Tazemetostat

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Tazemetostat
Tazemetostat.svg
Names
Trade namesTazverik, others
Other namesEPZ-6438
  • N-[(4,6-Dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide
Clinical data
Drug classEZH2 inhibitor[1]
Main usesEpithelioid sarcoma, non-Hodgkin lymphoma[1]
Side effectsPain, tiredness, nausea, decreased appetite, vomiting, constipation[1]
Routes of
use
By mouth[1]
External links
AHFS/Drugs.comMonograph
MedlinePlusa620018
Legal
License data
Legal status
Chemical and physical data
FormulaC34H44N4O4
Molar mass572.750 g·mol−1
3D model (JSmol)
  • CCN(C1CCOCC1)C2=CC(=CC(=C2C)C(=O)NCC3=C(C=C(NC3=O)C)C)C4=CC=C(C=C4)CN5CCOCC5
  • InChI=1S/C34H44N4O4/c1-5-38(29-10-14-41-15-11-29)32-20-28(27-8-6-26(7-9-27)22-37-12-16-42-17-13-37)19-30(25(32)4)33(39)35-21-31-23(2)18-24(3)36-34(31)40/h6-9,18-20,29H,5,10-17,21-22H2,1-4H3,(H,35,39)(H,36,40)
  • Key:NSQSAUGJQHDYNO-UHFFFAOYSA-N

Tazemetostat, sold under the brand name Tazverik, is a medication used to treat epithelioid sarcoma which cannot be removed by surgery and non-Hodgkin lymphoma that has failed other treatments.[1] It is taken by mouth.[1]

Common side effects include pain, tiredness, nausea, decreased appetite, vomiting, and constipation.[1] Other side effects may include secondary cancers including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia.[2] It works by blocking the activity of EZH2 .[3]

Tazemetostat was approved for medical use in the United States in 2020.[1] As of 2021 has not been fully approved in Europe; though has been granted an orphan designation.[4][5] In the United States it costs about 17,300 USD per month as of 2021.[6]

Medical uses

Most cases of epithelioid sarcoma begin in the soft tissue under the skin of an extremity, though it can start in other areas of the body.[2] Surgical removal is considered the main treatment when the cancer is localized to one area of the body.[2] Chemotherapy or radiation may also be given.[2] However, there is a high likelihood for local and regional spread of the disease even with treatment and approximately 50% of patients have metastatic disease at the time of diagnosis.[2] Metastatic disease is considered life-threatening to the patient.[2]

Dosage

It is taken at a dose of 800 mg twice per day.[1]

Mechanism of action

Tazemetostat blocks activity of the EZH2 methyltransferase, which may help keep the cancer cells from growing.[2] According to the NCI Drug Dictionary, "tazemetostat is an orally available, small molecule selective and S-adenosyl methionine (SAM) competitive inhibitor of histone methyl transferase EZH2, with potential antineoplastic activity. Upon oral administration, tazemetostat selectively inhibits the activity of both wild-type and mutated forms of EZH2. Inhibition of EZH2 specifically prevents the methylation of histone H3 lysine 27 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased tumor cell proliferation in EZH2 mutated cancer cells. EZH2, which belongs to the class of histone methyltransferases (HMTs), is overexpressed or mutated in a variety of cancer cells and plays a key role in tumor cell proliferation."[7]

History

The U.S. Food and Drug Administration (FDA) approved tazemetostat in January 2020,[2] based on the results of a clinical trial (NCT02601950) enrolling 62 subjects with metastatic or locally advanced epithelioid sarcoma.[2][8] During the clinical trial, subjects received 800 milligrams (mg) of tazemetostat twice a day until the disease progressed or the subject reached an unacceptable level of toxicity.[2][8] Tumor response assessments were performed every eight weeks during the clinical trial.[2] The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate).[2] The overall response rate was 15%, with 1.6% of subjects having a complete response and 13% having a partial response.[2] Of the nine subjects that had a response, six (67%) subjects had a response lasting six months or longer.[2]

The trial was conducted at 22 sites in France, United Kingdom, Taiwan, Italy, Canada, Belgium, and the United States.[8]

The FDA granted the application for tazemetostat accelerated approval and orphan drug designation.[2] The FDA granted the approval to Epizyme Inc.[2] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[9]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Tazemetostat Monograph for Professionals". Drugs.com. Retrieved 24 September 2021.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 "FDA approves first treatment option specifically for patients with epithelioid sarcoma, a rare soft tissue cancer". U.S. Food and Drug Administration (FDA) (Press release). 23 January 2020. Retrieved 23 January 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Lue JK, Amengual JE (October 2018). "Emerging EZH2 Inhibitors and Their Application in Lymphoma". Curr Hematol Malig Rep. 13 (5): 369–382. doi:10.1007/s11899-018-0466-6. PMID 30112706. S2CID 52010283.
  4. "Tazemetostat". SPS - Specialist Pharmacy Service. 17 September 2019. Retrieved 24 September 2021.
  5. "EU/3/18/2004: Orphan designation for the treatment of diffuse large B-cell lymphoma". Retrieved 24 September 2021.
  6. "Tazverik Prices, Coupons and Patient Assistance Programs". Retrieved 24 September 2021.
  7. "Tazemetostat". NCI Drug Dictionary. National Cancer Institute.
  8. 8.0 8.1 8.2 "Drug Trials Snapshots: Tazverik". U.S. Food and Drug Administration (FDA). 23 January 2020. Retrieved 22 February 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  9. "New Drug Therapy Approvals 2020". U.S. Food and Drug Administration (FDA). 31 December 2020. Retrieved 17 January 2021. Public Domain This article incorporates text from this source, which is in the public domain.

External links

External sites:
Identifiers: