystic fibrosis |journal=Journal of Managed Care & Specialty Pharmacy |volume=27 |issue=2 |pages=276–280 |doi=10.18553/jmcp.2021.27.2.276 |pmid=33506736 |s2cid=231771254 |doi-access=free |title-link=doi|pmc=10391049 }}

File:Elexacaftor_tezacaftor_ivacaftor_mechanism_of_action.png

File:Complex of Ivacaftor bound to CFTR.png

File:Ivacaftor.svg

Ivacaftor is a selective small-molecule potentiator of the CFTR protein that increases the protein's ability to open chloride channels.{{Cite web |title=Ivacaftor pathway, pharmacokinetics/pharmacodynamics |url=https://www.pharmgkb.org/pathway/PA166153178 |access-date=9 December 2021 |website=PharmGKB |archive-date=9 December 2021 |archive-url=https://web.archive.org/web/20211209011544/https://www.pharmgkb.org/pathway/PA166153178 |url-status=live }}{{Cite journal |vauthors=Zaher A, ElSaygh J, Elsori D, ElSaygh H, Sanni A |date=July 2021 |title=A Review of Trikafta: Triple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Therapy |journal=Cureus |volume=13 |issue=7 |pages=e16144 |doi=10.7759/cureus.16144 |doi-access=free |pmc=8266292 |pmid=34268058}} Its effectiveness is highly dependent on the amount of CFTR protein at the cell surface and the responsiveness of the mutant CFTR protein.{{Cite web |title=Ivacaftor |url=https://pubchem.ncbi.nlm.nih.gov/compound/16220172 |access-date=7 November 2021 |website=PubChem |archive-date=7 November 2021 |archive-url=https://web.archive.org/web/20211107202713/https://pubchem.ncbi.nlm.nih.gov/compound/16220172 |url-status=live }} Ivacaftor's primary target is to treat class III CFTR gating mutations like G551D as well as other less common mutations. 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.{{Cite journal |vauthors=Liu F, Zhang Z, Levit A, Levring J, Touhara KK, Shoichet BK, Chen J |date=June 2019 |title=Structural identification of a hotspot on CFTR for potentiation |journal=Science |volume=364 |issue=6446 |pages=1184–1188 |bibcode=2019Sci...364.1184L |doi=10.1126/science.aaw7611 |pmc=7184887 |pmid=31221859}}

File:Elexacaftor.svg

File:Tezacaftor.svg

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. 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.{{cite journal | vauthors = Ridley K, Condren M | title = Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy | journal = The Journal of Pediatric Pharmacology and Therapeutics | volume = 25 | issue = 3 | pages = 192–197 | date = 2020 | pmid = 32265602 | pmc = 7134581 | doi = 10.5863/1551-6776-25.3.192 }}

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.

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.

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.{{Cite journal |vauthors=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 |date=November 2019 |title=Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele |journal=The New England Journal of Medicine |volume=381 |issue=19 |pages=1809–1819 |doi=10.1056/NEJMoa1908639 |pmc=7282384 |pmid=31697873 |doi-access=free |title-link=doi |collaboration=VX17-445-102 Study Group}}{{Cite journal |vauthors=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 |date=April 2019 |title=Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles |journal=ERJ Open Research |volume=5 |issue=2 |pages=00082–2019 |doi=10.1183/23120541.00082-2019 |pmc=6571452 |pmid=31218221}}{{ClinicalTrialsGov|NCT03525444|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)}}

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.{{Cite press release |title=FDA approves new breakthrough therapy for cystic fibrosis |date=21 October 2019 |url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis |access-date=13 November 2019 |url-status=live |archive-url=https://web.archive.org/web/20191113165814/https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis |archive-date=13 November 2019 |website=U.S. Food and Drug Administration (FDA)}} {{PD-notice}} In December 2020, after an additional clinical trial was completed, and FDA approval was expanded for 177 other cystic fibrosis mutations.{{Cite web |title=FDA Approves Expansion of Modulators for People With Certain Rare Mutations |url=https://www.cff.org/News/News-Archive/2020/FDA-Approves-Expansion-of-Modulators-for-People-With-Certain-Rare-Mutations/ |access-date=3 October 2021 |website=Cystic Fibrosis Foundation |date=21 December 2020 |archive-date=3 October 2021 |archive-url=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/ |url-status=live }} FDA approval for children aged 6–11 was added in January 2021, after a third clinical trial was completed.{{Cite web |title=FDA Accepts Vertex Application for Expansion of Trikafta to Include Children ages 6-11 |url=https://www.cff.org/News/News-Archive/2021/FDA-Accepts-Vertex-Application-for-Expansion-of-Trikafta-to-Include-Children-ages-6-11/ |access-date=3 October 2021 |website=Cystic Fibrosis Foundation |date=26 January 2021 |archive-date=3 October 2021 |archive-url=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/ |url-status=live }} In 2023, approval was extended to children 2–5.{{cite web |title=FDA Approves Trikafta for Children Ages 2 Through 5 Years With Certain CF Mutations {{!}} Cystic Fibrosis Foundation |url=https://www.cff.org/news/2023-04/trikafta-approval-ages-2-5-mutations |website=www.cff.org |publisher=Cystic Fibrosis Foundation |access-date=28 March 2024 |language=en |date=26 April 2023}}

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.

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.{{Cite web |title=Trikafta Approved in Australia for CF Patients Starting at Age 12 |url=https://cysticfibrosisnewstoday.com/2021/03/30/trikafta-vertex-approved-australia-ages-12-and-up-f508del-mutation/ |access-date=28 November 2021 |vauthors=Maia M |date=30 March 2021 |archive-date=28 November 2021 |archive-url=https://web.archive.org/web/20211128222713/https://cysticfibrosisnewstoday.com/2021/03/30/trikafta-vertex-approved-australia-ages-12-and-up-f508del-mutation/ |url-status=live }} 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.{{Cite web |title=Trikafta placed on PBS |url=https://www.pbs.gov.au/medicine/item/12936W-12938Y/ |access-date=29 April 2022 |archive-date=29 September 2022 |archive-url=https://web.archive.org/web/20220929045341/https://www.pbs.gov.au/medicine/item/12936W-12938Y |url-status=live }}

{{update section|date=February 2023}}

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.{{Cite web |title=CF Therapy Trikafta Now Covered in 2 More Canadian Provinces |url=https://cysticfibrosisnewstoday.com/2021/09/29/cf-therapy-trikafta-now-covered-2-more-canadian-provinces/ |access-date=8 November 2021 |vauthors=Wexler M |date=29 September 2021 |archive-date=8 November 2021 |archive-url=https://web.archive.org/web/20211108144655/https://cysticfibrosisnewstoday.com/2021/09/29/cf-therapy-trikafta-now-covered-2-more-canadian-provinces/ |url-status=live }}

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.{{Cite press release |title=New medicine for cystic fibrosis patients |date=26 June 2020 |url=https://www.ema.europa.eu/en/news/new-medicine-cystic-fibrosis-patients |access-date=26 June 2020 |website=European Medicines Agency (EMA) |archive-date=28 June 2020 |archive-url=https://web.archive.org/web/20200628173707/https://www.ema.europa.eu/en/news/new-medicine-cystic-fibrosis-patients |url-status=live }}{{Cite web |date=28 July 2020 |title=Elexacaftor + ivacaftor + tezacaftor |url=https://www.sps.nhs.uk/medicines/elexacaftor-ivacaftor-tezacaftor/ |url-status=dead |archive-url=https://web.archive.org/web/20200918172422/https://www.sps.nhs.uk/medicines/elexacaftor-ivacaftor-tezacaftor/ |archive-date=18 September 2020 |access-date=21 August 2020 |website=SPS - Specialist Pharmacy Service}} It was approved for medical use in the European Union in August 2020.{{Cite web |date=23 June 2020 |title=Kaftrio EPAR |url=https://www.ema.europa.eu/en/medicines/human/EPAR/kaftrio |access-date=21 August 2020 |website=European Medicines Agency (EMA) |archive-date=20 September 2020 |archive-url=https://web.archive.org/web/20200920090623/https://www.ema.europa.eu/en/medicines/human/EPAR/kaftrio |url-status=live }}

In April 2022, {{Lang|no|Beslutningsforum for nye metoder}} approved the combination for treatment of cystic fibrosis.{{Cite web |date=25 April 2022 |title=Enige om Kaftrio: Innfører legemidler for pasienter med cystisk fibrose |url=https://nyemetoder.no/nyheter/enige-om-kaftrio-innforer-legemidler-for-pasienter-med-cystisk-fibrose |access-date=25 April 2022 |archive-date=25 April 2022 |archive-url=https://web.archive.org/web/20220425080546/https://nyemetoder.no/nyheter/enige-om-kaftrio-innforer-legemidler-for-pasienter-med-cystisk-fibrose |url-status=live }}

In February 2022, Pharmac recommended, with medium priority, funding for people aged 12 years and over.{{Cite web |title=Pharmac's clinical experts recommend funding Trikafta |date=23 February 2022 |url=https://pharmac.govt.nz/news-and-resources/news/2021-02-23-media-release-pharmacs-clinical-experts-recommend-funding-trikafta/ |access-date=2 April 2022 |archive-date=18 May 2022 |archive-url=https://web.archive.org/web/20220518212029/https://pharmac.govt.nz/news-and-resources/news/2021-02-23-media-release-pharmacs-clinical-experts-recommend-funding-trikafta/ |url-status=live }} 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.{{Cite web |date=4 December 2022 |title=Pharmac to fund life-extending drug Trikafta for those with cystic fibrosis |url=https://www.rnz.co.nz/news/national/480068/pharmac-to-fund-life-extending-drug-trikafta-for-those-with-cystic-fibrosis |website=Radio New Zealand |access-date=2 January 2023 |archive-date=2 January 2023 |archive-url=https://web.archive.org/web/20230102194544/https://www.rnz.co.nz/news/national/480068/pharmac-to-fund-life-extending-drug-trikafta-for-those-with-cystic-fibrosis |url-status=live }}{{Cite web |title=Cystic fibrosis 'miracle drug' could add decades to teen's life |url=https://www.nzherald.co.nz/northern-advocate/news/pharmac-deal-to-fund-trikafta-gives-hope-to-northlanders-with-cystic-fibrosis/BOSBUEQI65BZROVJII5PRHZAI4/ |access-date=8 February 2023 |archive-date=8 February 2023 |archive-url=https://web.archive.org/web/20230208063441/https://www.nzherald.co.nz/northern-advocate/news/pharmac-deal-to-fund-trikafta-gives-hope-to-northlanders-with-cystic-fibrosis/BOSBUEQI65BZROVJII5PRHZAI4/ |url-status=live }}

The list price of a year's treatment in the US is {{US$|322,000}} (formerly {{US$|311,000}}).{{Cite news |date=21 October 2019 |title=Vertex prices cystic fibrosis combo treatment at $311,000-per-year |work=Reuters |url=https://www.reuters.com/article/us-vertex-pharms-fda/vertex-prices-cystic-fibrosis-combo-treatment-at-311000-per-year-idUSKBN1X024U |access-date=23 October 2019 |vauthors=Maddipatla M, O'Donnell C |archive-date=23 October 2019 |archive-url=https://web.archive.org/web/20191023030813/https://www.reuters.com/article/us-vertex-pharms-fda/vertex-prices-cystic-fibrosis-combo-treatment-at-311000-per-year-idUSKBN1X024U |url-status=live }} 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".{{Cite web |title=Trikafta Very Effective CF Therapy, But Still Too Costly, ICER Reports |url=https://cysticfibrosisnewstoday.com/2020/05/08/trikafta-very-effective-cf-therapy-but-still-too-costly-icer-reports/ |access-date=21 August 2020 |vauthors=Martins I |date=8 May 2020 |archive-date=16 August 2020 |archive-url=https://web.archive.org/web/20200816194548/https://cysticfibrosisnewstoday.com/2020/05/08/trikafta-very-effective-cf-therapy-but-still-too-costly-icer-reports/ |url-status=live }}{{Cite web |date=27 April 2020 |title=Modulator Treatments for Cystic Fibrosis: Effectiveness and Value |url=https://icer.org/wp-content/uploads/2020/08/ICER_CF_Protocol_120619.pdf |access-date=21 August 2020 |website=Institute for Clinical and Economic Review |archive-date=4 July 2021 |archive-url=https://web.archive.org/web/20210704190716/https://icer.org/wp-content/uploads/2020/08/ICER_CF_Protocol_120619.pdf |url-status=live }}

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.{{Cite news | vauthors = King M |date=29 April 2022 |title=This 'life-saving' drug went from $21k a month, to just $6. Now these young Australians can plan a future beyond 30 |agency=Australian Broadcasting Corporation |url=https://www.abc.net.au/triplej/programs/hack/trikafta-listed-pbs-australia/13858822 |access-date=29 April 2022 |archive-date=29 April 2022 |archive-url=https://web.archive.org/web/20220429003149/https://www.abc.net.au/triplej/programs/hack/trikafta-listed-pbs-australia/13858822 |url-status=live }}

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%.{{Cite news |date=2024-06-13 |title=Lauterbachs Pharmagesetz: Milliardengeschenk für Konzerne? |url=https://www1.wdr.de/daserste/monitor/videos/lauterbachs-pharmagesetz-milliardengeschenk-fuer-konzerne-102.html |access-date=2024-06-14 |work=Monitor |language=de}}

In March 2023, Ireland's Health Service Executive approved funding for the provision of Kaftrio to people aged six and over with cystic fibrosis.{{Cite web |title=HSE to fund game-changing cystic fibrosis drug Kaftrio for children after marathon campaign |url=https://www.independent.ie/irish-news/hse-to-fund-game-changing-cystic-fibrosis-drug-kaftrio-for-children-after-marathon-campaign-42398667.html |website=Independent.ie |date=21 March 2023 |access-date=22 March 2023 |archive-date=22 March 2023 |archive-url=https://web.archive.org/web/20230322140357/https://www.independent.ie/irish-news/hse-to-fund-game-changing-cystic-fibrosis-drug-kaftrio-for-children-after-marathon-campaign-42398667.html |url-status=live }}{{Cite web | vauthors = Sheehy M |date=21 March 2023 |title=HSE approves 'groundbreaking' cystic fibrosis drug for children aged 6-11 |url=https://www.irishexaminer.com/news/arid-41098699.html |website=Irish Examiner |access-date=22 March 2023 |archive-date=22 March 2023 |archive-url=https://web.archive.org/web/20230322140357/https://www.irishexaminer.com/news/arid-41098699.html |url-status=live }}

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.{{Cite web |title=Vertex Announces Reimbursement Agreement in Spain for KAFTRIO (ivacaftor/tezacaftor/elexacaftor) in Combination With Ivacaftor to Treat People With Cystic Fibrosis 12 Years and Older With At Least One F508del Mutation in the CFTR Gene - ANSA.it |url=https://www.ansa.it/sito/notizie/economia/business_wire/news/2021-11-19_119232594.html |access-date=28 November 2021 |website=www.ansa.it |archive-date=28 November 2021 |archive-url=https://web.archive.org/web/20211128222710/https://www.ansa.it/sito/notizie/economia/business_wire/news/2021-11-19_119232594.html |url-status=live }}

In addition to Trikafta's high list price, Vertex has actively worked to prevent LMICs from accessing this drug combination. This has led to groups of patients in three countries, namely India, Ukraine and South Africa, to initiate legal and regulatory actions to compel their governments to allow for the importation or local production of low-cost generic versions of Trikafta through compulsory licensing.{{Cite news | vauthors = Nolen S, Robbins R |date=7 February 2023 |title='Miracle' Cystic Fibrosis Drug Kept Out of Reach in Developing Countries |work=The New York Times |url=https://www.nytimes.com/2023/02/07/health/cystic-fibrosis-drug-trikafta.html |access-date=8 February 2023 |archive-date=7 February 2023 |archive-url=https://web.archive.org/web/20230207235439/https://www.nytimes.com/2023/02/07/health/cystic-fibrosis-drug-trikafta.html |url-status=live }}{{Cite web | vauthors = Markx J |title=This Johannesburg woman needs Trikafta to treat her cystic fibrosis – and she's taking on a US medical drug giant to get it in SA |url=https://www.news24.com/you/news/local/this-johannesburg-woman-needs-trikafta-to-treat-her-cystic-fibrosis-and-shes-taking-on-a-us-medical-drug-giant-to-get-it-in-sa-20230320 |access-date=2023-09-17 |website=You |language=en-US}} In 2022, the estimated cost of manufacturing a year's supply of Trikafta was US$5,700.{{cite journal | vauthors = Guo J, Wang J, Zhang J, Fortunak J, Hill A | title = Current prices versus minimum costs of production for CFTR modulators | journal = Journal of Cystic Fibrosis | volume = 21 | issue = 5 | pages = 866–872 | date = September 2022 | pmid = 35440408 | doi = 10.1016/j.jcf.2022.04.007 | hdl-access = free | hdl = 10044/1/96753 }}

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.

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Category:Combination drugs

Category:Cystic fibrosis

Category:Orphan drugs