tezacaftor
{{Short description|Chemical compound}}
{{Use dmy dates|date=December 2024}}
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| DailyMedID = Tezacaftor
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| CAS_number = 1152311-62-0
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| PubChem = 46199646
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| DrugBank = DB11712
| ChemSpiderID = 28637762
| UNII = 8RW88Y506K
| KEGG = D11041
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| synonyms = VX-661
| IUPAC_name = 1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide
| C=26|H=27|F=3|N=2|O=6
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| StdInChI = 1S/C26H27F3N2O6/c1-24(2,13-33)22-8-14-7-18(17(27)10-19(14)31(22)11-16(34)12-32)30-23(35)25(5-6-25)15-3-4-20-21(9-15)37-26(28,29)36-20/h3-4,7-10,16,32-34H,5-6,11-13H2,1-2H3,(H,30,35)/t16-/m1/s1
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| StdInChIKey = MJUVRTYWUMPBTR-MRXNPFEDSA-N
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Tezacaftor is a medication used for the treatment of cystic fibrosis.{{cite web|date=7 March 2018|title=Drug Trials Snapshots: Symdeko|url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-symdeko|url-status=live|archive-url=https://web.archive.org/web/20191121034335/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-symdeko|archive-date=21 November 2019|access-date=20 November 2019|website=U.S. Food and Drug Administration (FDA) }} {{PD-notice}}{{cite press release | title=FDA expands approval of treatment for cystic fibrosis to include patients ages 6 and older | website=U.S. Food and Drug Administration (FDA) | date=21 June 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-expands-approval-treatment-cystic-fibrosis-include-patients-ages-6-and-older | archive-url=https://web.archive.org/web/20191121035703/https://www.fda.gov/news-events/press-announcements/fda-expands-approval-treatment-cystic-fibrosis-include-patients-ages-6-and-older | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}} {{PD-notice}} It is available in fixed-dose combination medications.{{cite journal | vauthors = Lommatzsch ST, Taylor-Cousar JL | title = The combination of tezacaftor and ivacaftor in the treatment of patients with cystic fibrosis: clinical evidence and future prospects in cystic fibrosis therapy | journal = Therapeutic Advances in Respiratory Disease | volume = 13 | issue = | pages = 1753466619844424 | date = 2019 | pmid = 31027466 | doi = 10.1177/1753466619844424 | pmc = 6487765 }}{{cite journal | vauthors = Paterson SL, Barry PJ, Horsley AR | title = Tezacaftor and ivacaftor for the treatment of cystic fibrosis | journal = Expert Review of Respiratory Medicine | volume = 14 | issue = 1 | pages = 15–30 | date = January 2020 | pmid = 31626570 | doi = 10.1080/17476348.2020.1682998 | s2cid = 204787700 | url = https://www.research.manchester.ac.uk/portal/en/publications/tezacaftor-and-ivacaftor-for-the-treatment-of-cystic-fibrosis(a60081ad-608e-43a3-8e4e-06fe89de284f).html }}{{cite journal | vauthors = Guerra L, Favia M, Di Gioia S, Laselva O, Bisogno A, Casavola V, Colombo C, Conese M | title = The preclinical discovery and development of the combination of ivacaftor + tezacaftor used to treat cystic fibrosis | journal = Expert Opinion on Drug Discovery | volume = 15 | issue = 8 | pages = 873–891 | date = August 2020 | pmid = 32290721 | doi = 10.1080/17460441.2020.1750592 | s2cid = 215773568 | hdl = 11586/295256 | hdl-access = free }}
The combination of tezacaftor with ivacaftor (brand name Symdeko) was approved for medical use in the United States in February 2018,{{cite web | title=Symdeko- tezacaftor and ivacaftor kit | website=DailyMed | date=9 February 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=302ae804-37db-44fd-ac2f-3dbdeda9aa4b | access-date=24 December 2024}} and in Canada in June 2018.{{cite web | title=Symdeko Product information | website=Health Canada | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=96881 | access-date=31 May 2022}} As brand name Symkevi it was approved for medical use in the European Union in October 2018.{{cite web | title=Symkevi EPAR | website=European Medicines Agency (EMA) | date=27 February 2017 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/symkevi | access-date=24 December 2024}}
The combination of tezacaftor with elexacaftor and ivacaftor (brand name Trikafta) was approved for medical use in the United States in October 2019,{{cite web|date=29 January 2020|title=Trikafta- elexacaftor, tezacaftor, and ivacaftor kit|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f354423a-85c2-41c3-a9db-0f3aee135d8d|access-date=22 August 2020|website=DailyMed}}{{cite web | title=Drug Trials Snapshots: Trikafta | website=U.S. Food and Drug Administration (FDA) | date=31 October 2019 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-trikafta | access-date=24 December 2024}}{{cite press release|title=FDA approves new breakthrough therapy for cystic fibrosis|website=U.S. Food and Drug Administration (FDA)|date=21 October 2019|url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis |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|url-status=live|access-date=13 November 2019}} {{PD-notice}} and in Canada in June 2021.{{cite web | title=Trikafta Product information | website=Health Canada | date=22 June 2021 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=100648 | access-date=24 December 2024}} As brand name Kaftrio it was approved for medical use in the European Union in August 2020.{{cite web | title=Kaftrio EPAR | website=European Medicines Agency (EMA) | date=14 December 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/kaftrio | access-date=24 December 2024}}
The combination of tezacaftor with vanzacaftor and deutivacaftor (brand name Alyftrek) was approved for medical use in the United States in December 2024.{{cite press release | title=Vertex Announces US FDA Approval of Alyftrek, a Once-Daily Next-in-Class CFTR Modulator for the Treatment of Cystic Fibrosis | publisher=Vertex | via=Business Wire | date=20 December 2024 | url=https://www.businesswire.com/news/home/20241220133127/en/ | access-date=24 December 2024}}
Mechanism of action
Tezacaftor acts as a corrector to help the folding and presentation of the CFTR protein to the cell surface, which improves its function for individuals with a F508del mutation.{{cite web | url = https://cysticfibrosisnewstoday.com/tezacaftor-vx-661-for-cystic-fibrosis | title = Tezacaftor (VX-661) for Cystic Fibrosis | work = Cystic Fibrosis News Today | publisher = BioNews Services, LLC | location = Pensacola, FL }}{{Cite journal|last=Ridley|first=Kaden|title=Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy|journal=The Journal of Pediatric Pharmacology and Therapeutics|year=2020|volume=25|issue=3|pages=192–197|doi=10.5863/1551-6776-25.3.192|pmid=32265602|pmc=7134581}}
Clinical trials
The EVOLVE and EXPAND study findings were published in 2017.{{cite web|date=13 February 2018|title=FDA Approves New Cystic Fibrosis Drug Combo - Symdeko approved for patients with specific CFTR mutations|url=https://www.medpagetoday.com/pulmonology/cysticfibrosis/71125|publisher=MedPage Today, LLC|vauthors=Boyles S}}
= EVOLVE trial =
The EVOLVE trial analyzed tezacaftor/ivacaftor in participants with cystic fibrosis, specifically with the homozygous for Phe508del mutation.{{Cite journal|last=Taylor-Cousar|first=Jennifer|date=23 November 2017|title=Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del|journal=New England Journal of Medicine|volume=377|issue=21|pages=2013–2023|doi=10.1056/NEJMoa1709846|pmid=29099344|s2cid=205102514|doi-access=free}} The EVOLVE trial is a phase 3, double-blinded, multicenter, randomized, placebo-controlled, parallel-group trial, that was which evaluated therapy with a combination of tezacaftor and ivacaftor in participants that are aged 12 years of age and older.
510 participants were randomized and 509 participants were given either 100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily or a placebo for 24 weeks. The combination of drugs was efficacious in participants who had cystic fibrosis with the Phe508del mutation and the adverse effects in both treatment groups were similar.
History
The US Food and Drug Administration (FDA) granted the application for tezacaftor and ivacaftor combination therapy orphan drug and priority review designations, and granted the approval of Symdeko to Vertex Pharmaceuticals.{{cite web | title=Tezacaftor and Ivacaftor Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | date=15 June 2017 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=577517 | access-date=25 October 2020}} The European Medicines Agency (EMA) designated the combination an orphan medicine.
The FDA and the EMA granted the application for elexacaftor, tezacaftor, and ivacaftor combination therapy an orphan drug designation.{{cite web | title=Trikafta Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=647618 | date = 29 August 2018 | access-date=24 December 2024}}{{cite web | title=EU/3/18/2116 - orphan designation for treatment of cystic fibrosis | website=European Medicines Agency (EMA) | date=14 December 2018 | url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-18-2116 | access-date=24 December 2024}}
The FDA granted the application for vanzacaftor, tezacaftor, and deutivacaftor combination therapy an orphan drug designation.{{cite web | title=Alyftrek Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=777220 | access-date=24 December 2024}}
Society and culture
= Names =
Tezacaftor is the international nonproprietary name.{{cite journal | vauthors = ((World Health Organization)) | year = 2016 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 76 | journal = WHO Drug Information | volume = 30 | issue = 3 | hdl = 10665/331020 | hdl-access = free | author-link = World Health Organization }}
References
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