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Glasdegib
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] 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] HistoryGlasdegib 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] References
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