Regulatory Decision Summary for Daurismo

The study B1371003, an ongoing, multi-center, open-label Phase 1b/2 trial was evaluated to support the use of glasdegib when administered in combination with low-dose cytarabine (LDAC) for the treatment of newly diagnosed and previously untreated acute myeloid leukemia (AML) in adult patients, who are age ≥75 years or who are not eligible to receive intensive induction chemotherapy.

This study was divided into a dose finding Phase 1b portion and a safety and efficacy Phase 2 portions. The dose finding Phase 1b portion evaluated starting glasdegib doses of 100 mg or 200 mg once daily (QD) and aimed at estimating the maximum tolerated dose of glasdegib in combination with 1 of 3 different chemotherapy options (Arms A [LDAC], B [decitabine], and C [7 days cytarabine + 3 days daunorubicin]). The Phase 2 portion consisted of 2 parts to evaluate the safety and efficacy of glasdegib in combination with chemotherapeutics.

The data from the combination of glasdegib + LDAC in the specific indicated population of 116 AML patients resulted in a significant improvement in overall survival compared to LDAC alone (hazard ratio [HR] = 0.463 [95% CI: 0.299, 0.717], p = 0.0002; mOS [95% confidence interval (CI)]: 8.3 months [4.7, 12.2] vs 4.3 months [1.9, 5.7]).

The most frequently reported all-causality AEs (≥30%) in the glasdegib 100 mg+LDAC arm were anaemia (38 [45.2%] patients), febrile neutropenia and nausea (30 [35.7%] patients each), decreased appetite (28 [33.3%] patients), fatigue and thrombocytopenia (26 [31.0%] patients each). The most frequently reported Grade 3 or higher all-causality AEs (≥30%) were anaemia (35 [41.7%] patients), febrile neutropenia (30 [35.7%] patients) and thrombocytopenia (26 [31.0%] patients). The most frequently reported all-causality SAEs (≥15%) were febrile neutropenia and pneumonia; treatment-related SAEs (≥4%) were febrile neutropenia, anaemia and pneumonia.

Glasdegib is embryotoxic, fetotoxic, and teratogenic in animals, which are all known effects of smoothened (SMO) inhibitors. There will be implementation of a pregnancy prevention program (PPP) to mitigate the potential fetotoxicity of glasdegib.

The results provided sufficient evidence for the safety and efficacy of  the use of glasdegib when administered in combination with low-dose cytarabine (LDAC) in the population of patients enrolled in the pivotal portion of the  study (who are age ≥75 years or who are not eligible to receive intensive induction chemotherapy).

The Product Monograph has been appropriately labeled regarding the safety and efficacy of glasdegib + LDAC. Specific warnings, precautions, and information on the Daurismo drug distribution plan and PPP have been added based on the SMO inhibitor class effect.

The Benefit-Risk profile of Daurismo is deemed favourable for the recommended indication.