Summary Basis of Decision for Mylotarg

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Mylotarg is located below.

Recent Activity for Mylotarg

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 Mylotarg

Date SBD issued: 2020-07-10

The following information relates to the new drug submission for Mylotarg.

Gemtuzumab ozogamicin

Drug Identification Number (DIN):

  • DIN 02494388 - 4.5 mg/vial powder for solution, intravenous administration

Pfizer Canada ULC

New Drug Submission Control Number: 223091

On November 28, 2019, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the drug product, Mylotarg.

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-risk profile of Mylotarg is favourable for use in combination therapy with daunorubicin (DNR) and cytarabine (AraC) in the treatment of adult patients with previously untreated, de novo CD33‑positive acute myeloid leukemia (AML), except acute promyelocytic leukemia.

1 What was approved?

Mylotarg, an anti neoplastic, was authorized for use in combination therapy with daunorubicin (DNR) and cytarabine (AraC) in the treatment of adult patients with previously untreated, de novo CD33‑positive acute myeloid leukemia (AML), except acute promyelocytic leukemia.

Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Mylotarg in combination with chemotherapy in pediatric patients with newly diagnosed AML has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

Use of Mylotarg in combination with DNR and AraC in newly‑diagnosed adult patients with de novo AML is supported by a randomized, controlled trial that included 50 patients greater than or equal to 65 years of age. No overall differences in safety or effectiveness were observed in this trial between these subjects and younger subjects.

Mylotarg is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Mylotarg 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.

Mylotarg (4.5 mg/vial gemtuzumab ozogamicin) is presented as a single-use vial containing 4.5 mg of lyophilized powder for solution for intravenous infusion only. In addition to the medicinal ingredient, the powder also contains the following non‑medicinal ingredients: dextran 40; dibasic sodium phosphate, anhydrous; monobasic sodium phosphate, monohydrate; sodium chloride; and sucrose.

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 Mylotarg Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Mylotarg approved?

Health Canada considers that the benefit-risk profile of Mylotarg is favourable for use in combination therapy with daunorubicin (DNR) and cytarabine (AraC) in the treatment of adult patients with previously untreated, de novo CD33‑positive acute myeloid leukemia (AML), except acute promyelocytic leukemia.

Acute myeloid leukemia is a heterogeneous disease of the blood and bone marrow that has an extremely poor prognosis. Acute myeloid leukemia is primarily a disease of later adulthood, with reported median ages at diagnosis between 65 to 67 years. Acute myeloid leukemia does occur in children, however it is less common. The 5-year survival for patients developing AML is estimated to be 21%. Acute myeloid leukemia is associated with a number of morphological, cytogenetic, molecular and immunophenotypic characteristics, which along with patient characteristics, guide treatment decisions and impact survival outcomes. The current standard therapy for patients with de novo AML includes a combination chemotherapy regimen consisting of DNR and cytarabine AraC. This is used in both an induction and consolidation phase of treatment. Midostaurin can be added to standard induction therapy and as maintenance therapy in patients with newly diagnosed AML that harbours a FMS-like tyrosine kinase 3 gene (FLT3) mutation.

The efficacy of Mylotarg, in combination with chemotherapy (DNR and AraC), as a first‑line treatment of patients with previously untreated, de novo AML was primarily evaluated in a Phase III clinical trial, ALFA‑0701. The trial design was an open‑label, parallel arm, multicentre clinical trial. The modified intent-to-treat population consisted of 271 randomized patients in total, 135 patients in the Mylotarg arm and 136 patients in the control arm. The study population included patients that were between 50 and 70 years of age. The primary endpoint of the trial was event free survival. Results from the trial, based on independent review analysis, demonstrated that the addition of Mylotarg to a standard chemotherapy regimen of DNR and AraC resulted in a clinically meaningful improvement in the event‑free survival, with a 34% reduction in the risk of induction failure, relapse or death with a hazard ratio (HR) = 0.66 (95% confidence interval [CI]: 0.49, 0.89). The median time to event, was 13.6 months (95% CI: 9.0, 19.2) for the Mylotarg arm and 8.5 months (95% CI: 7.5, 12.0) for the control arm. In addition, overall survival results showed a 19% reduction in the risk of death (HR = 0.81 [95% CI: 0.60, 1.1]). The median time to event, as estimated by the Kaplan‑Meier analysis, was 27.5 months (95% CI: 21.4, 45.6) for patients in the Mylotarg arm and 21.8 months (95% CI: 15.5, 27.4) for patients in the control arm. The overall survival result was not statistically significant.

The overall safety profile of Mylotarg is based on data from patients with AML from the combination therapy study ALFA‑0701, monotherapy studies, and from post-marketing experience. Retrospective review showed that the majority of patients in the trial experienced a treatment emergent adverse event (TEAE), 98.5% of patients in the Mylotarg arm and 94.2% of patients in the control arm. The incidence of hemorrhage and veno-occlusive disease, any Grade and Grade ≥3 was higher for patients in the Mylotarg arm compared to the control arm. The most commonly reported TEAEs that occurred with a higher incidence in the Mylotarg arm were epistaxis, purpura, hematoma, petechiae, blood blister, hematuria, gingival bleeding, mouth hemorrhage, and thrombocytopenia.

The incidence of treatment‑emergent serious adverse events (TESAEs) was higher for patients in the Mylotarg arm compared to the control arm, 67.2% vs. 55.5% respectively. The most commonly reported TESAEs in the Mylotarg arm were, thrombocytopenia, bronchopulmonary aspergillosis, septic shock, febrile bone marrow aplasia and bacterial sepsis.

To address the major safety concerns, a Serious Warnings and Precautions box containing increased risks of hepatotoxicity (including venoocclusive disease/sinusoidal obstruction syndrome), myelosuppression/cytopenias (including infections and bleeding/hemorrhagic events), tumor lysis syndrome, and infusion‑related reactions was included in the Mylotarg Product Monograph.

A Risk Management Plan (RMP) for Mylotarg 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 Mylotarg 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 Mylotarg was accepted.

Overall, the therapeutic benefits of Mylotarg therapy seen in the ALFA‑0701 clinical trial is positive and the benefits of Mylotarg therapy is considered to outweigh the potential risks. Mylotarg has an acceptable safety profile based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling, adequate monitoring, and treatment interruptions or modifications. Appropriate warnings and precautions are in place in the Mylotarg 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 Mylotarg?

Submission Milestones: Mylotarg

Submission MilestoneDate
Pre-submission meeting:2018-05-22
Submission filed:2018-12-19
Screening
Screening Acceptance Letter issued:2019-02-01
Review
Review of Risk Management Plan complete:2019-09-30
Quality Evaluation complete:2019-11-14
Clinical/Medical Evaluation complete:2019-11-25
Labelling Review complete:2019-11-25
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate:2019-11-28

The Canadian regulatory decision on the review of Mylotarg was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Gemtuzumab ozogamicin (the medicinal ingredient in Mylotarg) is an antibody‑drug conjugate composed of the CD33-directed monoclonal antibody (hP67.6; recombinant humanized immunoglobulin [Ig] G4, kappa antibody) that is covalently linked to the cytotoxic antitumor antibiotic calicheamicin (N‑acetyl gamma‑calicheamicin dimethyl hydrazide). Once introduced into the human body, through intravenous infusion, the antibody portion of gemtuzumab ozogamicin binds specifically to the CD33 antigen. The CD33 antigen is a protein found on the surface of myeloid leukemic blasts and immature normal cells of myelomonocytic lineage, but not on normal hematopoietic stem cells. After gemtuzumab ozogamicin binds to the CD33 antigen, the antigen‑antibody complex moves to the inside of the cell. Once inside the cell, the calicheamicin derivative is released. The calicheamicin derivative attaches to the deoxyribonucleic acid (DNA), resulting in DNA double‑strand breaks and death of the myeloid cell.

In vitro cytotoxicity assays showed that gemtuzumab ozogamicin was effective at selectively killing human leukemia cell line (HL‑60) target cells. Saturation of a high percentage of CD33 antigenic sites is presumed to be required for maximum delivery of calicheamicin to leukemic blast cells. Near maximal peripheral CD33 saturation was observed across studies after gemtuzumab ozogamicin dosing at dose levels of 2 mg/m2 and above.

The pharmacokinetic of gemtuzumab ozogamicin is described by measuring pharmacokinetic characteristics of the antibody (hP67.6) as well as total and unconjugated calicheamicin derivatives. Given that the hP67.6 portion renders target selectivity on the intact molecule, and that Mylotarg dosages are reported in terms of milligrams of protein (hP67.6), the hP67.6 concentration results are reported as the primary pharmacokinetic measures. After gemtuzumab ozogamicin binds to the target it is internalized and N-acetyl calicheamicin dimethyl hydrazide is released by hydrolytic cleavage.

No clinical pharmacokinetic data have been collected using the fractionated regimen; however, the pharmacokinetics have been simulated using a standard two-compartment population pharmacokinetic model with time-dependent clearance from the central compartment. Based on the simulations, although the total dose of the fractionated dosing regimen is half of that of the original dosing regimen (9 versus 18 mg/m2), the predicted total area under the plasma concentration time curve (AUC) of hP67.6 over the course of treatment is 25%, and maximum observed concentration (Cmax) is 24%, of the values for original 9 mg/m2 dosing regimen, since the pharmacokinetic is nonlinear. When gemtuzumab ozogamicin is administered at 3 mg/m2 on Days 1, 4, and 7, the Cmax of hP67.6, which would occur at the end of infusion, is predicted to be 0.38 mg/L following the first dose and increased to 0.63 mg/L after the third dose.

Overall, the pharmacodynamic and population pharmacokinetic model studies included in the Mylotarg New Drug Submission support the use of Mylotarg for the recommended indication.

For further details, please refer to the Mylotarg Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Mylotarg (gemtuzumab ozogamicin) in combination with daunorubicin (DNR) and cytarabine (AraC) for the treatment of adult patients with previously untreated de novo acute myeloid leukemia (AML) was based primarily on a Phase III, randomized, two parallel‑arm, open‑labelled clinical trial known as ALFA‑0701. The primary objective of the trial was to compare the clinical efficacy of daunorubicin (DNR) and cytarabine (AraC) in combination with fractionated doses of Mylotarg versus DNR and AraC alone.

The trial design of ALFA‑0701 consisted of 271 patients randomized in a 1:1 ratio to either the Mylotarg treatment arm (Mylotarg + DNR + AraC; number of patients [n] = 135) or to the control arm (DNR + AraC; n = 136). Depending on the randomized treatment arm, patients received induction therapy consisting of DNR (60 mg/m2 on Days 1 to 3) and AraC (200 mg/m2 on Days 1 to 7) in combination with or without Mylotarg 3 mg/m2 (up to maximum of one 4.5 mg vial) on Days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with DNR + AraC at the following dosing: DNR 35 mg/m2/day on Days 1 and 2, and AraC 1 g/m2 every 12 hours on Day 1 to Day 3. Mylotarg was not administered during second induction. Patients who experienced a response then received consolidation therapy with 2 courses of treatment including DNR (60 mg/m2 on Day 1 of consolidation course 1; 60 mg/m2 on Days 1 and 2 of consolidation course 2) and AraC (1 g/m2 every 12 hours on Days 1 to 4) with or without Mylotarg 3 mg/m2 (up to a maximum of one vial) on Day 1 according to their initial randomization. Patients who experienced remission were also eligible for allogeneic transplantation. An interval of at least 2 months between the last dose of Mylotarg and transplantation was recommended.

The primary efficacy endpoint in the ALFA‑0701 clinical trial was event‑free survival, as measured from the date of randomization until induction failure, relapse, or death by any cause. Induction failure and relapse were assessed by independent review with the date of induction failure set at the randomization date. The key secondary endpoint was overall survival. Overall survival was defined as the time from date of randomization to date of death due to any cause. Overall response, defined by patients who had a complete remission or complete remission with incomplete platelet recover was also assessed.

For the primary analysis of the trial, the median follow‑up time was 25.5 months for patients in the Mylotarg arm and 22.1 months for patients in the control arm. Results from the primary analysis demonstrated that Mylotarg added in fractionated doses (3 mg/m2 × 3) to standard induction chemotherapy for patients with previously untreated de novo AML resulted in a statistically significant improvement in event‑free survival. Based on independent review, the median time to event, as estimated by the Kaplan‑Meier analysis, was 13.6 months (95% confidence interval [CI]: 9.0, 19.2) for the Mylotarg arm and 8.5 months (95% CI: 7.5, 12.0) for the control arm. The corresponding hazard ratio (HR) was estimated to be 0.66 (95% CI: 0.49, 0.89), representing a 34% reduction in the risk of induction failure, relapse or death. The event‑free survival results, as per investigator assessment, were consistent with the independent review assessment with event‑free survival of 17.3 months in the Mylotarg arm and 9.5 months in the control arm (HR: 0.56, 95% CI: 0.42, 0.76). The independent review analysis of event‑free survival was considered, by Health Canada, to be the most relevant analysis of event‑free survival for this study. This analysis addressed concerns of bias and confounding factors that were expected in the investigator assessment based on the study design.

A key secondary endpoint in the ALFA‑0701 study was overall survival. The median follow‑up time for overall survival was 47.6 months and 41.0 months for patients in the Mylotarg arm and control arm, respectively. The median time to event, as estimated by the Kaplan‑Meier analysis, was 27.5 months (95% CI: 21.4, 45.6) for patients in the Mylotarg arm and 21.8 months (95% CI: 15.5, 27.4) for patients in the control arm. The HR for overall survival was estimated to be 0.81 (95% CI: 0.60, 1.10), representing a 19% reduction in the risk of death. However, the result for overall survival was not statistically significant.

Additionally, overall response, among the 271 randomized patients, was 74.1% for patients in the Mylotarg arm and 70.6% for patients in the control arm.

Indication

The New Drug Submission for Mylotarg was filed by the sponsor with the following indication:

  • Mylotarg is indicated for combination therapy with daunorubicin and cytarabine for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukemia (AML), except acute promyelocytic leukemia.

Health Canada revised the proposed indication and removed the wording 'patients age 15 years and above' and changed it to 'adult patients' based on the evidence submitted. The results observed in the meta‑analysis and the COG AAML0531 were insufficient to support an indication for patients aged 15 to 17 years old.

  • Mylotarg is indicated for combination therapy with daunorubicin and cytarabine for the treatment of adult patients with previously untreated, de novo CD33 positive acute myeloid leukemia (AML), except acute promyelocytic leukemia.

Supportive Study

Study COG AAML0531 was conducted in 1,063 pediatric and young adult patients, age 1 month to 29 years, with newly diagnosed de novo AML. The objective of this study was to compare the event‑free survival and overall survival of de novo AML patients randomized between the best current chemotherapy with or without Mylotarg.

The study design was a randomized, unblinded, Phase III study where patients were randomly assigned to either standard 5‑course chemotherapy alone (cytarabine, daunorubicin, and etoposide) or to the same chemotherapy with 2 doses of Mylotarg (3 mg/m2/dose). Mylotarg was administered once during induction treatment (Course 1) and once during intensification treatment (Course 2). The primary efficacy endpoint of event-free survival was improved for the Mylotarg arm (HR: 0.84; 95% CI: 0.71, 1.0) with marginally statistical significance (p = 0.0431). Overall survival was not improved in the Mylotarg arm compared to the no Mylotarg arm (HR: 0.90; 95% CI: 0.72, 1.33).

During the second intensification period, a larger proportion of patients in the Mylotarg arm experienced prolonged neutrophil recovery time (>59 days) as compared with the comparator arm (21.0% versus 11.5%), and while there were more deaths due to the disease under study in the comparator arm (83 [15.6%] versus 57 [10.7%] patients in the Mylotarg arm), there were more deaths due to infection in the Mylotarg arm (26 [4.9%] versus 16 [3.0%] patients in the comparator arm). The optimal dose of Mylotarg for use in pediatric patients has not been established. The study design had several limitations and the results of this study require cautious interpretation.

Overall, the results obtained from study COG AAML0531 do not provide sufficient evidence to support authorizing Mylotarg in the pediatric population with dosing regimen recommended in adult patients as shown in the Mylotarg Product Monograph for the following reasons:

  • event‑free survival was marginally significant with open‑label design and the event‑free survival was not blinded reviewed centrally. Additionally, there was no difference in overall survival between treatment arms;
  • some young adults were included in the trial;
  • the types, treatment course, and dosing regimen of chemotherapies were different from what were used in pivotal trial;
  • the dosing regimen of Mylotarg was different from what was used in the pivotal trial and what was recommended in the approved Mylotarg Product Monograph;
  • more patients died of infection in the Mylotarg treatment arm than in the no Mylotarg treatment arm. The optimal dose of Mylotarg in combination of chemotherapy cannot be established with the study.

Meta-analysis

The purpose of the meta-analysis was to assess efficacy and safety of Mylotarg in combination of chemotherapy compared with chemotherapy alone for newly diagnosed patients with AML and myelodysplastic syndrome.

A total of 5 randomized, open-label Phase III trials met the selection criteria. Individual patient data from these trials was included in this meta-analysis. Patients at least 15 years old with previous untreated AML were randomized to receive either standard induction chemotherapy or Mylotarg in combination with standard chemotherapy in these trials.

Among 3,331 patients included in the analysis, 1,663 patients (49.9%) were randomized to Mylotarg (3 mg/m² single dose, 3 × 3 mg/m² fractionated, or 6 mg/m² single dose) while 1,668 patients (50.1%) were randomized to chemotherapy alone (No Mylotarg).

The results obtained from the meta-analysis are insufficient to support an indication for patients aged 15 to 17 years old as only one trial included in meta-analysis contained pediatric patients (n = 44) and this trial failed to demonstrate efficacy of Mylotarg.

Based on the totality of evidence provided with respect to safety and efficacy of use in the pediatric population, a positive benefit-risk profile could not be established for patients between 15 to 17 years of age.

For more information, refer to the Mylotarg Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The overall safety evaluation of Mylotarg was based on data from the pivotal trial ALFA‑0701, previously described in the Clinical Efficacy section, monotherapy studies, and from post-marketing experience. The safety population from the pivotal trial ALFA‑0701 was represented by patients who had received at least one dose of Mylotarg (n = 131) or control treatment (n = 137).

Retrospective review showed that the majority of patients in the pivotal trial experienced a treatment‑emergent adverse event (TEAE), 98.5% of patients in the Mylotarg arm and 94.2% of patients in the control arm. The incidence of hemorrhage and veno-occlusive disease (VOD), any Grade and Grade ≥3 was higher for patients in the Mylotarg arm compared to the control arm. The most commonly reported TEAEs (any Grade) that occurred with a higher incidence in the Mylotarg arm were epistaxis (Mylotarg: 62.6% vs. control: 36.5%), purpura (Mylotarg: 26.0 vs. control: 14.6%), hematoma (Mylotarg: 25.2% vs. control: 17.5%), petechiae (Mylotarg: 22.9% vs. control: 16.8%), blood blister (Mylotarg: 22.1% vs. control: 8.0%), hematuria (Mylotarg: 19.1% vs. control: 10.2%), gingival bleeding (Mylotarg: 17.6% vs. control: 8.8%), mouth hemorrhage (Mylotarg: 16.0% vs. control: 4.4%) and, thrombocytopenia (Mylotarg: 15.3% vs. control: 0%).

The incidence of treatment‑emergent serious adverse events (TESAE) was higher for patients in the Mylotarg arm compared to the control arm, 67.2% vs. 55.5% respectively. The most clinically relevant serious adverse reactions in the Mylotarg arm were hepatotoxicity, including veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) (3.8%), hemorrhage (9.9%), severe infection (41.2%), and tumor lysis syndrome (TLS) (1.5%), and infusion related reactions. A Serious Warnings and Precautions box has been included in the Mylotarg Product Monograph to highlight these serious adverse reactions. The most commonly reported TESAEs in the Mylotarg arm were thrombocytopenia, bronchopulmonary aspergillosis, septic shock, febrile bone marrow aplasia, and bacterial sepsis. The incidence of fatal TEAE was similar between treatment arms.

Treatment discontinuations due to TEAEs was higher in the Mylotarg arm compared to the control arm, and mainly due to higher incidences of thrombocytopenia and VOD. The most frequently occurring hepatobiliary disorder was VOD. Two incidences of fatal VOD occurred in the Mylotarg arm. Of note, the majority of VOD cases developed without prior hematopoietic stem cell transplant. The incidence of hepatobiliary disorders, other than VOD, was higher for patients in the Mylotarg arm. The increase in the Mylotarg arm was due to higher incidences of hepatitis cholestatic, cholestatic liver injury, mixed liver injury, drug induced liver injury, and abnormal liver function tests.

Higher incidence of liver chemistry laboratory abnormalities were also observed for patients in the Mylotarg arm compared to the control arm. A higher incidence of Grade 3 and Grade 4 laboratory values were observed for patients in the Mylotarg arm, which included high alkaline phosphatase, high aspartate aminotransferase (AST), high bilirubin, low phosphate, low potassium, and low sodium. Patients in the Mylotarg arm experienced a higher incidence of persistent thrombocytopenia, and the time to recovery of platelets was longer for patients in the Mylotarg arm compared to the control arm. This was consistently observed throughout the treatment phases. In addition, the median number of platelet transfusions was higher for patients in the Mylotarg arm compared to the control arm, 23.0 vs. 12.0 respectively.

The number of deaths that occurred during the ALFA‑0701 trial was 80 (59.3%) in the Mylotarg arm and 88 (64.7%) in the control arm. Disease progression or relapse was the most common reason for death. Deaths as a result of septic shock, hemorrhage, and liver toxicity occurred more frequently in patients in the Mylotarg arm. The occurrence of early deaths (within 28 or 30 days of last dose of any study treatment) was similar between treatment arms. Treatment‑related mortality was slightly higher for patients in the Mylotarg arm, 5.3% versus 3.6% in the control arm. The increase was driven by deaths due to hemorrhage and hepatotoxicity. Overall, these risks have been captured appropriately in the Mylotarg Product Monograph.

During review of the Mylotarg New Drug Submission, the analysis of cardiac safety performed was deemed inadequate. No clinical cardiovascular examination of QT or PR prolongation was performed. Both QT and PR prolongations are a known risk associated with other antibody‑drug conjugates containing calicheamicin. QT prolongation has been observed in patients who have been treated with Mylotarg. This identified safety risk has been included in the Mylotarg Product Monograph. In addition, there is limited data on anti‑drug antibodies (ADA). Immunogenicity has been identified as an important potential risk in the Mylotarg Risk Management Plan. The sponsor currently has an ongoing Phase IV clinical trial (B1761031), which examines Mylotarg monotherapy in patients with relapsed/refractory CD33 positive AML. This study is examining pharmacokinetics, corrected QT-interval (QTc), and ADAs. The sponsor shall submit the results of this trial to Health Canada, if the trial outcomes impact the benefit/risk balance of Mylotarg.

For more information, refer to the Mylotarg Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non‑clinical toxicologic profile of gemtuzumab ozogamicin (the medicinal ingredient in Mylotarg) has been well characterized through the conduct of single- and repeat‑dose toxicity studies of up to 12 weeks in duration, and genetic toxicity, fertility (male and female) and early embryonic development, embryo fetal development, and tissue cross reactivity studies. Additional studies were conducted with N‑acetyl gamma‑calicheamicin dimethyl hydrazide and included single- and repeat‑dose toxicity studies of up to 6 weeks in duration, phototoxicity, and genetic toxicity studies.

The primary target organ effects of gemtuzumab ozogamicin were identified in liver, hematolymphopoietic tissues, kidney, eye, and male and female reproductive organs in both rats and monkeys following single- and/or repeat‑dose administration. Class effects observed with other antibody‑calicheamicin conjugates included nervous system findings (axonal degeneration) and neoplastic lesions (liver) in rats. Liver findings in monkeys with gemtuzumab ozogamicin and in an investigational antibody‑calicheamicin conjugate were consistent with microvascular liver injury and were considered to represent early stages of VOD/SOS, morphologically similar to that reported in clinical trials. Partial to complete reversibility of toxicities was demonstrated in the 6‑week studies in rats and monkeys following a 4‑week non‑dosing period, except for liver, kidney, and male reproductive effects in rats, and lymphoid atrophy/depletion in the monkey. However, because of differences in absorption, distribution, metabolism, and excretion characteristics for gemtuzumab ozogamicin and N‑acetyl gamma‑calicheamicin dimethyl hydrazide, there were differences in the severity and/or incidence of the toxicities between the two molecules. Dose-related decreases in body weight and/or food consumption were observed following single and repeat dosing with Mylotarg. Morbidity/mortality preceded by clinical signs of intolerance was observed after a single dose of Mylotarg given to rats or monkeys and during 12 weeks of dosing in monkeys (at exposures that exceeded the clinically relevant exposures). Effects on male fertility were observed while no effects on female fertility (except decreased corpora lutea) were identified, but evidence of embryo‑fetal toxicity was observed with Mylotarg in rats. Mylotarg was determined to be a clastogen. Pre‑neoplastic lesions were identified in the liver in rats after 6 weeks of dosing.

Non clinical studies using in vitro cytotoxicity assays showed that Mylotarg was effective at selectively killing CD33 positive target cells compared to unconjugated calicheamicin, a non specific antibody drug conjugate (ADC), or the hP67.6 antibody. Mylotarg also demonstrated selective, CD33 targeted, cytotoxic effects toward a significant proportion of AML bone marrow samples in a colony forming assay. Anti tumor activity of Mylotarg was also demonstrated in mouse models of AML using single and multiple doses, as well as in combination with DA chemotherapy.

Overall, the non clinical safety findings related to Mylotarg administration represent toxicities that can be monitored and/or are considered clinically manageable in the intended patient population. The identified safety issues can be managed through labelling, and adequate monitoring (where required). Appropriate warnings and precautions are in place in the Mylotarg Product Monograph to address the identified safety concerns. In view of the intended use of Mylotarg, there are no pharmacological/toxicological issues within this New Drug Submission which preclude authorization of the product.

For more information, refer to the Mylotarg Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

Mylotarg is an antibody drug conjugate composed of the monoclonal antibody hP67.6, which is a CD33‑directed recombinant humanized IgG4, kappa antibody that has been covalently linked to the cytotoxic agent N‑acetyl‑gamma‑calicheamicin.

Characterization of the Drug Substance

The drug substance intermediates gemtuzumab and the activated calicheamicin derivative (used to manufacture gemtuzumab ozogamicin) and gemtuzumab ozogamicin (the medicinal ingredient in Mylotarg) were extensively analyzed to determine their structural, physicochemical, and functional characteristics.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

The drug substance intermediate, gemtuzumab, is produced in genetically engineered mammalian NS0 cells. The manufacturing process consists of four stages, including cell culture, harvesting, and purification and buffer exchange. The purification process includes a series of chromatographic and filtration steps. The materials used in the manufacture of the drug substance intermediate are considered suitable and/or meet standards appropriate for their intended use. The controls associated with each manufacturing process unit operation were adequately described and justified. The performance of the manufacturing process is routinely monitored by in‑process testing using validated or qualified analytical methods against justified acceptance criteria. The manufacturing process was validated at the commercial manufacturing scale and/or characterized using qualified small-scale models, amongst others for its capability to remove specific impurities, including viruses. The second drug substance intermediate, activated calicheamicin derivative is manufactured using established chemical processing steps and has a suitable control strategy.

The drug substance, gemtuzumab ozogamicin, is produced by covalently attaching the activated calicheamicin derivative to gemtuzumab, followed by purification and formulation. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use. The controls associated with each manufacturing process unit operation were adequately described and justified. The performance of the manufacturing process is routinely monitored by in process testing using validated or qualified analytical methods against justified acceptance criteria. The manufacturing process was validated at the commercial manufacturing scale.

The drug product, Mylotarg, is manufactured by a process that includes mixing, sterile filtration, aseptic filling, lyophilisation, capping and sealing, and then visual inspection. The performance of the manufacturing process is routinely monitored by in‑process testing against justified acceptance criteria. The manufacturing process performance was validated at the manufacturing scale to establish the overall consistency and effectiveness of aseptic operations.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards, which incorporates tests to assess identity, purity, potency, and relevant characteristics of the dosage form. The associated analytical methods were validated or qualified, and the acceptance criteria were appropriately justified. The batch analysis data confirm that the proposed manufacturing process consistently yields drug substance of acceptable quality.

The provided batch analysis data confirm that the proposed manufacturing process consistently yields drug product of acceptable quality. Targeted in-house laboratory analysis of drug product release methods showed that those methods are suitable for their intended use.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf‑life and storage conditions for the drug substance and drug product were adequately supported. The proposed 60‑month shelf‑life when stored at 2°C to 8°C for the Mylotarg drug product is acceptable.

The proposed packaging and components are acceptable.

Facilities and Equipment

The design, operations, and controls of the respective facilities and equipment used in the manufacture of the drug substance and drug product production are acceptable.

An On‑Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the monoclonal antibody drug substance intermediate, drug substance, and drug product were not warranted since the facilities were recently evaluated to be in good standing.

The sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious agents (bioburden, mycoplasma, and viruses). Purification steps designed to remove and/or inactivate viruses are adequately validated.

Raw materials of animal and recombinant origin used in the manufacturing process have been adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.