Summary Basis of Decision for Tecartus
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 Tecartus is located below.
Recent Activity for Tecartus
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 Tecartus
Date SBD issued: 2021-12-06
The following information relates to the new drug submission for Tecartus.
Brexucabtagene autoleucel
Drug Identification Number (DIN):
- DIN 02516667 - 2 x 106 chimeric antigen receptor (CAR)-positive viable T cells per kilogram body weight, with a maximum of 2 x 108 CAR-positive viable T cells, suspension, intravenous administration
Gilead Sciences Canada Inc.
New Drug Submission Control Number: 246355
On June 8, 2021, Health Canada issued a Notice of Compliance to Gilead Sciences Canada, Inc. for the drug product Tecartus.
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 Tecartus is favourable for the treatment of adult patients with relapsed or refractory mantle cell lymphoma after two or more lines of systemic therapy including a Bruton’s tyrosine kinase inhibitor.
1 What was approved?
Tecartus, an antineoplastic agent, was authorized for the treatment of adult patients with relapsed or refractory mantle cell lymphoma after two or more lines of systemic therapy including a Bruton’s tyrosine kinase inhibitor.
The efficacy and safety of Tecartus have not been established in pediatric patients (<18 years of age). Therefore, Tecartus is not authorized for pediatric use.
Evidence from a clinical study suggests that efficacy and safety in geriatric patients (≥65 years of age) were consistent with the overall treated patient population.
Tecartus is contraindicated in patients who are hypersensitive to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Tecartus 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.
Each patient-specific, single infusion bag of Tecartus contains a suspension of anti-CD19 chimeric antigen receptor (CAR)-positive viable T cells in approximately 68 mL. The target dose is 2 x 106 CAR-positive viable T cells per kg body weight (range: 1 x 106 to 2 x 106 CAR-positive viable T cells/kg), with a maximum of 2 x 108 CAR-positive viable T cells for patients 100 kg and above.
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 Tecartus Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Tecartus approved?
Health Canada considers that the benefit-risk profile of Tecartus is favourable for the treatment of adult patients with relapsed or refractory mantle cell lymphoma after two or more lines of systemic therapy including a Bruton’s tyrosine kinase inhibitor.
Mantle cell lymphoma is an aggressive subtype of non-Hodgkin’s lymphoma. The lymphoma cells in mantle cell lymphoma are thought to originate from antigen-naïve pre-germinal centre B cells within the mantle zone of the lymph node and express a number of surface markers including CD19. Mantle cell lymphoma most frequently affects males and the median age at diagnosis is estimated at 68 years. This type of lymphoma accounts for approximately 5% to 7% of all non-Hodgkin’s lymphoma cases worldwide. Based on an estimated incidence rate of approximately 10,400 new cases of non-Hodgkin’s lymphoma in Canada in 2020, it is estimated that roughly 520 to 730 new cases of mantle cell lymphoma would have been diagnosed last year in Canada.
There is no recognized standard of care for patients with relapsed or refractory mantle cell lymphoma. The optimal sequence of treatments has yet to be defined and the choice of regimen is influenced heavily by response duration to frontline therapy. Options for relapsed or refractory mantle cell lymphoma include chemotherapy, chemoimmunotherapy, stem cell transplant (for eligible patients), targeted agents such as bortezomib, and Bruton’s tyrosine kinase inhibitors. Given the high response rates for Bruton’s tyrosine kinase inhibitors, many patients could be considered for this treatment in the relapsed or refractory setting. Despite high response rates, Bruton’s tyrosine kinase inhibitors are not considered curative and most patients will have disease progression following Bruton’s tyrosine kinase inhibitor treatment. Outcomes to salvage therapy following Bruton’s tyrosine kinase inhibitor treatment are generally poor, thus, novel therapeutic strategies are needed.
Brexucabtagene autoleucel, the medicinal ingredient in Tecartus, is a CD19-directed genetically modified autologous T-cell immunotherapy. Tecartus contains a patient’s own T cells, which are harvested and then genetically modified ex vivo by retroviral transduction to express a chimeric antigen receptor (CAR) comprising a murine anti-CD19 single-chain variable fragment (scFv) linked to CD28 and CD3-zeta costimulatory domains. The anti-CD19 CAR T cells are expanded and infused back into the patient, where they can recognize and eliminate CD19-expressing mantle lymphoma cells.
The clinical efficacy of Tecartus was evaluated in a single-arm, open-label, multicentre, pivotal Phase II clinical study ZUMA-2 conducted in adult patients with relapsed or refractory mantle cell lymphoma. All patients enrolled in the ZUMA-2 study had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton’s tyrosine kinase inhibitor (ibrutinib or acalabrutinib). These patients also had disease progression after their last regimen or refractory disease to their most recent therapy. Patients with active or serious infections, prior allogeneic hematopoietic stem cell transplantation, detectable cerebrospinal fluid malignant cells or brain metastases, and any history of central nervous system lymphoma or central nervous system disorders were excluded from the study.
Patients in the ZUMA-2 study were enrolled to one of two cohorts and received either a single-dose, one-time intravenous infusion of Tecartus at a target dose of 2 x 106 (Cohort 1) or 0.5 x 106 (Cohort 2) CAR-positive viable T cells/kg body weight. The efficacy of Tecartus was evaluated in 68 patients who received Tecartus in Cohort 1. The primary efficacy endpoint in the study was objective response rate as assessed by an independent review committee using the International Working Group Lugano Classification for non-Hodgkin lymphoma.
With a median follow-up time of 16.8 months, efficacy results from the ZUMA-2 study showed that 91% (95% confidence interval [CI]: 81.8, 96.7) of patients had an objective response; 65% of patients achieved a complete remission and 26% of patients achieved a partial remission. The median time to response was 1.0 month (range: 0.8 to 3.1 months). These results are clinically meaningful when compared against a historical control rate for objective response rate of 28%, defined by the sponsor based on a meta-analysis of objective response rates to salvage therapy after discontinuing treatment with a Bruton’s tyrosine kinase inhibitor.
The safety profile of Tecartus in patients with relapsed or refractory mantle cell lymphoma was characterized based on data from 82 patients treated with Tecartus in the pivotal ZUMA-2 study. The safety profile was generally consistent regardless of whether patients received a target dose of 2 x 106 (Cohort 1) or 0.5 x 106 (Cohort 2) CAR-positive viable T cells/kg. The median duration of follow-up was 19.2 months.
The most commonly reported non-hematological adverse reactions (in ≥20% of patients) were pyrexia, cytokine release syndrome, hypotension, encephalopathy, fatigue, tachycardia, other pathogen infections, chills, hypoxia, cough, tremor, musculoskeletal pain, edema, headache, nausea, motor dysfunction, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, aphasia, hypertension, and renal insufficiency.
Serious adverse reactions occurred in 65% of patients. The most commonly reported serious adverse reactions (in ≥2% of patients) were encephalopathy, other pathogen infections, pyrexia, cytokine release syndrome, hypoxia, aphasia, renal insufficiency, pleural effusion, respiratory failure, bacterial infections, dyspnea, fatigue, non-ventricular arrhythmia, viral infections, diarrhea, hypertension, motor dysfunction, seizure, tachycardia, and thrombosis.
The most consequential serious adverse reactions related to Tecartus were cytokine release syndrome, neurologic adverse reactions, and infections. Fatal adverse events were reported for three (3.7%) patients. Cytokine release syndrome was reported in 91% of patients receiving Tecartus, with 15% of patients experiencing a Grade 3 or higher (severe or life-threatening) event. Serious adverse reactions associated with cytokine release syndrome include hypotension, fever, hypoxia, acute kidney injury, and tachycardia. Neurologic adverse reactions occurred in 68% of patients, 33% of whom experienced Grade 3 or higher adverse reactions. Serious adverse reactions including encephalopathy, aphasia, and seizures have occurred after treatment with Tecartus. Cytokine release syndrome and neurologic adverse reactions, although potentially life-threatening, were managed effectively in the ZUMA-2 study. The events were generally reversible and no deaths were attributed to cytokine release syndrome or neurologic adverse reactions.
A Serious Warnings and Precautions box is included in the Tecartus Product Monograph to highlight the risks of life-threatening reactions associated with cytokine release syndrome and/or neurologic adverse reactions. The Tecartus Product Monograph also includes management algorithms for cytokine release syndrome and neurologic adverse reactions. Although treatment with Tecartus is associated with serious risks, the safety profile of Tecartus is generally consistent with that of the product class (CAR T-cell therapies). Furthermore, Tecartus is only available through a controlled distribution plan. This plan requires health professionals to be trained in handling and administration of Tecartus, and in monitoring and management of serious adverse reactions related to treatment. In addition, the clinical settings in which Tecartus is administered must have access to emergency equipment and an appropriate intensive care facility.
A Risk Management Plan (RMP) for Tecartus was submitted by Gilead Sciences Canada, 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.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Tecartus Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Tecartus was accepted.
Overall, the therapeutic benefits of Tecartus therapy seen in the pivotal ZUMA-2 clinical study are considered to outweigh the potential risks. Tecartus 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 Tecartus 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 Tecartus?
The drug submission for Tecartus was reviewed under the Priority Review Policy. The sponsor presented substantial evidence of clinical effectiveness to demonstrate that Tecartus provides an effective treatment option for a disease that is not adequately managed by current treatments marketed in Canada.
Submission Milestones: Tecartus
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-04-15 |
| Request for priority status | |
| Filed | 2020-08-27 |
| Approval issued by the Director, Biologic and Radiopharmaceutical Drugs Directorate | 2020-09-24 |
| Submission filed | 2020-11-13 |
| Screening | |
| Screening Acceptance Letter issued | 2020-12-10 |
| Review | |
| Quality Evaluation complete | 2021-06-07 |
| Non-Clinical Evaluation complete | 2021-06-03 |
| Clinical/Medical Evaluation complete | 2021-06-07 |
| Biostatistics Evaluation complete | 2021-06-07 |
| Review of Risk Management Plan pending as of: | 2021-06-08 |
| Labelling Review complete | 2021-06-04 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2021-06-08 |
The Canadian regulatory decision on the review of Tecartus 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 and Applications Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Brexucabtagene autoleucel, the medicinal ingredient in Tecartus, is a CD19-directed genetically modified autologous T-cell immunotherapy that binds to CD19-expressing cancer cells and normal B cells. Studies demonstrated that following anti-CD19 CAR T cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta costimulatory domains activate downstream signalling cascades that lead to T-cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines. This sequence of events leads to killing of CD19-expressing cells.
The pharmacodynamics and pharmacokinetics of Tecartus in adult patients with relapsed or refractory mantle cell lymphoma were primarily evaluated in the pivotal Phase II study ZUMA-2 (described in the Clinical Efficacy section). In this study, patients were enrolled in one of two cohorts to receive a one-time intravenous infusion of Tecartus at either a target dose of 2 x 106 chimeric antigen receptor (CAR)-positive viable T cells/kg body weight (Cohort 1 - pivotal cohort) or 0.5 x 106 CAR-positive viable T cells/kg body weight (Cohort 2).
Peak levels of anti-CD19 CAR T cells occurred within the first 7 to 15 days after Tecartus infusion. At the dose of 2 x 106 anti-CD19 CAR-positive viable T cells/kg, Tecartus levels decreased to near baseline at three months post infusion. At the dose of 0.5 x 106 anti-CD19 CAR-positive viable T cells/kg, the peak levels and the area under the time-concentration curve (AUC) from 0 to 28 days (AUC0-28d) of Tecartus were approximately 60% of those in patients treated at the dose of 2 x 106 anti-CD19 CAR-positive viable T cells/kg. No significant impact of age and sex on Tecartus cellular kinetics was observed.
Cellular kinetic parameters of Tecartus in adult patients with relapsed or refractory mantle cell lymphoma were associated with objective response to treatment. The median peak anti-CD19 CAR T-cell level in responders versus non-responders was 97.52 cells/μL (range: 0.24 to 2,589.47 cells/μL; number of patients [n] = 62) versus 0.39 cells/μL (range: 0.16 to 22.02 cells/μL; n = 5), respectively. The median AUC0-28d in patients with an objective response was 1,386.28 cells/μL•days (range: 3.83 to 27,700 cells/μL•days; n = 62) versus 5.51 cells/μL•days in non-responders (range: 1.81 to 293.86 cells/μL•days; n = 5).
Higher Tecartus exposures were observed in patients with higher grades of cytokine release syndrome or neurologic adverse reactions (Grade ≥3 vs. Grade ≤2). Patients who received both tocilizumab and corticosteroids for management of cytokine release syndrome or neurologic adverse reactions had higher Tecartus exposure than patients who received either medication alone or neither medication. Tecartus induced B-cell aplasia in the majority of treated patients.
With respect to the immunogenicity potential of Tecartus, no confirmed anti-CAR T cell antibodies were observed. Based on an initial screening assay, 17 patients tested positive for antibodies. However, a confirmation orthogonal cell-based assay demonstrated that all 17 patients were antibody negative at all the time points tested. Immunogenicity is listed as an important potential risk in the Risk Management Plan and will be monitored in future clinical studies and in the post-market setting.
For further details, please refer to the Tecartus Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Tecartus was evaluated in a single-arm, open-label, multicentre, pivotal Phase II study ZUMA-2, in adult patients with relapsed or refractory mantle cell lymphoma. Eligible patients for the study had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton’s tyrosine kinase inhibitor (ibrutinib or acalabrutinib). Patients had disease progression after their last regimen or refractory disease to their most recent therapy. The study excluded patients with active or serious infections, prior allogeneic hematopoietic stem cell transplant, detectable cerebrospinal fluid malignant cells or brain metastases, and any history of central nervous system lymphoma or central nervous system disorders.
In the ZUMA-2 study, patients were enrolled in one of two cohorts to receive a one-time intravenous infusion of Tecartus at a target dose of 2 x 106 chimeric antigen receptor (CAR)-positive viable T cells/kg body weight (Cohort 1 - pivotal cohort) or 0.5 x 106 CAR-positive viable T cells/kg body weight (Cohort 2).
In Cohort 1, 74 patients were leukapheresed (i.e., their cells were collected) and 68 patients received a single infusion of Tecartus. Three patients did not receive Tecartus due to manufacturing failure. Two patients did not receive Tecartus due to progressive disease and death following leukapheresis. One patient who had received lymphodepleting chemotherapy was not treated with Tecartus due to ongoing active atrial fibrillation.
Among the 68 patients who received Tecartus in Cohort 1, 61 (90%) received the target dose of 2 x 106 anti-CD19 CAR-positive viable T cells/kg. The remaining 7 patients received doses of 0.6, 1.0, 1.6, 1.8, 1.8, 1.9 and 1.9 x 106 anti-CD19 CAR-positive viable T cells/kg. All 14 patients in Cohort 2 received a dose of 0.5 x 106 CAR-positive viable T cells/kg. The lymphodepleting regimen consisted of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously, both given on the fifth, fourth, and third day before administration of Tecartus. Bridging therapy between leukapheresis and lymphodepleting chemotherapy was permitted to control disease burden.
Of the 68 patients treated with Tecartus in Cohort 1, the median age was 65 years (range: 38 to 79 years), 84% were male, and 91% were white. Most patients (85%) had stage IV disease and 54% had bone marrow involvement. The median number of prior therapies was three (18% had received two prior therapies; 81% had received three or more prior therapies). Forty-three percent of patients had relapsed mantle cell lymphoma after autologous hematopoietic stem cell therapy, while the remaining patients had either relapsed after (18%) or were refractory to (40%) their last therapy for mantle cell lymphoma. Twenty-five (37%) patients received bridging therapy following leukapheresis and prior to administration of Tecartus.
The efficacy of Tecartus was evaluated in 68 patients who received Tecartus in Cohort 1. The primary efficacy endpoint in the ZUMA-2 study was objective response rate (ORR) as assessed by an independent review committee using the International Working Group Lugano Classification. With a median follow-up time of 16.8 months, the ORR was 91% (95% confidence interval [CI]: 81.8, 96.7); 65% of patients achieved a complete remission (CR) and 26% achieved a partial remission (PR). The median time to response was 1.0 month (range: 0.8 to 3.1 months). These results are clinically meaningful when compared against a historical control rate for ORR of 28%, defined by the sponsor based on a meta-analysis of ORRs to salvage therapy after discontinuing treatment with a Bruton’s tyrosine kinase inhibitor. The median duration of response (DOR) was not reached (95% CI: 10.4, not estimable [NE]) with a median follow-up time for DOR of 13.8 months (95% CI: 11.3, 20.5). The DOR was longer in patients with a best response of CR (median not reached; 95% CI: 14.4, NE) compared to patients with a best response of PR (median 2.2 months; 95% CI: 1.4, 4.9). Of the 44 patients who achieved CR, two patients had stable disease and 22 patients had PR at their initial tumour assessment and converted to CR with a median time to conversion of 2.3 months (range: 1.8 to 8.1 months). The ORR and CR rates in patient subgroups were generally consistent with those rates in the overall patient population, including in subgroups of age (<65 years vs. ≥65 years), sex, and number of prior regimens received.
Overall, Tecartus treatment was shown to induce clinically meaningful responses with durable remissions in a patient population with no standard treatment option and with generally poor response rates to existing therapies. The risks associated with Tecartus can be effectively managed with appropriate supportive care and continued monitoring in the post-market setting. The benefit-risk profile of Tecartus is considered favourable for the treatment of adult patients with relapsed or refractory mantle cell lymphoma after two or more lines of systemic therapy including a Bruton’s tyrosine kinase inhibitor.
Indication
The New Drug Submission for Tecartus was filed by the sponsor with the following indication:
Tecartus is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma previously treated with a Bruton’s tyrosine kinase inhibitor.
Following review of the submitted information, Health Canada revised the proposed indication to reflect more accurately the patient population treated in the pivotal study. Accordingly, Health Canada approved the following indication:
Tecartus is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma after two or more lines of systemic therapy including a Bruton’s tyrosine kinase inhibitor.
For more information, refer to the Tecartus Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
Evidence of clinical safety of Tecartus was derived from 82 patients who were treated with Tecartus in the pivotal ZUMA-2 study, which is described in detail in the Clinical Efficacy section. The safety profile of Tecartus was generally consistent regardless of whether patients received a target dose of 2 x 106 (Cohort 1) or 0.5 x 106 (Cohort 2) CAR-positive viable T cells/kg. The median duration of follow-up was 19.2 months.
The most commonly reported non-hematological adverse reactions (in ≥20% of patients) included pyrexia (94%), cytokine release syndrome (91%), hypotension (57%), encephalopathy (51%), fatigue (50%), tachycardia (45%), other pathogen infections (43%), chills (41%), hypoxia (40%), cough (39%), tremor (38%), musculoskeletal pain (35%), edema (35%), headache (35%), nausea (35%), motor dysfunction (33%), constipation (29%), diarrhea (28%), decreased appetite (26%), dyspnea (26%), rash (22%), insomnia (21%), pleural effusion (21%), aphasia (20%), hypertension (20%), and renal insufficiency (20%).
Serious adverse reactions occurred in 65% of patients. The most commonly reported serious adverse reactions (in ≥2% of patients) included encephalopathy (26%), other pathogen infection (22%), pyrexia (20%), cytokine release syndrome (15%) , hypoxia (9%), aphasia (6%), renal insufficiency (6%), pleural effusion (5%), respiratory failure (5%), bacterial infections (4%), dyspnea (4%), fatigue (4%), non-ventricular arrhythmia (4%), viral infections (4%), diarrhea (2%), hypertension (2%), motor dysfunction (2%), seizure (2%), tachycardia (2%), and thrombosis (2%).
Grade 3 or higher adverse reactions were reported in 65% of patients. The most commonly reported Grade 3 or higher non-hematological adverse reactions included infections (32%) and encephalopathy (24%). The most commonly reported Grade 3 or higher hematological adverse reactions included neutropenia (99%), leukopenia (98%), lymphopenia (96%), thrombocytopenia (65%) and anemia (56%). Grade 5 (fatal) adverse events were reported in three patients: organizing pneumonia, staphylococcal bacteremia, and cardiac arrest.
Cytokine release syndrome, including life-threatening reactions, is a known adverse reaction to CAR T-cell therapy. In the ZUMA-2 study, cytokine release syndrome occurred in 91% of patients receiving Tecartus. Grade 3 or higher cytokine release syndrome was observed in 15% of patients. Among patients with cytokine release syndrome, key manifestations (>10%) included fever (99%), hypotension (60%), hypoxia (37%), chills (33%), tachycardia (27%), headache (24%), fatigue (16%), increased alanine aminotransferase (13%), nausea (13%), increased aspartate aminotransferase (12%), diarrhea (11%), and sinus tachycardia (11%). Serious adverse reactions associated with cytokine release syndrome included hypotension, fever, hypoxia, acute kidney injury, and tachycardia.
Severe neurologic adverse reactions, including those that were life-threatening, occurred following treatment with Tecartus. In the ZUMA-2 study, neurologic adverse reactions occurred in 68% of patients, 33% of whom experienced Grade 3 or higher (severe or life-threatening) adverse reactions. The most commonly reported neurologic adverse reactions (>10%) included encephalopathy (51%), tremor (38%), aphasia (20%), and delirium (18%). Serious adverse reactions including encephalopathy, aphasia, and seizures have occurred after treatment with Tecartus.
Cytokine release syndrome and neurologic adverse reactions require close monitoring and prompt intervention to prevent life-threatening complications or death. Consistent with the labelling practices for other CAR T-cell products, management algorithms for cytokine release syndrome and neurologic adverse reactions are included in the Tecartus Product Monograph. In the ZUMA-2 study, cytokine release syndrome and neurologic adverse reactions were generally reversible using these management algorithms.
A Serious Warnings and Precautions box is included in the Tecartus Product Monograph to highlight the risk of life-threatening reactions associated with cytokine release syndrome and/or neurologic adverse reactions. In addition, the Serious Warnings and Precautions box also emphasizes that Tecartus should be administered by experienced health professionals at specialized treatment centres.
Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified, and to allow for the safe and effective use of Tecartus. Overall, the benefit-risk profile of Tecartus is favourable for the approved indication.
For more information, refer to the Tecartus Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Proof-of-concept studies demonstrated that engineered T cells encoded with a human anti-CD19 construct were capable of inducing cytokine release when cocultured with CD19 expressing cells, leading to the cytotoxicity of tumour-derived cell lines. Two non-clinical studies demonstrated that Tecartus is capable of proliferating stably and eliciting an immune and cytotoxic response against CD19 expressing tumour cells in vitro. An animal study showed that engineered T cells encoded with a murine anti-CD19 construct significantly reduced lymphoma cell numbers and tumour size, and significantly increased survival rates in irradiated mice challenged with murine lymphoma cells, compared to the control group.
As Tecartus consists of engineered human T cells, there are no representative in vitro assays, ex vivo models, or in vivo models that can accurately address the toxicological characteristics of the human product. Hence, traditional toxicology studies used for drug development were not performed.
No carcinogenicity or genotoxicity studies have been conducted with Tecartus. Considering the genetic modification in order to manufacture Tecartus, there is a theoretical risk of secondary malignancies. Clinical and non-clinical evidence from other anti-CD19 CAR T-cell products suggests that the risk of developing secondary malignancies due to treatment is low. In addition, a vector integration site analysis using a similar product to Tecartus showed a very low probability of genetic integration of the vector into human genome.
No studies evaluating the effects of Tecartus on fertility, reproduction, and development have been conducted; however, the risk of fetal toxicity cannot be reasonably ruled out. It is unknown if Tecartus is excreted in human milk. Precaution should be exercised when using Tecartus in breastfeeding women. Key non-clinical uncertainties and precaution recommendations are adequately presented in the Tecartus Product Monograph.
For more information, refer to the Tecartus Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Tecartus (brexucabtagene autoleucel) is a CD19-directed genetically modified autologous cell-based therapy. Tecartus is produced from leukapheresis material obtained from individual patients; and as such, the product is unique to each patient. The patient’s T cells are genetically modified ex vivo by retroviral transduction to express a chimeric antigen receptor (CAR) comprising a murine anti-CD19 single-chain variable fragment (scFv) linked to CD28 and CD3-zeta costimulatory domains. The anti-CD19 CAR T cells are expanded and infused back into the patient, where they can recognize and eliminate CD19-expressing mantle lymphoma cells.
While the retroviral vector, PG13-CD19-H3, encoding the anti-CD19 CAR gene that is introduced in the patient’s T cells is considered the drug substance, the manufacturing process is continuous, without a distinction between the drug substance and drug product that is typical of biologic drugs. The anti-CD19-expressing autologous T cells are the drug product, brexucabtagene autoleucel, marketed under the brand name Tecartus. The vector is a critical starting material, as it encodes the gene for a CAR specific for CD19. Vector quality was tested using validated methods, and stability and release specifications for the vector were appropriately established.
Characterization of the Drug Substance
Brexucabtagene autoleucel, the active component of Tecartus, is a suspension of autologous CD4+ and CD8+ T cells enriched from peripheral blood cells collected by leukapheresis, and genetically modified ex vivo by transduction with a retroviral vector encoding chimeric antigen receptor directed against human CD19 (CD19 CAR).
Tecartus is manufactured using a continuous process without a clear distinction between the drug substance and drug product. Multiple lots of drug product were characterized regarding the integration of CAR transgene, CAR expression, antigen recognition and engagement, T cell activation and proliferation, production of cytokines and chemokines, cytotoxic activity against target cells, and cell phenotype composition. Tecartus drug product comprises primarily CD4+ and CD8+ T cell populations. Only transduced cells are capable of increased proliferation, cytokine secretion, and cytolytic activity in the presence of CD19, all relevant to the proposed mechanism of action.
Tecartus process-derived and product-related impurities were characterized, and are controlled through a combination of appropriate sourcing and testing of materials, validated clearance by the manufacturing process, and testing of process intermediates and finished product. Tecartus comprises primarily CD3+ cells with cellular impurities present at levels below the limit of quantitation, demonstrating the robust capability of the manufacturing process, given the heterogeneous starting material.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Tecartus is manufactured using a continuous process, without a clear distinction between the drug substance and drug product. The critical starting materials include leukapheresis material as the source of autologous cells, and retroviral vector to deliver the CD19 CAR transgene.
The peripheral blood mononuclear cells are collected from a patient at a qualified apheresis centre, via a standard leukapheresis procedure. The cells are transported under cold conditions to the manufacturing site, and stored under appropriate conditions until further processing, which occurs within a defined time period. The CD4+ and CD8+ T cells are then enriched from the leukapheresis material by immunomagnetic selection, formulated, cryopreserved under controlled rate conditions, and stored in the vapour phase of liquid nitrogen at or below -150 °C until further processing. The cryopreserved T cells are then thawed, activated with immobilized anti-CD3 and soluble anti-CD28 antibodies in the presence of IL-2, and transduced with the immobilized retroviral vector containing the CD19 CAR transgene, producing the active substance brexucabtagene autoleucel. Finally, the transduced T cells are expanded in cell culture, washed, formulated into a suspension, cryopreserved under controlled rate conditions, and stored in the vapour phase of liquid nitrogen at or below -150 °C. Tecartus manufacture is predominantly a closed process, with open operations performed under appropriate environmental conditions. The frozen brexucabtagene autoleucel is packed in a validated shipping container, and returned under validated conditions to clinical site to be infused back into the patient.
Results from multiple Process Performance Qualification (PPQ) campaigns demonstrated consistency of the manufacturing process under nominal operating conditions. To ensure that the manufacturing process remains in the state of control, a formal Ongoing Process Verification program is in place.
Validation and/or performance characterization studies specific to selected unit operations were also performed, including in-process hold times, aseptic process simulations, drug product homogeneity, filling consistency, transportation, and chain of identity.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The Human Serum Albumin (HSA), used as an excipient and a wash buffer component was confirmed to be manufactured using materials, process, and controls identical to those of a product approved in Canada for clinical use. The compatibility of the brexucabtagene autoleucel with the excipients and primary packaging is supported by the provided stability data.
Control of the Drug Substance and Drug Product
Lot release specification was established to define the acceptable quality of brexucabtagene autoleucel drug product. The specification includes product characteristics selected based on knowledge and understanding gained through product development and manufacturing experience. The associated analytical methods were validated according to International Conference on Harmonisation (ICH) guidelines, and acceptance criteria were appropriately justified.
Batch analysis data were provided for lots of brexucabtagene autoleucel drug product generated in support of clinical studies and generated during the process performance qualification phase. The data demonstrate that the manufacturing process consistently yields product whose quality meets the applicable specification.
Tecartus is a Schedule D (biologic) drug and is, therefore, subject to Health Canada’s Lot Release Program as per Health Canada’s Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.
Consistency lot testing was not conducted for Tecartus, as the product is autologous and therefore highly individualized to each patient.
The sponsor is expected to submit fax-back forms covering all lots released. Fax-back forms are submitted by the sponsor to Health Canada to attest that the relevant specifications have been met.
Stability of the Drug Substance and Drug Product
The apheresis material collection bag is transported at 2 to 16 °C to the Tecartus manufacturing facility using refrigerated containers qualified for shipments of up to 74 hours in duration. The proposed shipping conditions are supported by the provided validation data.
The enriched T cells may be cryopreserved during Tecartus manufacture, and stored for up to 24 months at or below -150 °C in the vapour phase of liquid nitrogen. The proposed shelf-life is supported by the provided stability data. The conditions used to recover the cryopreserved enriched T cell for further processing have been appropriately qualified.
Tecartus drug product may be stored at or below -150 °C in the vapor phase of liquid nitrogen for up to 12 months. The proposed shelf-life is supported by the provided primary and supporting stability data.
Tecartus drug product is transported to clinic for infusion at or below -150 °C in a high volume dry vapour shipper qualified for shipments of up to 240 hours in duration. Tecartus must be frozen at or below -150 °C in the vapour phase of liquid nitrogen until the patient is ready for treatment. Once thawed, the product is stable for up to 3 hours, and must not be refrozen. The proposed in-use period was supported by available stability data for material subjected to simulated administration conditions.
Facilities and Equipment
An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of Tecartus drug product was waived, as a successful OSE had been recently performed for another product whose manufacturing process was similar.
The site involved in production of Tecartus is compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
Apheresis material is collected according to local guidelines. The process includes screening of potential patients for human adventitious viruses 30 days before the apheresis procedure.
Tecartus drug product is an autologous cell-based therapy, precluding the use of traditional virus clearance methods. Biological safety of Tecartus concerning viral and Transmissible Spongiform Encephalopathy/Bovine Spongiform Encephalopathy adventitious agents is ensured through a detailed review of relevant supporting documentation provided by the respective suppliers of starting and ancillary materials.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| TECARTUS | 02516667 | GILEAD SCIENCES CANADA INC | BREXUCABTAGENE AUTOLEUCEL 200000000 CELLS / BAG |