Summary Basis of Decision for Besponsa
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 Besponsa is located below.
Recent Activity for Besponsa
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.
Post-Authorization Activity Table (PAAT) for Besponsa
Updated:
The following table describes post-authorization activity for Besponsa a product which contains the medicinal ingredient inotuzumab ozogamicin.For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02473909 - 0.9 mg/vial, inotuzumab ozogamicin, powder for solution, intravenous
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02473909) market notification | Not applicable | Date of first sale:2018-05-03 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 204077 | 2017-03-30 | Issued NOC2018-03-15 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Besponsa
Date SBD issued: 2018-08-22
The following information relates to the new drug submission for Besponsa.
Inotuzumab ozogamicin
0.9 mg/vial, powder for solution, intravenous
Drug Identification Number (DIN):
- 02473909
Pfizer Canada Inc.
New Drug Submission Control Number: 204077
On March 15, 2018 Health Canada issued a Notice of Compliance to Pfizer Canada Inc., Licensee for the drug product Besponsa.
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 Besponsa is favourable as a monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL).
1 What was approved?
Besponsa, an antineoplastic agent, was authorized as a monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL).
Besponsa is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.
In order to receive Besponsa, patients must have documented baseline CD22-positive (>0%) leukemic blasts determined by a validated CD22 assay. Assessment for CD22-positive leukemic blasts should have been performed by laboratories with demonstrated proficiency in the specific technology being utilized. The clinical benefit of Besponsa in patients with CD22-negative precursor B-cell ALL has not been established. Therefore, Besponsa is not recommended for these patients.
Besponsa was approved for use under the conditions stated in the Besponsa Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Besponsa (0.9 mg, inotuzumab ozogamicin) is presented as a lyophilized powder for solution for intravenous use. In addition to the medicinal ingredient, Besponsa also contains sucrose, polysorbate 80, sodium chloride, and tromethamine.
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 Besponsa Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Besponsa approved?
Health Canada considers that the benefit-risk profile of Besponsa is favourable as a monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL).
CD22 positive B-cell precursor ALL is a malignancy of immature B cells. It is characterized by a rapid proliferation and accumulation of CD22-positive immature and functionless B lymphocytes in the bone marrow, blood, lymphatics and other organs. Symptoms typically arise due to bone marrow failure and spread to other organs. While most patients (approximately 85%) will achieve some type of disease remission after induction therapy, approximately 15% of patients will have disease that is refractory to treatment. Moreover, relapse occurs in about 20-50% of those who have achieved remission. Relapse or refractory disease is associated with a poor prognosis (3-6 month survival), thus it is considered a serious life-threatening condition.
In Canada, first line treatment for Philadelphia chromosome negative (Ph-) precursor B-cell ALL in children, adolescents and adults involves the use of chemotherapy (plus or minus radiation), for the purpose of remission induction, central nervous system prophylaxis, consolidation and maintenance. Oral tyrosine kinase inhibitor (TKI) therapy is used for those patients that are Philadelphia chromosome positive (Ph+). The long-term goal is for patients to achieve a complete hematological remission and proceed to bone marrow transplant.
For patients who have disease relapse or whose disease is refractory to frontline treatment, a variety of second-line chemotherapy induction regimens are used which may include:
- the use of therapies based on a backbone of vincristine, corticosteroids, and anthracyclines;
- fludarabine plus cytarabine plus granulocyte-colony stimulating factor (FLAG) +/-idarubicin;
- cyclophosphamide, vincristine, doxorubicin, dexamethasone, and methotrexate and cytarabine (Hyper-CVAD);
- high dose cytarabine (HIDAC);
- clofarabine or methotrexate-based regimens;
- mitoxantrone plus cytarabine (MXN/Ara-C).
In addition, new targeted therapies are also available as treatment options for relapsed or refractory B-cell precursor ALL. These options include biologics such as CD19 B-cell targeting agent blinatumomab for Ph- ALL or additional tyrosine kinase inhibitor therapy (e.g., imatinib, dasatinib, and ponatinib) for Ph+ ALL. Despite the advances in targeting agent development, there still remains a need for new alternative therapies which can help relapsed or refractory ALL patients achieve a rapid complete hematological remission and proceed to bone marrow transplant.
Besponsa (inotuzumab ozogamicin) is a CD22-directed antibody-drug conjugate (ADC). Inotuzumab is a humanized immunoglobulin class G subtype 4 (IgG4) antibody which specifically recognizes human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic semi-synthetic product. N-acetyl-gamma-calicheamicin is covalently attached to the antibody via a linker composed of the condensation product of 4-(4'-acetylphenoxy)-butanoic acid (AcBut) and 3-methyl-3-mercaptobutane hydrazide (known as dimethylhydrazide). Non-clinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumour cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-stranded deoxyribonucleic acid (DNA) breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
Besponsa has been shown to be efficacious in adult patients with relapsed or refractory CD22-positive B-cell precursor ALL. The market authorization was based primarily on a multicentre, global, open-label, two-arm, pivotal Phase III study (B1931022) which compared the efficacy of Besponsa treatment versus (vs.) defined Investigator's choice of chemotherapy (control arm), in adult patients with relapsed or refractory CD22-positive B-cell ALL due to receive either Salvage 1 or 2 treatment. Defined Investigator's choice of chemotherapy was based on one of three predefined chemotherapy regimens (fludarabine plus cytarabine plus granulocyte colony-stimulating factor [FLAG], mitoxantrone plus cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]). The B1931022 study included two primary endpoints, hematological remission rate (complete remission/incomplete hematologic recovery [CR/CRi]), as assessed by an independent external Endpoint Adjudication Committee (EAC), and overall survival. The results of the study revealed that Besponsa treatment demonstrated a clinically meaningful and statistically significant improvement in hematological remission rate (CR/CRi) compared to the control arm (81% vs. 32%, respectively; p<0.0001). Additionally, the CR/CRi was supported by the achievement of a durable response and minimal residual disease negativity that favoured Besponsa treatment over the control arm. Notably, 48% of the Besponsa-treated patients proceeded to potentially lifesaving hematopoietic stem cell transplant (HSCT) as compared to approximately 22% of the patients in the control arm. These results were further supported by a 23% decreased risk in death in favour of Besponsa (hazard ratio: 0.77; 97.5% CI 0.58-1.03) with a p value equal to 0.04, and 1-month improvement in median overall survival favouring the Besponsa treatment arm compared to the control arm (7.7 vs. 6.7 months, respectively).
The safety profile of Besponsa was based primarily on the pivotal Phase III study B1931022. Severe, fatal and or life-threatening safety risks identified with the use of Besponsa include post-HSCT non-relapse mortality, hepatotoxicity (associated with veno-occlusive disease [VOD]), myelosuppression/cytopenia (including infections and hemorrhagic events), tumour lysis syndrome, infusion-related reactions and QT interval prolongation. These significant safety risks are identified in a Serious Warnings and Precautions box in the Besponsa Product Monograph. Furthermore, given the significant hepatotoxicity observed in patients treated with Besponsa, the sponsor was requested by the United States (US) Food and Drug Administration (FDA) to conduct two additional clinical studies. One interventional study will evaluate a lower dose level of Besponsa in patients at higher risk of for hepatotoxicity (including VOD post transplant) and the other observational study will evaluate the toxicity of Besponsa in patients after HSCT.
The most common (≥10%) adverse reactions observed in patients who received Besponsa include thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, increased transaminases, abdominal pain, increased gamma-glutamyltransferase, hyperbilirubinemia, lymphopenia, diarrhea, constipation, vomiting, stomatitis, increased alkaline phosphatase, decreased appetite and chills. Generally, the most common Grade 3 and 4 adverse reactions (≥2%) were the same as those listed for most common (≥10%) adverse reactions, with the exception of chills, decreased appetite, constipation, vomiting and diarrhea.
Overall, the safety risks were predominantly mitigated in the pivotal study B1931022 by dose reduction, dose interruption, dose discontinuation and standard medical practice.
A Risk Management Plan (RMP) for Besponsa was submitted by Pfizer Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe identified and potential important risks, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize the risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Besponsa 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 Besponsa was accepted.
Overall, the therapeutic benefits of Besponsa therapy seen in the Phase III pivotal study are positive, and the benefits of Besponsa are considered to outweigh the risks in the target patient population. Besponsa 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. Warnings and precautions are in place in the Besponsa 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 Besponsa?
Submission Milestones: Besponsa
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2017-02-07 |
| Submission filed: | 2017-03-30 |
| Screening | |
| Screening Acceptance Letter issued: | 2017-05-19 |
| Review | |
| On-Site Evaluation: | 2018-02-12 - 2018-02-16 |
| Biostatistics Evaluation complete: | 2018-03-22 |
| Quality Evaluation complete: | 2018-03-12 |
| Clinical Evaluation complete: | 2018-03-15 |
| Review of Risk Management Plan complete: | 2017-12-21 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-03-15 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2018-03-15 |
The Canadian regulatory decision on the quality, non-clinical and clinical review of Besponsa was based on a critical assessment of the data package submitted to Health Canada.
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?
In addition to requirements outlined in the Food and Drugs Act and Regulations, the sponsor has also agreed to conduct and provide Health Canada with the following studies in fulfillment of the United States Food and Drug Administration postmarketing requirements:
- An interventional clinical study to evaluate the efficacy, safety, and pharmacokinetics of at least two dose levels of Besponsa in patients at higher risk of developing veno-occlusive disease (VOD) post transplant.
- An observational clinical study to further characterize the toxicity of Besponsa in patients after hematopoietic stem cell transplantation using transplant registry data.
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
Besponsa (inotuzumab ozogamicin) is a CD22-directed antibody-drug conjugate (ADC) that, upon binding, is rapidly internalized and hydrolyzed, and delivers a genotoxic payload (ozogamicin) to the leukemic blasts.
Exposure to Besponsa was maintained and increased with each cycle reaching maximum serum concentrations and highest mean trough levels by Cycle 4 of treatment. The mean maximum concentration (Cmax) of inotuzumab ozogamicin was 308 ng/mL. Based on the population pharmacokinetic analysis, the mean simulated total area under the concentration-time curve (AUC) per cycle at steady state was 100,000 ng·hr/mL.
The pharmacokinetics of inotuzumab ozogamicin was characterized by a 2-compartment model with linear and time-dependent clearance components. Baseline body surface area was a significant covariate of the clearance parameters, supporting a body surface-based dosing approach.
No formal pharmacokinetic studies of inotuzumab ozogamicin have been conducted in patients with hepatic or renal impairment. Due to the limited data available, dosing recommendations in patients with severe renal impairment, and moderate or severe hepatic impairment could not be made.
Besponsa is associated with QT interval prolongation. In the pivotal ALL study (B1931022), increased QT intervals (corrected for heart rate using Fridericia's formula, QTcF) of ≥60 milliseconds (ms) from baseline were measured in 4/162 (3%) patients in the Besponsa treatment arm and 3/124 (2%) patients in the Investigator's choice of chemotherapy arm. One patient (0.6%) in the Besponsa arm had a treatment-emergent maximum QTcF >480 ms. QTcF values >500 ms were not observed in the Besponsa treatment arm.
For further details, please refer to the Besponsa Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Besponsa in patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) were assessed in a randomized, open-label, international, multicentre Phase III study (B1931022).
The key inclusion criteria were eligible patients ≥18 years of age with Philadelphia chromosome-negative (Ph-) or Philadelphia chromosome-positive (Ph+) relapsed or refractory B-cell precursor ALL. All patients were required to have ≥5% bone marrow blasts and to have received 1 or 2 previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome-positive B-cell precursor ALL were required to have disease that failed treatment with at least one tyrosine kinase inhibitor and standard multi-agent induction chemotherapy. All evaluable patients had B-cell precursor ALL that expressed CD22, with ≥90% of evaluable patients exhibiting ≥70% leukemic blast CD22 positivity prior to treatment, as assessed by flow cytometry performed at a central laboratory. Notably, patients were required to have adequate liver function (serum bilirubin <1.5 times the upper limit of normal and both aspartate transaminase [AST] and alanine transaminase [ALT] <2.5 times the upper limit of normal). Patients were excluded if there was any history of liver issues such as hepatitis, veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS), liver disease or alcohol abuse.
The study included 326 patients with relapsed or refractory ALL who were randomized in a 1:1 ratio and stratified based on the duration of first remission (<12 months or ≥12 months), salvage status (Salvage 1 or 2) and age (<55 or ≥55 years). Patients received either treatment with Besponsa or one of three predefined control chemotherapy regimens which was chosen by the Investigator and referred to as the control arm. These treatments included a choice of fludarabine plus cytarabine plus granulocyte-colony stimulating factor (FLAG) or mitoxantrone plus cytarabine (MXN/Ara-C), or high-dose cytarabine (HIDAC). Patients randomized to FLAG or MXN/Ara-C received up to 4 chemotherapy cycles. Patients randomized to HIDAC received up to 2 cycles. All three treatment options are considered standard practice in Canada for the proposed indication.
Study B1931022 included two primary endpoints, hematological remission rate (complete remission [CR] or complete remission with incomplete hematologic recovery [CRi]), as assessed by the independent external Endpoint Adjudication Committee (EAC), and overall survival. Overall survival was defined as the time from randomization to the date of death due to any cause. All patients were followed for survival after disease progression every 3 months for up to 5 years or 2 years after randomization of the last patient, whichever occurred first.
The secondary endpoints included minimal residual disease (MRD) negativity, defined by flow cytometry as leukemic cells comprising <1 × 10-4 (<0.01%) of bone marrow nucleated cells as assessed by a central laboratory, duration of remission (DoR), patients that proceed to HSCT.
Complete remission/incomplete hematologic recovery, MRD, and DoR were analyzed in the initial intent-to-treat 218 randomized patients (ITT218), while overall survival and HSCT rate were analyzed in intent-to-treat 326 randomized patients (ITT326).
Based on the results from the primary analysis of CR/CRi (ITT218 population), Besponsa demonstrated a consistent, clinically meaningful and statistically significant superior CR/CRi compared to the control (Investigator's choice of chemotherapy), irrespective of the baseline factors or stratification factors. Specifically, the independent external EAC assessed CR/CRi of 81% (95% Confidence Interval [CI]: 72-88%) in the Besponsa treatment arm as compared to 32% (95% CI: 21-39%) in the control arm, with p<0.0001; therefore favouring Besponsa over the control arm. This observation was further supported by the secondary endpoints DoR (hazard ratio: 0.50, 95% CI: 0.30-0.83; median DoR of 5.4 months vs. 3.5 months) and an MRD negativity of 78% vs. 28% among patients with CR/CRi again favouring the Besponsa arm compared to the control arm. Notably, patients treated with Besponsa had a CR that doubled (36% vs. 17%) that of the control arm. Moreover, a majority of patients with CR achieved MRD negativity of 90% (95% CI: 76-97%) as compared to only 32% (95% CI: 13-57%) of CR patients in the control arm. Overall, the high CR/CRi coupled with the high MRD negativity translated into a total of 79 patients proceeding to HSCT as compared to 35 patients in the control arm in the ITT population, which was considered clinically meaningful given that it is the only potentially lifesaving option for the relapse or refractory setting.
Overall survival was a co-primary endpoint in the pivotal B1931022 study. The primary analysis of overall survival (ITT326 population) demonstrated a 23% decreased risk in death (hazard ratio: 0.77; 97.5% CI: 0.58-1.03) with a p value equal to 0.04. Since the 2-sided alpha value of 0.05 was split evenly between the two co-primary endpoints (CR/CRi and overall survival) and some alpha was spent at the second interim analysis of overall survival, the overall survival was not statistically significant as it failed to meet the prespecified two-sided boundary of p equal to 0.025. Additionally, based on the overall survival analysis of the stratified ITT326 population, the median survival favoured the Besponsa arm by only 1 month as compared to the control arm (7.7 vs. 6.7 months). Although an improvement in the median overall survival of one month is modest, the clinical benefit of Besponsa is reflected in the hazard ratio of 0.77 showing 23% lower risk of death for Besponsa compared with the control arm, and the improvement in the long term overall survival (24-month overall survival of 22.6% vs. 9.6%) It is notable that overall survival was likely confounded by the higher number of patients that received subsequent induction therapies in the control arm (52%) as compared to the Besponsa arm (30%), the higher post-HSCT non-relapse mortality in the Besponsa arm as compared to the control arm (39% vs. 27%), and the higher number of patients proceeding to potentially lifesaving HSCT in the Besponsa arm (79 patients) as compared to the control arm (36 patients). As a result, the co-primary endpoint of CR/CRi, a globally accepted indicator of benefit in ALL, was more heavily weighted in the determination of Besponsa's efficacy.
Indication
The New Drug Submission for Besponsa was filed by the sponsor with the following proposed indication:
- Besponsa is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Health Canada approved the following indication:
- Besponsa is indicated as a monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia.
The revisions made are in-line with the key inclusion criteria and more accurately reflect the conditions of use in the pivotal study (B1931022).
Clinical Safety
The clinical safety of Besponsa in patients with relapsed or refractory ALL was primarily evaluated in a randomized, open-label, international, multicentre pivotal Phase III study (B1931022) previously described in the Clinical Efficacy section.
In the pivotal study, the median duration of treatment in the Besponsa arm was substantially longer when compared to the control arm (9 weeks vs. 1 week). Notably, none of the adverse reactions were adjusted for the substantially longer exposure to therapy in the Besponsa arm. Nevertheless, Besponsa was noted to be associated with significant safety risks in the pivotal study.
The most common adverse reactions (≥10%) associated with Besponsa when compared to the control arm were: thrombocytopenia (51% vs. 61%), neutropenia (49% vs. 45%), infection (48% vs. 76%), anemia (36% vs. 59%), leukopenia (35% vs. 43%), fatigue (35% vs. 25%), hemorrhage (33% vs. 28%), pyrexia (32% vs. 42%), nausea (31% vs. 46%), headache (28% vs. 27%), febrile neutropenia (26% vs. 53%), increased transaminases (26% vs. 13%), abdominal pain (23% vs. 23%), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) 14% vs. 2%, increased gamma-glutamyltransferase (21% vs. 8%), hyperbilirubinemia (21% vs. 17%), alkaline phosphatase increased (13% vs. 7%), chills (11% vs. 11%), stomatitis (13% vs. 26%), vomiting (15% vs. 24%), constipation (16% vs. 24%), diarrhea (17% vs. 38%), and lymphopenia (18% vs. 27%), respectively. Generally, the most common Grade 3 and 4 adverse reactions (≥2%) were the same as those listed for most common adverse reactions (≥10%), with the exception of chills, decreased appetite, constipation, vomiting, and diarrhea.
Deaths (Grade 5 adverse events [frequency not adjusted for exposure duration]) were reported in 26/164 (16%) in patients who received Besponsa and 16/143 (11%) in the control arm. The most common (≥2 patients) reasons for deaths (Grade 5 adverse events) were disease progression, veno-occlusive disease, pneumonia, and sepsis in the Besponsa treatment arm and disease progression, respiratory failure, multiple organ failure, and sepsis in the Investigator's choice of chemotherapy arm.
The serious adverse events (≥2%) were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD/SOS, and fatigue. The most frequent and significant serious adverse event was VOD/SOS, the risk for which was generally higher in the Besponsa treatment arm (pre- and post-HSCT) as compared to the control arm (14% vs. 2%). The risk for VOD/SOS increased substantially for patients in the Besponsa treatment arm that proceeded to HSCT as compared to the control arm (22% vs. 9%). Moreover, VOD/SOS was also observed in patients in the Besponsa treatment arm (5/164 or 3%), who did not receive transplant as compared to no patients in the control arm (0/143 or 0%).
Overall, 26/164 patients (16%) in the Besponsa arm and 9/143 patients (6%) in the control arm discontinued treatment due to an adverse reaction. A total of 3/164 patients (3%) in the Besponsa arm and 3/143 patients (2%) in the control arm had a dose reduction due to an adverse reaction, and 69/164 patients (42%) in the Besponsa arm and 11/143 patients (8%) in the control arm had a dose delay due to an adverse reaction.
In patients who received Besponsa, the most common (≥2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), increased transaminases (2%), and hemorrhage (2%). The most common (≥5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), increased transaminases (6%), and febrile neutropenia (5%). The most common (≥1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).
A higher frequency of hepatotoxicity, and post-HSCT non-relapse mortality (39% vs. 23%), were observed in the Besponsa arm as compared to the control arm, respectively. The most frequent cause of the post-HSCT non-relapse mortality was hepatotoxicity (i.e., VOD/SOS), followed by myelosuppression (i.e., infections). The risks for VOD/SOS are outlined in the Warnings and Precautions section of the Product Monograph.
Neutropenia, thrombocytopenia, anemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some of which were life-threatening, were reported in patients receiving Besponsa. Thrombocytopenia and neutropenia were reported in 83/164 (51%) and 81/164 (49%) patients, respectively. Grade 3 thrombocytopenia and neutropenia were reported in 23/164 (14%) patients and 33/164 (20%) patients, respectively. Grade 4 thrombocytopenia and neutropenia were reported in 46/164 (28%) patients and 45/164 (27%) patients, respectively. Febrile neutropenia, which may be life-threatening, was reported in 43/164 (26%) patients.
Complications associated with neutropenia and thrombocytopenia (including infections and bleeding/hemorrhagic events, respectively) were reported. Infections, including serious infections, some of which were life-threatening or fatal, were reported in 79/164 (48%) patients. Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, were reported in 8/164 (5%) patients. Bacterial, viral, and fungal infections were reported.
Bleeding/hemorrhagic events, mostly mild in severity, were reported in 54/164 (33%) patients. Grade 3/4 bleeding/hemorrhagic events were reported in 8/164 (5%) patients. One Grade 5 bleeding/hemorrhagic event (intra-abdominal hemorrhage) was reported in 1/164 (1%) patient. The most common bleeding event was epistaxis which was reported in 24/164 (15%) patients.
Besponsa is associated with QT interval prolongation. In the pivotal ALL study (B1931022), increases in QT interval (corrected for heart rate using Fridericia's correction formula, QTcF) of ≥60 ms from baseline were measured in 4/162 (3%) patients. No patients had QTcF values >500 ms. Grade 2 QT prolongation was reported in 9/162 (6%) patients. No Grade ≥3 QT prolongation or events of Torsade de Pointes were reported.
Tumour lysis syndrome, which may be life-threatening or fatal, was reported in 4/164 (2%) patients Grade 3 and 4 tumour lysis syndrome was reported in 3/164 (2%) patients.
Infusion-related reactions, all of which were Grade ≤2 in severity, were reported in 4/164 (2%) patients. Infusion-related reactions generally occurred in Cycle 1 shortly after the end of the Besponsa infusion and resolved spontaneously or with medical management. Premedication, with a corticosteroid, antipyretic, and antihistamine, is recommended prior to dosing in all patients.
As with all therapeutic proteins, there is also the potential to develop immunogenicity with ongoing treatment. In clinical studies of Besponsa in patients with relapsed or refractory ALL, the immunogenicity of Besponsa was evaluated using an electrochemiluminescence (ECL) based immunoassay to test for anti-inotuzumab ozogamicin antibodies. For patients whose sera tested positive for anti-inotuzumab ozogamicin antibodies, a cell-based luminescence assay was performed to detect neutralizing antibodies.
In clinical studies of Besponsa in patients with relapsed or refractory ALL, 7/236 (3%) patients tested positive for anti-inotuzumab ozogamicin antibodies. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies. In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-inotuzumab ozogamicin antibodies did not affect clearance following Besponsa treatment. The number of patients was too small to assess the impact of anti-inotuzumab ozogamicin antibodies on efficacy and safety.
Altogether, the safety risks, although significant, were predominantly mitigated in the pivotal trial by dose reduction, dose interruption, dose discontinuation and standard medical practice. The key hepatic and hematologic toxicities are labelled throughout the Besponsa Product Monograph, including the Warnings and Precautions section, as well as the Adverse Reactions section. Additionally, to ensure safe and effective drug use and to enhance communication of toxicity to prescribers, severe, life-threatening and fatal toxicities including post-HSCT non-relapse mortality, hepatotoxicity (including VOD/SOS), myelosuppression/cytopenias (associated with infections and hemorrhage), QT interval prolongation, tumour lysis syndrome and infusion-related reactions have been added to the Serious Warnings and Precautions box.
For more information, refer to the Besponsa Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Inotuzumab ozogamicin demonstrated potent, selective and dose-dependent cytotoxicity against ALL cell lines in vitro, and established subcutaneous ALL and systemically disseminated ALL tumours in vivo. The in vivo and in vitro efficacy correlated with the pharmacodynamic depletion of CD22 positive cells.
Additionally, in vitro and in vivo exposure to inotuzumab ozogamicin was sufficient to identify that it is:
1) metabolized via non-enzymatic reduction, thus co-administered inducers or inhibitors of cytochrome P450 (CYP) or uridine 5'-diphospho-glucuronosyltransferase enzymes would unlikely affect the exposure to ozogamicin;
2) primarily eliminated via fecal route with biliary contribution;
3) clastogenic;
4) able to induce embryo-fetal toxicity;
5) able to impair fertility;
6) able to induce significant liver, hematolymphopoietic tissue, and reproductive organ toxicity; and
7) able to induce irreversible preneoplastic changes in the liver of rats and monkeys.
In summary, the non-clinical package was evaluated and considered acceptable to support the New Drug Submission. The key non-clinical findings and related risks are included in the final Besponsa Product Monograph.
For more information, refer to the Besponsa Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Inotuzumab ozogamicin, the medicinal ingredient in Besponsa, is an antibody-drug conjugate (ADC) which consists of a recombinant, humanized monoclonal antibody (hinge-mutated immunoglobulin γ-4 with kappa light chains, IgG4κ) covalently linked to a fully characterized semi-synthetic N-acetyl derivative of γ-calicheamicin, a cytotoxic antibiotic (natural product) produced by microbial fermentation.
Non-clinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumour cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-γ-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. N-acetyl-γ-calicheamicin dimethylhydrazide induces double-stranded deoxyribonucleic acid (DNA) breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
Characterization of the Drug Substance
Detailed characterization studies were performed to provide assurance that the drug substance, inotuzumab ozogamicin, consistently exhibits the desired characteristic structure and biological activity.
Impurities and degradation products arising from manufacturing and/or storage were identified and characterized. Levels of these impurities and degradation products in the drug substance and/or drug product are consistently within the established limits and are considered acceptable.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The manufacturing process of the drug substance is based on two separate intermediate materials, the activated calicheamicin derivative and the monoclonal antibody inotuzumab (G544 antibody).
Activated calicheamicin derivative is manufactured from N-acetyl-γ-calicheamicin derived from γ-calicheamicin prepared by fermentation of Micromonospora echinospora ssp. calichensis. Activated linker is added to N-acetyl-γ-calicheamicin in three steps, including reaction, purification, and isolation. The resulting activated calicheamicin derivative is transferred into glass bottles, dried, and stored.
Inotuzumab is expressed in a Chinese Hamster Ovary (CHO) cell line developed using recombinant DNA techniques. The cell line is cryopreserved using two-tier cell banking system. The cell banks have been thoroughly characterized, and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated the stability of these cell banks.
Inotuzumab is manufactured in a process initiated using cells recovered from a thawed working cell bank vial. The cell mass is progressively expanded until sufficient for the inoculation of the production bioreactor. After a predetermined cell culture period, the contents of the production bioreactor are harvested and clarified to remove cells and cell debris. The clarified harvest is then processed by chromatographic and membrane filtration steps. The ranges of critical process parameters and the routine in-process controls along with acceptance criteria were described for each step. The inotuzumab drug substance intermediate manufacturing process is considered acceptable.
Inotuzumab ozogamicin is produced in a conjugation reaction involving the inotuzumab drug substance intermediate and the activated calicheamicin derivative drug substance intermediate. The antibody-drug conjugate is subsequently processed by chromatographic and membrane filtration steps. The ranges of critical process parameters, and the routine in-process controls along with acceptance criteria, were described for each step. The inotuzumab ozogamicin drug substance manufacturing process is considered acceptable.
The drug product manufacturing process consists of thawing of the frozen active substance under controlled conditions, mixing, and filtration into a container. The formulation buffer is then added to the mixed active substance to dilute the protein concentration to 0.25 mg/mL. The formulated finished product is then sterilely filtered and aseptically filled into vials. Upon completion of the lyophilization cycle, the vials are stoppered and capped with an overseal. Following the capping operation, the vials are visually inspected and stored at 2°C to 8°C. The sponsor has demonstrated the ability of the drug product manufacturing site to consistently produce drug product of acceptable quality.
The materials used in the manufacture of the drug substance and drug product (including biologically sourced materials) are considered suitable and meet standards appropriate for their intended use.
Control of the Drug Substance and Drug Product
The control strategy, including the specifications, for inotuzumab ozogamicin drug substance and drug product, was defined based on the enhanced process knowledge and product understanding enabled by the Quality by Design (QbD) approach. The proposed control strategy ensures a suitable level of robustness for the manufacturing process performance and quality of the resulting drug substance and drug product. Analytical procedures have been carefully selected according to their ability to confirm the quality of the drug substance and drug product, and validated in compliance with ICH guidelines.
The drug substance and drug product are tested against suitable reference standards, where appropriate.
Through Health Canada's lot release testing and evaluation program, three drug product lots were tested using a subset of batch release methods. The test results confirmed that the selected methods used are acceptable for their intended use and supported the dossier review recommendation.
Stability of the Drug Substance and Drug Product
The proposed shelf life and storage conditions for the drug substance and drug product were adequately supported by the submitted stability data. The shelf life of 36 months at 2 to 8°C, proposed for Besponsa drug product is considered acceptable.
The proposed packaging components are considered acceptable.
Facilities and Equipment
An On-Site Evaluation (OSE) of the facility involved in the manufacture of the inotuzumab ozogamicin drug substance and drug product was conducted from February 12 to February16, 2018. Based on this evaluation, the facility obtained a "compliant" rating.
Adventitious Agents Safety Evaluation
Raw materials of animal and recombinant DNA origin, used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin. Purification process steps designed to remove and/or inactivate viruses are adequately validated.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BESPONSA | 02473909 | PFIZER CANADA ULC | INOTUZUMAB OZOGAMICIN 0.9 MG / VIAL |