Glasdegib

Last updated
Glasdegib
Glasdegib.svg
Clinical data
Trade names Daurismo
Other namesPF-04449913
AHFS/Drugs.com Monograph
MedlinePlus a619004
ATC code
Legal status
Legal status
Identifiers
  • 1-[(2R,4R)-2-(1H-Benzimidazol-2-yl)-1-methyl-4-piperidinyl]-3-(4-cyanophenyl)urea
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.244.738 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H22N6O
Molar mass 374.448 g·mol−1
3D model (JSmol)
  • CN1CCC(CC1C2=NC3=CC=CC=C3N2)NC(=O)NC4=CC=C(C=C4)C#N
  • InChI=1S/C21H22N6O/c1-27-11-10-16(24-21(28)23-15-8-6-14(13-22)7-9-15)12-19(27)20-25-17-4-2-3-5-18(17)26-20/h2-9,16,19H,10-12H2,1H3,(H,25,26)(H2,23,24,28)/t16-,19-/m1/s1
  • Key:SFNSLLSYNZWZQG-VQIMIIECSA-N

Glasdegib, sold under the brand name Daurismo, is a medication for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults older than 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy. [5] [6] [7] It is taken by mouth and is used in combination with low-dose cytarabine. [6]

Contents

The recommended dose of glasdegib is 100 mg orally once daily on days 1 to 28 in combination with cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control. [6]

The most common adverse reactions are anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. [5]

It is a small molecule inhibitor of sonic hedgehog, which is a protein overexpressed in many types of cancer. It inhibits the sonic hedgehog receptor smoothened (SMO), as do most drugs in its class. [8]

History

Glasdegib was approved for medical use in the United States in December 2018. [5] [6] [9] [10] [11]

FDA approval was based on a multicenter, open-label, randomized study (BRIGHT AML 1003, NCT01546038) that included 115 subjects with newly-diagnosed AML who met at least one of the following criteria: a) age 75 years or older, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology Group performance status of 2, or d) baseline serum creatinine >1.3 mg/dL. [5] Subjects were randomized 2:1 to receive glasdegib, 100 mg daily, with LDAC 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle (N=77) or LDAC alone (N=38) in 28-day cycles until disease progression or unacceptable toxicity. [5] The trial was conducted in United States, Canada and Europe. [12]

Efficacy was established based on an improvement in overall survival (date of randomization to death from any cause). [5] With a median follow-up of 20 months, median survival was 8.3 months (95% CI: 4.4, 12.2) for the glasdegib + LDAC arm and 4.3 months (95% CI: 1.9, 5.7) for the LDAC alone arm and HR of 0.46 (95% CI: 0.30, 0.71; p=0.0002). [5]

Glasdegib was granted priority review and orphan drug designation by the U.S. Food and Drug Administration (FDA). [5] [13] It was granted orphan drug designation by the European Medicines Agency (EMA) in October 2017. [14]

Glasdegib was approved for medical use in the European Union in June 2020. [3]

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References

  1. ↑ "Summary Basis of Decision (SBD) for Daurismo". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  3. 1 2 "Daurismo EPAR". European Medicines Agency (EMA). 28 April 2020. Retrieved 25 September 2020.
  4. ↑ "Daurismo Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  5. 1 2 3 4 5 6 7 8 "FDA approves glasdegib for AML in adults age 75 or older or who have comorbidities". U.S. Food and Drug Administration (FDA) (Press release). 21 November 2018. Retrieved 25 March 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  6. 1 2 3 4 "Daurismo- glasdegib tablet, film coated". DailyMed. 26 November 2019. Retrieved 25 March 2020.
  7. ↑ Thomas X, Heiblig M (April 2020). "An evaluation of glasdegib for the treatment of acute myelogenous leukemia". Expert Opinion on Pharmacotherapy. 21 (5): 523–530. doi:10.1080/14656566.2020.1713094. PMID   32027196. S2CID   211044663.
  8. ↑ "Glasdegib - AdisInsight". Adisinsight.springer.com. Retrieved 2017-05-22.
  9. ↑ "Drug Approval Package: Daurismo (glasdegib)". U.S. Food and Drug Administration (FDA). 17 December 2018. Retrieved 25 March 2020.
  10. ↑ "Daurismo: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 25 March 2020.
  11. ↑ Hoy SM (February 2019). "Glasdegib: First Global Approval". Drugs. 79 (2): 207–213. doi:10.1007/s40265-018-1047-7. PMID   30666593. S2CID   58541521.
  12. ↑ "Drug Trial Snapshot: Daurismo". U.S. Food and Drug Administration (FDA). 21 November 2018. Retrieved 25 March 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  13. ↑ "Search Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 25 March 2020.
  14. ↑ "EU/3/17/1923". European Medicines Agency (EMA). 17 September 2018. Retrieved 25 March 2020.


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