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Drugs

, Volume 79, Issue 2, pp 207–213 | Cite as

Glasdegib: First Global Approval

  • Sheridan M. HoyEmail author
AdisInsight Report
  • 123 Downloads

Abstract

Glasdegib (DAURISMO™) is an oral inhibitor of the Hedgehog signalling pathway, the activation of which is associated with a number of malignancies. It has been developed by Pfizer and was approved in November 2018 in the USA for use in combination with low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukaemia (AML) in patients aged ≥ 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy. Glasdegib is the first Hedgehog pathway inhibitor to be approved for AML in the USA. It received orphan designation for the treatment of AML in the USA in June 2017 and in the EU in October 2017, and for the treatment of myelodysplastic syndrome (MDS) in the USA in October 2017. It is also undergoing clinical development for use in select haematological and other malignancies, including MDS, in various countries worldwide. This article summarizes the milestones in the development of glasdegib leading to its use in combination with low-dose cytarabine for the treatment of newly-diagnosed AML in patients aged ≥ 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy.

Notes

Compliance with Ethical Standards

Funding

The preparation of this review was not supported by any external funding.

Conflicts of interest

During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the author on the basis of scientific completeness and accuracy. Sheridan Hoy is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

References

  1. 1.
    Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood. 2012;119(10):2196–204.CrossRefGoogle Scholar
  2. 2.
    Pfizer. US FDA approves DAURISMO™ (glasdegib) for adult patients with newly-diagnosed acute myeloid leukemia (AML) for whom intensive chemotherapy is not an option. 2018. http://www.pfizer.com/. Accessed 23 Nov 2018.
  3. 3.
    Pfizer. DaurismoTM (glasdegib) tablets, for oral use: US prescribing information. 2018. http://www.fda.gov/. Accessed 26 Nov 2018.
  4. 4.
    US FDA. FDA approves new treatment for patients with acute myeloid leukemia. 2018. http://www.fda.gov/. Accessed 23 Nov 2018.
  5. 5.
    US FDA. Orphan drug designations and approvals. 2017. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/listResult.cfm. Accessed 20 Dec 2018.
  6. 6.
    European Medicines Agency. Public summary of opinion on orphan designation: glasdegib maleate for the treatment of acute myeloid leukaemia. 2018. http://www.ema.europa.eu/. Accessed 23 Nov 2018.
  7. 7.
    Pfizer. New phase 2 results show investigational compound glasdegib improved overall survival in acute myeloid leukemia and high-risk myelodysplastic syndrome [media release]. http://www.pfizer.com. Accessed 3 Dec 2016.
  8. 8.
    Martinelli G, Oehler VG, Papayannidis C, et al. Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study. Lancet Haematol. 2015;2(8):e339–46.CrossRefGoogle Scholar
  9. 9.
    Wagner AJ, Messersmith WA, Shaik MN, et al. A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2015;21(5):1044–51.CrossRefGoogle Scholar
  10. 10.
    Lancet JE, Komrokji RS, Sweet KL, et al. Phase 2 trial of smoothened (SMO) inhibitor PF-04449913 (PF-04) in refractory myelodysplastic syndromes (MDS) [abstract]. In: 58th American Society of Hematology Annual Meeting. 2016.Google Scholar
  11. 11.
    Shaik N, Da Costa LM, Hee B, et al. A thorough QT study to evaluate the effect of glasdegib on cardiac repolarization in healthy adult subjects [abstract no. T-092]. J Pharmacokinet Pharmacodyn. 2018;45(Suppl 1):S87.Google Scholar
  12. 12.
    Lin S, Shaik M, Ruiz A. Population pharmacokinetics of glasdegib in patients with advanced hematologic and solid tumors [abstract no. PII-086]. Clin Pharmacol Ther. 2018;103(Suppl 1):S78.Google Scholar
  13. 13.
    Savona MR, Pollyea DA, Stock W, et al. Phase Ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. Clin Cancer Res. 2018;24(10):2294–303.CrossRefGoogle Scholar
  14. 14.
    Lam JL, Vaz A, Hee B, et al. Metabolism, excretion and pharmacokinetics of [14C] glasdegib (PF-04449913) in healthy volunteers following oral administration. Xenobiotica. 2017;47(12):1064–76.CrossRefGoogle Scholar
  15. 15.
    Minami Y, Minami H, Miyamoto T, et al. Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci. 2017;108(8):1628–33.CrossRefGoogle Scholar
  16. 16.
    Cortes JE, Heidel FH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2018.  https://doi.org/10.1038/s41375-018-0312-9.CrossRefPubMedGoogle Scholar
  17. 17.
    Tremblay G, Arondekar B, Chan G, et al. Covariate adjusted indirect treatment comparison (ITC) of glasdegib plus low dose Ara-C versus a hypomethylating agent for acute myeloid leukemia patients ineligible for intensive chemotherapy. In: 59th American Society of Hematology Annual Meeting. 2017.Google Scholar
  18. 18.
    Cortes JE, Douglas Smith B, Wang ES, et al. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: phase 2 study results. Am J Hematol. 2018;93(11):1301–10.CrossRefGoogle Scholar
  19. 19.
    Jamieson C, Cortes JE, Oehler V, et al. Phase 1 dose-escalation study of PF-04449913, an oral hedgehog (Hh) inhibitor, in patients with select hematologic malignancies [abstract no. 424]. Blood. 2011;118(21):424.Google Scholar
  20. 20.
    Borate U, Smith BD, Gore S, et al. Phase 1b study of glasdegib (PF-04449913) in combination with azacitidine in patients with higher risk myelodysplastic syndrome, oligoblastic acute myeloid leukemia, or chronic myelomonocytic leukemia [abstract no. P255]. Haematologica. 2016;101(Suppl 1):73–4.Google Scholar
  21. 21.
    Cortes JE, Dombret H, Merchant AA, et al. Phase 3, randomized, placebo-controlled trials evaluating glasdegib in combination with intensive or nonintensive chemotherapy in patients with untreated acute myeloid leukemia [abstract no. TPS7073]. J Clin Oncol. 2018;36(15 Suppl).Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

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