Summary Basis of Decision for Daurismo
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Daurismo is located below.
Recent Activity for Daurismo
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Daurismo
Date SBD issued: 2020-07-10
The following information relates to the new drug submission for Daurismo.
Glasdegib (supplied as glasdegib maleate)
Drug Identification Number (DIN):
- DIN 02498472 - 25 mg tablet, oral administration
- DIN 02498480 - 100 mg tablet, oral administration
Pfizer Canada ULC
New Drug Submission Control Number: 225793
On April 28, 2020, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the drug product Daurismo.
The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit‑harm‑uncertainty profile of Daurismo is favourable in combination with low‑dose cytarabine, 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.
Daurismo is only available through a controlled distribution program called the Daurismo Pregnancy Prevention Program (DPPP). Under this program, only prescribers and pharmacies registered with the program are able to prescribe and dispense the product, respectively. In addition, Daurismo can only be dispensed to patients who are registered and meet all the conditions of the DPPP.
1 What was approved?
Daurismo, an antineoplastic agent, was authorized in combination with low‑dose cytarabine, 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.
Daurismo is only available through a controlled distribution program called the Daurismo Pregnancy Prevention Program (DPPP). Under this program, only prescribers and pharmacies registered with the program are able to prescribe and dispense the product, respectively. In addition, Daurismo can only be dispensed to patients who are registered and meet all the conditions of the DPPP.
The safety and efficacy of Daurismo in the pediatric population (<18 years of age) have not been established. Adverse changes in growing bone, including premature partial to complete closure of the epiphyseal plate were observed in non‑clinical toxicity studies. Daurismo is not indicated for use in the pediatric population.
In the clinical studies of Daurismo with low-dose cytarabine, 98% of the patients were age 65 years or older and 60% of the patients were age 75 years or older.
Daurismo is contraindicated in:
- female patients who are pregnant,
- breastfeeding female patients,
- female patients of childbearing potential who do not comply with effective contraceptive measures,
- male patients who do not comply with effective contraceptive measures.
- children and adolescents aged below 18 years, or
- patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non‑medicinal ingredient, or component of the container.
Daurismo was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Daurismo (25 mg and 100 mg glasdegib, supplied as glasdegib maleate) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains dibasic calcium phosphate anhydrous, hypromellose, iron oxide yellow (25 mg tablet), iron oxide red and iron oxide yellow (100 mg tablet), lactose monohydrate, macrogol, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide, and triacetin.
For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Daurismo Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Daurismo approved?
Health Canada considers that the benefit‑harm‑uncertainty profile of Daurismo is favourable 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.
Daurismo is only available through a controlled distribution program called the Daurismo Pregnancy Prevention Program (DPPP). Under this program, only prescribers and pharmacies registered with the program are able to prescribe and dispense the product, respectively. In addition, Daurismo can only be dispensed to patients who are registered and meet all the conditions of the DPPP.
Acute myeloid leukemia is a heterogeneous group of aggressive blood cancers, characterized by increased blast counts, pancytopenia causing infections and bleeding, and reduced survival. It is the second most common category of leukemia in adults, and the most common type of acute leukemia. The median age of patients at diagnosis is 65 years, and the incidence increases with age. Standard treatments with intensive induction chemotherapy may induce complete remissions in the majority of patients, but disease relapse remains a significant problem, resulting in decreased survival.
Glasdegib, the medicinal ingredient in Daurismo, is an inhibitor of the Smoothened (SMO) protein. The SMO protein is involved in Hedgehog signalling, which has key roles in a wide range of biological processes and is disrupted in various types of cancer.
A pivotal Phase Ib/II study, BRIGHT AML 1003 (Study B1371003), was conducted in patients aged 55 years and older with newly diagnosed AML to evaluate the clinical efficacy and safety of Daurismo in combination with LDAC compared to treatment with LDAC alone. The primary endpoint of this study was overall survival. A significant improvement was observed in patients with AML treated with Daurismo and LDAC relative to patients treated with LDAC alone.
Daurismo was generally well tolerated, and the observed safety profile was consistent with that established for elderly patients with AML receiving chemotherapy. In patients treated with Daurismo combined with LDAC, the most frequently reported all‑causality adverse events (in ≥30% of patients) were anemia, febrile neutropenia, nausea, decreased appetite, fatigue, and thrombocytopenia.
Co-administration of Daurismo with cytochrome P450 (CYP) 3A4 inducers or drugs prolonging the QTc interval should be avoided. The Daurismo Product Monograph contains a list of established or potential drug‑drug interactions, along with appropriate precautionary measures.
A Serious Warnings and Precautions box has been included in the Daurismo Product Monograph to highlight several risks. These risks are primarily related to reproductive toxicity and the need for patients to comply with the conditions of the controlled distribution program.
A Risk Management Plan (RMP) for Daurismo was submitted by Pfizer Canada ULC to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Daurismo Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Daurismo was accepted.
Daurismo has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Daurismo Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Daurismo?
Submission Milestones: Daurismo
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2018-07-17 - 2018-10-11 |
| Submission filed: | 2019-03-15 |
| Screening | |
| Screening Deficiency Notice issued: | 2019-05-02 |
| Response filed: | 2019-05-29 |
| Screening Acceptance Letter issued: | 2019-07-05 |
| Review | |
| Biostatistics Evaluation complete: | 2020-02-04 |
| Review of Risk Management Plan complete: | 2020-03-06 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2020-04-06 |
| Quality Evaluation complete: | 2020-04-27 |
| Clinical/Medical Evaluation complete: | 2020-04-27 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2020-04-28 |
The Canadian regulatory decision on the review of Daurismo was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was consulted as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post‑market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Glasdegib, the medicinal ingredient in Daurismo, is an inhibitor of the Hedgehog signal transduction pathway. Hedgehog signalling is involved in a wide range of biological processes and disrupted in various types of cancer. Glasdegib binds to Smoothened (SMO), a transmembrane protein which stimulates the nuclear localization of glioma‑associated oncogene (GLI) transcription factors and the induction of Hedgehog target genes. The binding of glasdegib to SMO inhibits SMO activity, thereby blocking Hedgehog signalling. The SMO protein is implicated in the maintenance of leukemic stem cell dormancy and resistance to chemotherapy and targeted therapy.
The pharmacokinetics of glasdegib was well characterized in patients and in healthy subjects. The pharmacokinetic studies included in the submission were adequately designed, and reasonable conclusions were drawn based on the findings of the studies. The population pharmacokinetic analysis was conducted adequately, and overall, the final model fits the observed data. The conclusions drawn from the pharmacokinetic studies are considered robust.
For further details, please refer to the Daurismo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Daurismo was demonstrated through a pivotal Phase Ib/II study, BRIGHT AML 1003 (Study B1371003). This study was conducted in 116 patients aged 55 years and older with newly diagnosed acute myeloid leukemia (AML), who met at least one of the following criteria:
- age ≥75 years,
- severe cardiac disease,
- baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, or
- baseline serum creatinine >1.3 mg/dL.
The study also included 16 patients with high‑risk myelodysplastic syndrome (MDS). Although Daurismo was not authorized for the treatment of MDS, data from the patients with MDS were included in the safety analysis.
In Phase Ib, 100 mg Daurismo once daily was selected as the recommended dose for Phase II, based on the observed tolerability profile in combination with low‑dose cytarabine (LDAC) or intensive chemotherapy.
In Phase II, patients were randomized in a 2:1 ratio to receive 100 mg Daurismo once daily in combination with LDAC (number of patients [n] = 78), or LDAC alone (n = 38). In each group, LDAC was administered subcutaneously twice per day, on Days 1 to 10 of a 28‑day cycle. Treatment in both groups continued until disease progression or until the patient experienced an unacceptable level of toxicity. Patients were stratified based on cytogenetic risk (good/intermediate or poor) at the time of randomization. The median follow‑up time was 20 months.
The primary endpoint of this study was overall survival (OS), measured from the date of randomization, to death from any cause. Among the 116 patients with AML, a significant improvement was observed in patients treated with Daurismo and LDAC relative to patients treated with LDAC alone. The hazard ratio (HR) was 0.463 (95% confidence interval [CI]: 0.299, 0.717; p = 0.0002). The median OS values (95% CI) were 8.3 months (4.7, 12.2) in patients treated with Daurismo and LDAC, and 4.3 months (1.9, 5.7) in patients treated with LDAC alone.
Indication
| Sponsor's proposed indication | Health Canada-approved indication |
| Daurismo (glasdegib) is indicated, in combination with low‑dose cytarabine, for the treatment of adult patients with previously untreated acute myeloid leukemia (AML). | Daurismo (glasdegib) is indicated, in combination with low‑dose cytarabine, 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. |
The indication was revised to more accurately reflect the patient population in the pivotal study.
For more information, refer to the Daurismo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
Daurismo was well‑tolerated in patients with AML, with 13 of 75 patients (78 patients at study initiation) continuing treatment with Daurismo and LDAC for one year or longer. None of the 36 patients treated with LDAC alone (38 patients at study initiation) continued treatment for one year or longer.
The safety profile observed for Daurismo was consistent with that established for elderly patients with AML receiving chemotherapy, including cytopenias (not accompanied by increased frequencies of sepsis or bleeding) and gastrointestinal adverse events. It was also in line with the known safety profile of SMO inhibitors.
In patients treated with 100 mg Daurismo combined with LDAC, the most frequently reported all‑causality adverse events (in ≥30% of patients) were anemia (45.2%), febrile neutropenia (35.7%), nausea (35.7%), decreased appetite (33.3%), fatigue (31.0%,) and thrombocytopenia (31.0%). The most frequently reported Grade 3 or higher all‑causality adverse events were anemia (41.7%), febrile neutropenia (35.7%) and thrombocytopenia (31.0%). The most frequently reported all‑causality serious adverse events (in ≥15% of patients) were febrile neutropenia and pneumonia, and the most frequently reported treatment‑related serious adverse events (in ≥4% of patients) were febrile neutropenia, anemia and pneumonia.
Co-administration of Daurismo with cytochrome P450 (CYP) 3A4 inducers or drugs prolonging the QTc interval should be avoided. This has been specified in a list of established or potential drug‑drug interactions in the Daurismo Product Monograph, along with appropriate precautionary measures.
A Serious Warnings and Precautions box has been included in the Daurismo Product Monograph to highlight several risks, primarily related to reproductive toxicity. Daurismo is available only through a controlled distribution program called the Daurismo Pregnancy Prevention Program (DPPP), as it was shown to be embryotoxic, fetotoxic, and teratogenic in animals. The requirements of the DPPP are detailed in the Daurismo Product Monograph, and patients must agree to all conditions prior to starting treatment.
The Serious Warnings and Precautions box also highlights the fact that Daurismo is not indicated for use in pediatric patients, and has not been studied in this population. Additionally, Daurismo should be initiated and monitored only under the supervision of a physician qualified in the use of cancer therapies, and with a full understanding of the risks of Daurismo therapy and monitoring requirements.
Health Canada has determined that appropriate measures are in place to address the safety concerns identified for Daurismo. The benefit‑harm‑uncertainty profile is considered favourable for the patient population for which Daurismo is indicated, due to the severity of the disease and the limited treatment options available.
For more information, refer to the Daurismo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Glasdegib, the medicinal ingredient in Daurismo, was efficacious against tumours in a medulloblastoma tumour model. In patient‑derived xenograft models of acute myeloid leukemia, the combination of glasdegib and cytarabine was more beneficial than cytarabine alone, or the combination of cytarabine and daunorubicin. In safety pharmacology studies in dogs, no adverse effects were observed on the central nervous system and respiratory system. However, prolongation of the QTc interval was detected in telemetered dogs.
Glasdegib was widely distributed in the tissues, with the highest concentrations detected in the uveal tract, liver, kidney and renal structures, adrenal gland, and pancreas. The kidney was the main target organ of toxicity, based on repeat‑dose toxicity studies in rats and dogs. Signs of toxicity were also detected in growing bones and teeth, the testes, and peripheral nerves in rats only, and in the liver in dogs only. Weight loss, alopecia, and muscle tremors/twitching, which are known class effects of SMO inhibitors, were all observed in both rats and dogs. These toxicities were generally dose‑dependent and observed at exposures from <0.03 to 8 times the clinically relevant exposure. After 16 weeks of recovery, toxicities affecting the kidneys, peripheral nerves, and seminiferous tubules, and the observed muscle tremors/twitching were found to be completely reversible. Partial recovery was observed in the liver. No recovery was observed with respect to weight loss, alopecia, effects on bones and teeth, and testicular hypospermatogenesis.
The major metabolic pathways for glasdegib are oxidation (N‑demethylation, hydroxylation, and dehydrogenation) and glucuronidation. Three metabolites of glasdegib were detected in humans, but not in non‑clinical species. According to International Council for Harmonisation (ICH) guidelines, characterization was not required, as exposure to each metabolite was less than 10% in the non‑clinical toxicity studies. The ICH guidelines also state that evaluation of metabolites not identified in the non‑clinical toxicity species is not warranted for treatments indicated for advanced cancer.
Glasdegib was not found to be genotoxic, and tested negative in assays evaluating mutagenicity, clastogenicity, and aneugenicity. Carcinogenicity was not evaluated, as it is not required according to ICH guidelines.
The effects of glasdegib on embryo‑fetal development were examined in rats and rabbits. Repeat dosing of glasdegib during the period of organogenesis resulted in embryotoxicity, fetotoxicity, teratogenicity, and embryo‑fetal lethality in both species. The complete resorption of fetuses, low fetal body weights, and fetal developmental abnormalities or malformations were all observed following the administration of glasdegib. A no‑observed‑adverse‑effect level (NOAEL) was not established for developmental effects of glasdegib in either species.
No dedicated fertility studies were conducted with glasdegib. However, adverse effects including hypospermatogenesis and the degeneration of seminiferous tubules were detected in repeat‑dose toxicity studies in rats.
There were no studies conducted to determine whether glasdegib can be secreted into milk.
The results of the non‑clinical studies as well as the potential risks to humans have been included in the Daurismo Product Monograph. Considering the intended use of Daurismo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Daurismo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Daurismo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| DAURISMO | 02498472 | PFIZER CANADA ULC | GLASDEGIB (GLASDEGIB MALEATE) 25 MG |
| DAURISMO | 02498480 | PFIZER CANADA ULC | GLASDEGIB (GLASDEGIB MALEATE) 100 MG |