Summary Basis of Decision for Breyanzi
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 Breyanzi is located below.
Recent Activity for Breyanzi
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 Breyanzi
Date SBD issued: 2022-08-16
The following information relates to the new drug submission for Breyanzi.
Lisocabtagene maraleucel
Drug Identification Number (DIN):
- DIN 02527138 ‑ 60 × 106 to 120 × 106 chimeric antigen receptor (CAR)‑positive viable T cells, suspension, intravenous administration
Celgene Inc.
New Drug Submission Control Number: 247562
On May 6, 2022, Health Canada issued a Notice of Compliance to Celgene Inc. for the drug product Breyanzi.
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 Breyanzi is favourable for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
1 What was approved?
Breyanzi, an antineoplastic agent, was authorized for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Breyanzi in pediatric patients (less than 18 years of age) has not been established. Therefore, Health Canada has not authorized an indication for pediatric use.
In the clinical trial of Breyanzi, 71 (40%) of the 176 patients were 65 years of age or older, and 15 (9%) were 75 years of age or older.
Breyanzi (60 × 106 to 120 × 106 chimeric antigen receptor-positive [CAR+] viable T cells) is presented as a cell suspension for intravenous infusion. In addition to the medicinal ingredient, the suspension contains caprylic acid, Cryostor CS10, human albumin, magnesium chloride, N‑acetyl‑DL‑tryptophan, potassium chloride, sodium acetate trihydrate, sodium chloride, sodium gluconate, and water for injection.
The use of Breyanzi is contraindicated in patients who are hypersensitive to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Breyanzi Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was Breyanzi approved?
Health Canada considers that the benefit-risk profile of Breyanzi is favourable for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy, including: diffuse large B-cell lymphoma (DLBCL) not otherwise specified; primary mediastinal large B-cell lymphoma (PMBCL); high grade B-cell lymphoma; and DLBCL arising from follicular lymphoma.
Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non‑Hodgkin’s lymphoma (NHL). Only a small percentage of patients who are refractory to initial treatment or relapse after an initial response will experience prolonged disease‑free survival with salvage chemoimmunotherapy alone. The incidence of NHL in Canada is approximately 7 per 100,000 people. Diffuse large B cell lymphoma is considered the most aggressive subtype of all NHLs. Indolent NHL is also called slow‑growing or low‑grade lymphoma, and the most common subtype is follicular lymphoma.
Standard chemoimmunotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R‑CHOP]) is curative in approximately 60% of patients. However, an estimated 20% to 30% of patients relapse after an initial remission, and 10% of those patients have primary refractory disease. For a first relapse which is chemosensitive, high‑dose chemotherapy with autologous hematopoietic stem cell transplantation (AHSCT) is a treatment option. However, in approximately 50% of cases, relapsed patients are resistant to second‑line chemotherapy, which do not allow for AHSCT, and may have comorbidities that also preclude AHSCT.
In Canada, there is no one universal standard treatment regimen for patients with DLCBL after failure of two or more lines of therapy. Allogenic AHSCT can yield durable remissions in a subset of patients. However, patients that are not able to achieve sufficient disease control with salvage therapy are usually not considered for allogenic AHSCT due to the elevated relapse risk.
Breyanzi (lisocabtagene maraleucel) is a genetically modified autologous (patient‑derived) cellular immunotherapy developed to recognize the B cell antigen Cluster of Differentiation (CD) 19. The patient’s T cells are transduced with a lentiviral vector encoding a CD19‑specific chimeric antigen receptor (CAR), which is expressed on the surface of the cells. The CD19 protein is present on the surface of all cells in the B-cell lineage, including malignant cells that comprise large B-cell lymphomas. When Breyanzi is infused into the patient, the anti-CD19 CARs present on T cells interact with the CD19 expressed on the B cells, which activates a signalling cascade that leads to the elimination of CD19‑expressing cells.
At the time of market authorization of Breyanzi, two CD19-targeted CAR T‑cell therapies were authorized for the treatment of DLBCL: tisagenlecleucel; and axicabtagene ciloleucel. Polatuzumab vedotin and tafasitamab had also been authorized for the treatment of DLBCL.
Unlike previous cellular therapy products, the final drug product for Breyanzi consists of two separate components: a CD8‑positive (CD8+) component; and a CD4‑positive (CD4+) component, present at a ratio range from 0.8 to 1.2. Each component is manufactured separately. The target range for the number of combined viable CAR‑positive (CAR+) T cells from both components is 60 × 106 to 120 × 106 T cells.
The efficacy, safety, and pharmacology of Breyanzi were evaluated in a single-arm, open‑label clinical study, TRANSCEND (017001). This study was conducted in adult patients with various subtypes of relapsed or refractory B-cell NHL after at least two lines of therapy or after AHSCT. As TRANSCEND was a Phase I study, the patients were treated with different dose levels and regimens. The efficacy analysis focused on patients that received a single infusion of Breyanzi within the proposed dose range for marketing authorization (60 × 106 to 120 × 106 CAR+ T cells), hereafter referred to as the DL2S cohort.
In the DL2S cohort, 176 patients aged 18 to 79 years were treated with Breyanzi. The median age was 63 years. The median number of prior systemic therapies was 3, with 46% of patients having received 2 prior regimens and 52% of patients having received 3 prior regimens or more. Following treatment, 168 patients were evaluable for efficacy. Eight of the 176 patients were not evaluable for efficacy as they did not have baseline positron emission tomography (PET)-positive disease or confirmation of PET‑positive disease after anticancer therapy for disease control as determined by an independent review committee (IRC).
The primary tumour‑centric endpoint was the objective response rate (ORR), which was assessed by an IRC and based on the Lugano Classification (2014). Secondary endpoints included complete response rate and duration of response (DOR) as determined by an IRC. The ORR was determined to be 73.8% (95% confidence interval [CI]: 66.5, 80.3). The median DOR was 16.8 months (range: 6.0 ‑ not reached). The complete response rate was 52.4% (95% CI: 44.5, 60.1), and the partial response rate was 21.4% (95% CI: 15.5, 28.4). Response durations were longer in patients who achieved a complete response, relative to patients with a best response of partial response.
The clinical safety evaluation included 213 patients who received a dose of Breyanzi within the proposed dose range for marketing authorization. Patients included in this evaluation participated in the main clinical study, TRANSCEND, or in a supportive study, TRANSCEND WORLD (BCM‑001).
The most common adverse events of any grade (reported in ≥20% of patients), in order of most to least common, were fatigue, cytokine release syndrome (CRS), headache, nausea, diarrhea, encephalopathy, hypotension, cough, infections – pathogen unspecified, pyrexia, abdominal pain, constipation, and dizziness.
The most common Grade 3 or higher adverse reactions (>2%) were infections ‑ pathogen unspecified, febrile neutropenia, encephalopathy, hypotension, abdominal pain, aphasia, CRS, decreased appetite, delirium, dizziness, dyspnea, gastrointestinal haemorrhage, bacterial infection, and renal insufficiency. Grade 5 (fatal) adverse events were reported in 7 patients (cardiomyopathy, leukoencephalopathy [attributed to prior fludarabine exposure], septic shock [considered unrelated to Breyanzi], candida sepsis, pulmonary hemorrhage, multiple organ dysfunction syndrome, and respiratory failure).
A Serious Warnings and Precautions box in the Breyanzi Product Monograph highlights the risks of CRS and neurologic toxicities. Guidelines and instructions to support the safe use of Breyanzi are included in the Product Monograph.
Overall, the data reviewed indicate that Breyanzi had a positive effect on tumour‑centric endpoints in a group of patients who do not have standard treatment options after having received 2 or more prior lines of therapy.
A Risk Management Plan (RMP) for Breyanzi was submitted by Celgene Inc. to Health Canada. 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. Upon review, the RMP was considered to be acceptable.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Breyanzi Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Breyanzi was accepted.
Breyanzi 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 Breyanzi 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 issued 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 Breyanzi?
The review of the New Drug Submission (NDS) for Breyanzi was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Breyanzi NDS was made independently based on the Canadian review.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Breyanzi
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-06-23 |
| New Drug Submission filed | 2020-12-17 |
| Screening | |
| Screening Acceptance Letter issued | 2021-02-05 |
| Review | |
| Request granted to pause review clock for 90 days (extension to respond to clarification request) | 2021-10-13 |
| Request granted to pause review clock for 90 days (extension to respond to clarification request) | 2021-12-24 |
| Request granted to pause review clock for 22 days (extension to respond to clarification request) | 2022-02-25 |
| Review of Risk Management Plan completed | 2022-04-11 |
| Quality evaluation completed | 2022-04-29 |
| Non-clinical evaluation completed | 2022-05-02 |
| Clinical/medical evaluation completed | 2022-05-05 |
| Biostatistics evaluation completed | 2022-05-05 |
| Labelling review completed | 2022-05-05 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2022-05-06 |
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
As described above, the clinical review of the New Drug Submission for Breyanzi was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Clinical Pharmacology
Breyanzi consists of genetically modified autologous (patient-derived) T cells, which express a chimeric antigen receptor (CAR) directed against the B-cell antigen Cluster of Differentiation (CD) 19. The CD19 protein is present on the surface of all cells in the B-cell lineage, including malignant cells that comprise large B-cell lymphomas. When Breyanzi is infused into the patient, the anti-CD19 CARs present on T cells interact with the CD19 expressed on the B cells, which activates a signalling cascade that leads to the elimination of CD19‑expressing cells.
The pharmacokinetics and pharmacodynamics of Breyanzi were evaluated in the main clinical study, TRANSCEND (described in the Clinical Efficacy section). Patients included in the evaluation received one dose of Breyanzi at one of three target dose levels: 50 × 106 CAR‑positive (CAR+) T cells; 100 × 106 CAR+ T cells; and 150 × 106 CAR+ T cells.
Pharmacodynamic responses were evaluated over a 4‑week period following infusion with Breyanzi by measuring the transient elevation of soluble biomarkers. Peak elevation of soluble biomarkers was observed within the first 14 days after infusion and returned to baseline levels within 28 days. B‑cell aplasia (defined as CD19-positive [CD19+] B cells comprising less than 3% of peripheral blood lymphocytes) is an on-target effect of Breyanzi. It was observed in the majority of patients for up to one year following infusion with Breyanzi.
Following infusion, an initial expansion of Breyanzi was observed, followed by a bi‑exponential decline. The median time to maximal expansion in peripheral blood was 11 days after infusion, and Breyanzi was present in peripheral blood for up to 2 years.
The median maximum plasma concentration (Cmax) was 2.17‑fold higher in responders (number of patients [n] = 122) than in non‑responders (n = 35) at 32,093.2 and 14,776.0 copies/µg, respectively. The median exposure as measured by the area under the concentration-time curve (AUC) from Days 0 to 28 (AUC0‑28d) was 1.92‑fold higher in responders than in non‑responders at 265,237.5 and 138,183.9 day*copies/µg, respectively.
Tocilizumab and corticosteroids were required by some patients for the management of cytokine release syndrome (CRS) and neurologic toxicities, and were associated with increases in the median Cmax and median AUC0‑28d. The median Cmax and AUC0‑28d values were 3.87‑fold and 3.69‑fold higher, respectively, in patients treated with tocilizumab (n = 33) than in patients who did not receive tocilizumab (n = 132). Similarly, the median Cmax and AUC0‑28d values were 4.32‑fold and 3.73‑fold higher, respectively, in patients treated with corticosteroids (n = 29) than in patients who did not receive corticosteroids (n = 136).
In patients less than 65 years old (n = 98), the median Cmax was 2.48‑fold higher and the median AUC0‑28d was 2.64‑fold higher than the corresponding values observed in patients aged 65 years and older (n = 67). Sex, race, ethnicity, and body weight did not show clear relationships to Cmax and AUC0‑28d.
For further details, please refer to the Breyanzi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
An open‑label clinical study, TRANSCEND (017001), was conducted to evaluate the efficacy, safety, and pharmacology of Breyanzi in adult patients with relapsed or refractory B-cell non-Hodgkin’s Lymphoma (NHL). Patients enrolled in this study had various subtypes including: diffuse large B-cell lymphoma (DLBCL) not otherwise specified (53%); DLBCL transformed from indolent lymphoma arising from follicular lymphoma (19%); high‑grade lymphoma (15%); and primary mediastinal large B-cell lymphoma (PMBCL) (8%).
Patients eligible for the study must have been previously treated with an anthracycline and rituximab (or another CD20‑targeted agent). Patients must also have relapsed or refractory disease after at least two lines of therapy or after autologous hematopoietic stem cell transplant (auto‑HSCT). Patients were excluded from the study if they had an active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection at the time of screening, or if they had uncontrolled systemic fungal, bacterial, viral, or other infection at the time of leukapheresis or Breyanzi administration. Patients with central nervous system (CNS)-only involvement by malignancy were excluded from the study, however, patients with secondary CNS involvement were allowed in the study.
As TRANSCEND was a Phase I study, the patients were treated with different dose levels and regimens. During the study, the sponsor decided to move forward with 60 × 106 to 120 × 106 CAR+ T cells as the proposed dose for marketing authorization due to data indicating a longer duration of response with no impact on the safety profile. Therefore, the efficacy analysis focussed on patients who received a single infusion of Breyanzi within this dose range (hereafter referred to as the DL2S cohort).
Patients were able to receive bridging chemotherapy (anticancer treatment) while waiting for their cells to be manufactured. In this case, a washout of the prior therapy was required before initiating lymphodepleting chemotherapy (LDC). Patients receiving LDC were treated with fludarabine (30 mg/m2/day for 3 days) plus cyclophosphamide (300 mg/m2/day for 3 days) prior to treatment with Breyanzi. Doses of LDC could be reduced at the discretion of the investigator, and LDC was completed 2 to 7 days before infusion. In the DL2S cohort, 176 of 227 patients (78%) received Breyanzi (after two lines of systemic therapy). Patients who had undergone leukapheresis but did not receive the infusion either died, had progressive disease, were ineligible for infusion, or withdrew from participating in the study.
Patients in the DL2S cohort received varying levels of CAR+ T cells within the range of 60 × 106 to 120 × 106 CAR+ T cells (median dose 92 × 106 CAR+ T cells). As with other CAR+ T-cell therapies, determining the minimal effective dose is challenging due to the various factors involved, including the status of the patient at the time of infusion.
In total, 176 patients aged 18 to 79 years were treated with Breyanzi. The median age was 63 years. The B‑cell histology types represented in the patient population included DLBCL not otherwise specified (n = 94), DLBCL transformed from follicular lymphoma (n = 33), high‑grade B‑cell lymphoma (n = 26), and PMBCL (n = 14), for which treatment with Breyanzi has been authorized. Other B‑cell histology types represented in this population included marginal zone lymphoma (n = 4), chronic lymphocytic leukemia/small lymphocytic leukemia (n = 2), FL3B (n = 2), and Waldenström’s macroglobulinaemia (n = 1). For B‑cell histology types not included in the indication, there was not enough data to make a clear benefit‑risk assessment at the time of authorization. All patients had received at least 2 lines of therapy. The median number of prior systemic therapies was 3, with 46% of patients having received 2 prior regimens and 52% of patients having received 3 prior regimens or more.
The efficacy analysis only included patients who received the proposed dose for marketing authorization of 60 × 106 to 120 × 106 CAR+ T cells, with 168 patients evaluable for efficacy. Eight of the 176 patients were not evaluable for efficacy as they did not have baseline positron emission tomography (PET)-positive disease or confirmation of PET‑positive disease after anticancer therapy for disease control as determined by an independent review committee (IRC).
The primary tumour‑centric endpoint was the objective response rate (ORR), which was assessed by an IRC and based on the Lugano Classification (2014). Secondary endpoints included complete response rate and duration of response (DOR) as determined by an IRC. The ORR was determined to be 73.8% (95% confidence interval [CI]: 66.5, 80.3). The median DOR was 16.8 months (range: 6.0 ‑ not reached). The complete response rate was 52.4% (95% CI: 44.5, 60.1), and the partial response rate was 21.4% (95% CI: 15.5, 28.4). Response durations were longer in patients who achieved a complete response, relative to patients with a best response of partial response.
Overall, the data reviewed indicate that Breyanzi had a positive effect on tumour‑centric endpoints in a group of patients that do not have standard treatment options after having received 2 or more prior lines of therapy.
Indication
| Sponsor's proposed indication | Health Canada-approved indication |
Breyanzi (lisocabtagene maraleucel) is a CD19‑directed genetically modified autologous T‑cell immunotherapy indicated for:
|
Breyanzi (lisocabtagene maraleucel) is a CD19‑directed genetically modified autologous T‑cell immunotherapy indicated for:
|
The proposed indication was revised to better reflect the patient population studied in the TRANSCEND study.
For more information, refer to the Breyanzi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety evaluation included 213 patients that received a dose of Breyanzi ranging from 60 × 106 to 120 × 106 CAR+ T cells (the proposed dose for marketing authorization) in the main clinical study, TRANSCEND (described in the Clinical Efficacy section), and a supportive study, TRANSCEND WORLD (BCM‑001).
The most common adverse events of any grade (reported in ≥20% of patients), in order of most to least common, were fatigue, cytokine release syndrome (CRS), headache, nausea, diarrhea, encephalopathy, hypotension, cough, infections - pathogen unspecified, pyrexia, abdominal pain, constipation, and dizziness.
The most common Grade 3 or higher adverse reactions (>2%) were infections ‑ pathogen unspecified, febrile neutropenia, encephalopathy, hypotension, abdominal pain, aphasia, CRS, decreased appetite, delirium, dizziness, dyspnea, gastrointestinal haemorrhage, bacterial infection, and renal insufficiency. Grade 5 (fatal) adverse events were reported in 7 patients (cardiomyopathy, leukoencephalopathy [attributed to prior fludarabine exposure], septic shock [considered unrelated to Breyanzi], candida sepsis, pulmonary hemorrhage, multiple organ dysfunction syndrome, and respiratory failure).
A Serious Warnings and Precautions box in the Breyanzi Product Monograph highlights the risks of CRS and neurologic toxicities. The incidence rate of CRS was 38%, with 3% of cases considered to be Grade ≥3 in severity. Nervous system disorders of any grade were reported in 28% of patients, with 9% of cases being Grade 3 or 4 in severity. Patients should be monitored for signs of CRS after treatment with Breyanzi, as fatal or life‑threatening reactions can occur. Severe or life‑threatening CRS should be treated with tocilizumab with or without corticosteroids. The infusion of Breyanzi should be delayed if the patient has unresolved serious medical events. Neurologic toxicities also occurred following treatment with Breyanzi, and may be severe or life‑threatening. Neurologic toxicities can occur concurrently with CRS, after CRS resolution, or in the absence of CRS. Patients should be monitored for neurologic events after treatment with Breyanzi, and supportive care and/or corticosteroids should be provided as needed. Breyanzi must be administered under the supervision of healthcare professionals experienced in hematological malignancies at a qualified treatment centre.
For more information, refer to the Breyanzi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
As described above, the review of the non-clinical component of the New Drug Submission for Breyanzi was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
The outcomes of non‑clinical pharmacology studies demonstrated the binding specificity of lisocabtagene maraleucel to cells expressing human Cluster of Differentiation (CD) 19. The specific response of lisocabtagene maraleucel towards CD19‑positive tumours consists of T-cell activation, proliferation, cytokine secretion, and cytolytic activity. Cell viability was observed to increase when CD8‑positive and CD4‑positive cells were cultured together. The expression of CD19 was absent or low in most normal tissues, except in B lymphocytes and tissues expected to have high B lymphocyte presence. The results from drug interaction studies supported the future use of lisocabtagene maraleucel in patients undergoing standard of care therapy or who may require adjunct therapy.
The non-clinical safety and toxicology studies included a human tissue cross‑reactivity study, mapping of the genomic insertion sites of the lentiviral vector (LVV) in transduced T cells, and a study evaluating the interleukin‑2 (IL‑2) dependence of lisocabtagene maraleucel cells. The results showed cross-reactivity of the lisocabtagene maraleucel binding domain towards mononuclear leukocytes in various human tissues. Additional cross‑reactivity was detected in the liver hepatocytes, esophagus, tonsils, cervix, and prostate. However, toxicity was not observed in these tissues. Genotoxicity assays and carcinogenicity studies were not conducted. In vitro expansion studies conducted in healthy donors and in patients showed no evidence for transformation and/or immortalization and no preferential integration near genes of concern in lisocabtagene maraleucel cells.
Given the nature of the product, non-clinical studies on fertility were not conducted.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Breyanzi Product Monograph. Considering the intended use of Breyanzi, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Breyanzi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As described above, the review of the quality component of the New Drug Submission for Breyanzi was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Breyanzi is a suspension of autologous (patient-derived) T cells, isolated from peripheral blood cells collected by leukapheresis, and genetically engineered ex vivo to express a chimeric antigen receptor (CAR) directed against the B cell antigen Cluster of Differentiation (CD) 19. The CD19 protein is expressed on the surface of all B cells, including B cell lineage tumours. A lentiviral vector (LVV) encoding the anti-CD19 CAR gene transduces the patient's T cells, and the anti-CD19 CAR may then be expressed on the cell surface. The manufacturing process is continuous, without a distinction between the drug substance and drug product that is typical of biologic drugs. The anti-CD19 CAR-expressing autologous T cells are the cell product, lisocabtagene maraleucel, marketed under the brand name Breyanzi. Following the infusion of Breyanzi into the patient, the anti-CD19 CAR on the T cells engages with CD19 on the surface of B cells. This activates the T cells and initiates a signalling cascade that ultimately results in the elimination of CD19-expressing cells.
Characterization of the Drug Substance
Breyanzi (lisocabtagene maraleucel) consists of enriched CD8‑positive (CD8+) and CD4‑positive (CD4+) T cells at a defined ratio, which have been separately activated and transduced with a replication-incompetent LVV encoding an anti‑CD19 CAR. The CAR for Breyanzi consists of an extracellular CD19-specific single chain fragment variable (scFv) binding domain, a hinge domain from immunoglobulin G4, a CD28 transmembrane domain, and CD3ζ signaling and 4‑1BB costimulatory domains.
The CD8+ and CD4+ drug product components have been extensively characterized, including molecular characteristics of the CAR, and phenotypic characteristics of the cells. Functionality of the drug product involved in the mechanism of action was also confirmed, including CD19-specific CAR-mediated activity. The results confirmed that Breyanzi is a highly pure CD3‑positive (CD3+) cell product containing predominantly CD8+ or CD4+ effector memory and central memory T cells, capable of CD19-specific functionality consistent with the proposed mechanism of action.
Manufacturing Process of the Drug Substance and Drug Product and Process Controls
The LVV manufacturing process steps include host cell expansion, transient transfection, harvesting, purification, formulation, and aseptic filling. The manufacturing process has been validated and required materials qualified, and in-process controls have been appropriately established.
Leukapheresis material is collected from the patient at a qualified apheresis centre and transported under qualified conditions to the manufacturing site for the cell product. The chain of identity is established at the time of leukapheresis collection, and is maintained throughout the manufacturing process to dose administration by validated computer-based systems and labels with human-readable identifiers.
The CD8+ and CD4+ T cells are sequentially immune‑selected from the leukapheresis material, formulated, filled into bags, and cryopreserved at ≤-130 °C as separate components. The subsequent processing steps are carried out on the CD8+ and CD4+ components separately. The cells are thawed, activated, and undergo transduction with the LVV (which encodes the anti‑CD 19 CAR), followed by expansion. Finally, the cells are harvested, volume‑reduced, washed, formulated, aseptically filled into vials, and cryopreserved for storage at ≤-130 °C until shipment.
Process parameters and in-process controls for each unit operation were established through systematic risk assessment and process characterization data. The process controls are a part of the integrated control strategy.
The consistency of the manufacturing process for the cell product was confirmed in qualification runs using leukapheresis material from healthy donors. Process performance and product quality attributes were assessed against predefined acceptance criteria. Extended characterization and monitoring confirmed that residual process- and product-related impurities are consistently removed to safe levels. The integrity of aseptic operations was supported by sterilizing filtration validation and media fill simulations.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of lisocabtagene maraleucel with the excipients and primary packaging is supported by the stability data provided.
Control of the Drug Substance and Drug Product
Breyanzi is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.
Consistency lot testing was not conducted for Breyanzi, as the product is autologous and therefore highly individualized.
Evidence was provided to support control of materials. To maintain lot consistency, Finished Lentiviral Vector (FLV) is released per specifications. The CD8+ and CD4+ drug product components are subject to highly similar but separate release specifications. These specifications account for minor differences due to the input cell phenotype, and were established based on process and product knowledge gained through clinical and manufacturing experience.
Stability of the Drug Substance and Drug Product
Unopened vials of the CD8+ and CD4+ components of Breyanzi may be stored for up to 13 months in the vapour phase of liquid nitrogen (≤-130 °C). The proposed shelf-life and storage conditions for Breyanzi were adequately supported by the provided stability data, and are considered satisfactory.
Breyanzi must be thawed prior to administration. Once Breyanzi has been drawn into syringes, administration must occur as soon as possible. The total time from removal from frozen storage to patient administration should not exceed 2 hours at room temperature (15 °C to 25 °C).
Facilities and Equipment
Based on risk assessment scores determined by Health Canada, an on‑site evaluation (OSE) was not warranted for the LVV manufacturing site, but an OSE was warranted for the cell product manufacturing site.
A Virtual Evaluation of the Product and Facility (VEPF) was conducted for the cell product manufacturing site. An on-site evaluation (OSE) was not feasible due to the coronavirus disease 2019 (COVID-19) pandemic.
Boardroom sessions, facility tours, and witnessing of unit operations were all conducted virtually. Some observations were made during the VEPF, and the manufacturing site was ultimately issued a compliant rating.
Adventitious Agents Safety Evaluation
The risks of viral contamination of Breyanzi and the LVV are minimized through the sourcing and screening of raw materials, inspection of vendor certificates, and validated inactivation. The materials used in manufacturing, which are of animal or human origin, are the leukapheresis material, lentiviral vector, 25% Human Albumin Solution (excipient), Human Serum Albumin, fetal bovine serum (media supplement), and lactobionic acid. Based on the source animal species, geographical origin, tissue type, and production process documented in vendor certificates, the risks associated with adventitious transmissible spongiform encephalopathy (TSE) agents in biological raw materials were determined to be low.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BREYANZI | 02527138 | BRISTOL-MYERS SQUIBB CANADA | LISOCABTAGENE MARALEUCEL 120000000 CELLS |