Tezacaftor

Tezacaftor is a drug used for the treatment of cystic fibrosis (CF) in people six years and older, who have a F508del mutation, the most common type of mutation in the CFTR gene.^[2][3] It is sold as a fixed-dose combination with ivacaftor under the brand name Symdeko.^[4][5][6] It was approved by the U.S. FDA in 2018.^[2] The combination of elexacaftor, tezacaftor, and ivacaftor is being sold as Trikafta.^[7]

Tezacaftor

Clinical data
Trade names	Symdeko (with ivacaftor)
Other names	VX-661
License data	US DailyMed: Tezacaftor
Routes of administration	By mouth
ATC code	R07AX31 (WHO) (combination with ivacaftor)
Legal status
Legal status	CA: ℞-only[1] US: ℞-only
Identifiers
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
CAS Number	1152311-62-0
PubChem CID	46199646
DrugBank	DB11712
ChemSpider	28637762
UNII	8RW88Y506K
KEGG	D11041
CompTox Dashboard (EPA)	DTXSID40673070
Chemical and physical data
Formula	C26H27F3N2O6
Molar mass	520.505 g·mol−1
InChI InChI=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 Key:MJUVRTYWUMPBTR-MRXNPFEDSA-N

In 2019, the U.S. Food and Drug Administration (FDA) approved a combination of elexacaftor, tezacaftor, and ivacaftor.^[8]

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.^[2][9][10]

Clinical trials

The EVOLVE and EXPAND study findings were published in 2017.^[11]

EVOLVE trial

The EVOLVE trial analyzed tezacaftor/ivacaftor in patients with cystic fibrosis, specifically with the homozygous for Phe508del mutation.^[12] 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 patients that are 12 and older.^[12]

510 patients were randomized and 509 patients were given either 100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily or a placebo for 24 weeks.^[12] The combination of drugs was efficacious in patients who had cystic fibrosis with the Phe508del mutation and the adverse effects in both treatment groups were similar.^[12]

History

The U.S. Food and Drug Administration (FDA) granted the application for tezacaftor and ivacaftor combination therapy orphan drug designation and priority review, and granted the approval of Symdeko to Vertex Pharmaceuticals Incorporated.^[3][13]

References

1. "Symdeko Product information". Health Canada. Retrieved 31 May 2022.
2. "Drug Trials Snapshots: Symdeko". U.S. Food and Drug Administration. 7 March 2018. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain.
3. "FDA expands approval of treatment for cystic fibrosis to include patients ages 6 and older". U.S. Food and Drug Administration (FDA) (Press release). 21 June 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain.
4. Lommatzsch ST, Taylor-Cousar JL (2019). "The combination of tezacaftor and ivacaftor in the treatment of patients with cystic fibrosis: clinical evidence and future prospects in cystic fibrosis therapy". Therapeutic Advances in Respiratory Disease. 13: 1753466619844424. doi:10.1177/1753466619844424. PMC 6487765. PMID 31027466.
5. Paterson SL, Barry PJ, Horsley AR (January 2020). "Tezacaftor and ivacaftor for the treatment of cystic fibrosis". Expert Review of Respiratory Medicine. 14 (1): 15–30. doi:10.1080/17476348.2020.1682998. PMID 31626570. S2CID 204787700.
6. Guerra L, Favia M, Di Gioia S, Laselva O, Bisogno A, Casavola V, Colombo C, Conese M (August 2020). "The preclinical discovery and development of the combination of ivacaftor + tezacaftor used to treat cystic fibrosis". Expert Opinion on Drug Discovery. 15 (8): 873–891. doi:10.1080/17460441.2020.1750592. hdl:11586/295256. PMID 32290721. S2CID 215773568.
7. "Trikafta- elexacaftor, tezacaftor, and ivacaftor kit". DailyMed. 29 January 2020. Retrieved 22 August 2020.
8. "FDA approves new breakthrough therapy for cystic fibrosis". U.S. Food and Drug Administration (FDA) (Press release). 21 October 2019. Archived from the original on 13 November 2019. Retrieved 13 November 2019. This article incorporates text from this source, which is in the public domain.
9. "Tezacaftor (VX-661) for Cystic Fibrosis". Cystic Fibrosis News Today. Pensacola, FL: BioNews Services, LLC.
10. Ridley, Kaden (2020). "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. doi:10.5863/1551-6776-25.3.192. PMC 7134581. PMID 32265602.
11. Boyles S (13 February 2018). "FDA Approves New Cystic Fibrosis Drug Combo - Symdeko approved for patients with specific CFTR mutations". MedPage Today, LLC.
12. Taylor-Cousar, Jennifer (23 November 2017). "Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del". New England Journal of Medicine. 377 (21): 2013–2023. doi:10.1056/NEJMoa1709846. PMID 29099344. S2CID 205102514.
13. "Tezacaftor and Ivacaftor Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 15 June 2017. Retrieved 25 October 2020.

External links

• "Tezacaftor". Drug Information Portal. U.S. National Library of Medicine.
• "Ivacaftor regimen with Tezacaftor". Drug Information Portal. U.S. National Library of Medicine.