Summary Basis of Decision for Yescarta

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

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

Recent Activity for Yescarta

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 Yescarta

Date SBD issued: 2019-08-15

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

Axicabtagene ciloleucel

Drug Identification Number (DIN):

  • DIN 02485648 - 2 × 106 to 2 × 108 chimeric antigen receptor (CAR)-positive viable T cells, suspension, intravenous administration

Gilead Sciences Canada Inc.

New Drug Submission Control Number: 218389

On February 13, 2019, Health Canada issued a Notice of Compliance to Gilead Sciences Canada, Inc. for the drug product Yescarta.

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 Yescarta is favourable for the treatment of adult patients with relapsed or refractory 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, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

1 What was approved?

Yescarta, an antineoplastic agent, was authorized for the treatment of adult patients with relapsed or refractory 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, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

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

Yescarta 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.

Yescarta (2 × 106 chimeric antigen receptor [CAR]-positive viable T cells per kilogram [kg] body weight, with a maximum of 2 × 108 CAR-positive viable T cells) is presented as a cell suspension in a patient-specific single infusion bag. In addition to the medicinal ingredient, the suspension contains CryoStor CS10, sodium chloride, and human serum albumin.

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

2 Why was Yescarta approved?

Health Canada considers that the benefit-risk profile of Yescarta is favourable for the treatment of adult patients with relapsed or refractory 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, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

The safety and efficacy of Yescarta have not been established in pediatric patients (<18 years of age), and it is therefore not authorized for pediatric use.

Evidence from clinical studies is not adequate to determine whether there are significant differences in the safety and effectiveness of Yescarta between geriatric patients (≥65 years of age) and younger patients.

Large B-cell lymphoma is a serious and life-threatening condition, particularly if it is relapsed or refractory after two or more lines of systemic therapy. Relapsed or refractory large B-cell lymphoma can be treated with cytotoxic chemotherapies, anti-CD20 monoclonal antibodies, allogeneic or second autologous hematopoietic stem cell transplants (HSCT), radiotherapy, or by participation in clinical trials. However, the objective response to these treatments is low, and disease prognosis is poor. In September 2018, Health Canada granted market authorization for tisagenlecleucel, a CD19-directed genetically modified autologous T cell immunotherapy for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Overall, effective therapies are still urgently needed.

The clinical efficacy of Yescarta was evaluated primarily in the single-arm, open-label, pivotal Phase I/II trial ZUMA-1, in patients with relapsed or refractory large B-cell lymphoma. All patients had received two or more lines of systemic therapy, and had refractory disease to the most recent therapy or relapse within one year of receiving autologous HSCT. Prior therapies must have included anti-CD20 antibody therapy and an anthracycline-containing regimen.

Following completion of a lymphodepleting conditioning regimen, Yescarta was administered as a single intravenous infusion, at a target dose of 2 × 106 chimeric antigen receptor (CAR)-positive viable T-cells/kg of body weight. The maximum dose was 2 × 108 CAR-positive viable T-cells. Bridging chemotherapy was not allowed.

The objective response rate (ORR) was the primary efficacy endpoint, and was determined by an independent review committee using the 2007 revised International Working Group (IWG) response criteria for malignant lymphoma in the 101 patients treated with Yescarta in the Phase II part of the ZUMA-1 study. The ORR was 72%, with complete remission observed in 51% of patients and partial remission observed in 21% of patients. The median follow-up time was 15.1 months.

As a historical control, the sponsor conducted a retrospective pooled analysis of outcomes in patients with refractory DLBCL, referred to as SCHOLAR-1. Data for this analysis were sourced from databases of three treatment centres and two large randomized clinical trials, and patients were chosen to be consistent with the main disease characteristics of ZUMA-1 patients.

The ORR in SCHOLAR-1 was 26% (compared to 72% in ZUMA-1), with 7% of patients experiencing complete remission. The median overall survival was 6.3 months. The evidence gained through this analysis is not equivalent to that which could have been provided by a control group within the ZUMA-1 trial. However, the large difference in ORR observed between ZUMA-1 and SCHOLAR-1 is unlikely to be due to differences in patient populations and disease characteristics.

Overall, the ORR and the complete remissions observed in response to treatment with Yescarta are considered clinically meaningful for a patient population in which effective treatment options are limited.

The safety analysis was conducted in 108 patients who received Yescarta at the recommended doses in both Phases I and II of ZUMA-1. The median duration of follow-up in this population was 15.4 months.

The primary safety concerns related to Yescarta treatment are cytokine release syndrome (CRS) and neurologic adverse reactions. These are listed in a Serious Warnings and Precautions box in the Yescarta Product Monograph, along with the instruction that Yescarta should only be administered by experienced healthcare professionals at specialized treatment centres.

Cytokine release syndrome (CRS) is a known adverse reaction to CAR T-cell therapy. It can cause end organ dysfunction, and has been associated with a wide range of serious adverse events. In ZUMA-1, CRS was reported in 93% of patients, with 12% of patients experiencing Grade 3 CRS or higher. The symptoms of CRS most often observed in ZUMA-1 (in ≥10% of patients) were fever (76%), hypotension (41%), tachycardia (21%), hypoxia (21%), and chills (19%).

Neurologic adverse reactions were observed in 65% of ZUMA-1 patients, with 31% of patients experiencing Grade 3 or higher events. The most common signs of neurologic toxicities observed in ZUMA-1 (in ≥10% of patients) were encephalopathy (37%), tremor (31%), confusional state (27%), aphasia (18%), and somnolence (17%). Serious adverse reactions occurring in patients treated with Yescarta include encephalopathy, aphasia, delirium, and seizures. Fatal and serious cases of cerebral edema occurred in patients treated with Yescarta on other clinical studies conducted by the sponsor.

Cytokine release syndrome and neurologic adverse reactions were generally reversible in ZUMA-1, but required close monitoring and prompt intervention to prevent life-threatening complications or death.

Yescarta is available through a controlled distribution plan, in which only trained healthcare professionals are allowed to administer the treatment. Additionally, the clinical settings in which Yescarta is administered must have access to emergency equipment and an appropriate intensive care facility.

A Risk Management Plan (RMP) for Yescarta was submitted by Gilead Sciences Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Yescarta 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 Yescarta was accepted.

Overall, the therapeutic benefits of Yescarta therapy seen in the pivotal study are considered to outweigh the potential risks. Appropriate warnings and precautions are in place in the Yescarta 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 Yescarta?

The drug submission for Yescarta was reviewed under the Priority Review Policy. Sufficient evidence was provided to demonstrate that when the request for priority status was filed, Yescarta provided an effective option for a disease which is not adequately managed by treatments marketed in Canada.

Submission Milestones: Yescarta

Submission MilestoneDate
Pre-submission meeting:2017-06-08
Request for priority status
Filed:2018-05-18
Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics:2018-06-19
Submission filed:2018-07-19
Screening
Screening Acceptance Letter issued:2018-08-17
Review
On-Site Evaluation:2018-12-03 - 2018-12-07
Review of Risk Management Plan complete:2018-12-11
Quality Evaluation complete:2019-02-07
Clinical/Medical Evaluation complete:2019-02-07
Biostatistics Evaluation complete:2019-02-12
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2019-02-12
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate:2019-02-13

The Canadian regulatory decision on the clinical and quality review of Yescarta was based on a critical assessment of the data package submitted to Health Canada. The publically available Summary of Product Characteristics (SmPC) from the European Medicines Agency (EMA) and Prescribing Information (PI) from the United States Food and Drug Administration (FDA) were used as added references.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

The sponsor is additionally expected to complete the following activities to continue to develop the safety profile of Yescarta:

  • Conduct and enroll Canadian patients treated with Yescarta in a post-marketing, prospective observational study to characterize the long-term safety of Yescarta, including secondary malignancies.
  • Monitor and study bridging chemotherapy in patients treated with Yescarta in ongoing Yescarta clinical trials. The need for conditioning chemotherapy when a patient's white blood cell count is ≤1000 cells/mcl after debulking therapy may also be assessed in ongoing Yescarta clinical trials.
  • Utilize ongoing or future Yescarta studies to compare tocilizumab response in the management of cytokine release syndrome using an every eight hour dosing schedule to the response data from ZUMA-1 available in this submission, in which a four- to six-hour dosing schedule was investigated.

5 What post-authorization activity has taken place for Yescarta?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (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. The PAAT will continue to be updated during the product's life cycle.

At this time, no PAAT is available for Yescarta. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

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

Clinical Pharmacology

Yescarta consists of genetically modified autologous (patient-derived) T cells, which express a chimeric antigen receptor (CAR) directed against the B-cell antigen CD19. 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 Yescarta 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 cellular kinetics of Yescarta (axicabtagene ciloleucel) were studied in adults with relapsed or refractory diffused large B-cell lymphoma. A rapid expansion was observed, which reached peak levels between seven and 14 days following infusion. The number of axicabtagene ciloleucel cells in the blood was positively associated with an objective response. Three months after infusion, the number of cells had declined to levels close to baseline. Age and gender did not appear to significantly affect the cellular kinetics of Yescarta.

No formal drug-drug interaction studies were conducted with Yescarta. However, it can cause prolonged B-cell aplasia and hypogammaglobulinemia, which can reduce the effectiveness of vaccines. While the safety of live viral vaccines remains unknown in patients receiving Yescarta, the risk of systemic infection should not be disregarded. Additionally, immunosuppressive agents may have a lymphotoxic effect and reduce the effectiveness of Yescarta, which is produced from viable T cells.

In the pivotal study, ZUMA-1, cytokine release syndrome (CRS) and neurologic toxicities were managed with tocilizumab and/or corticosteroids. There was no evidence in the clinical trial setting that tocilizumab or corticosteroids reduced the effectiveness of Yescarta.

Immunogenicity was also examined in ZUMA-1. Three patients (3%) had low levels of anti-Yescarta antibodies at baseline, with no titre elevation post-treatment. There was no evidence that the kinetics, safety, or efficacy of Yescarta were compromised in these patients. The sponsor is expected to continue studying the immunogenicity of Yescarta post-authorization, including monitoring for severe infusion or hypersensitivity reactions, and examining the humoral and cellular immunogenicity of Yescarta in ongoing and future clinical trials.

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

Clinical Efficacy

The clinical efficacy of Yescarta was evaluated primarily in the single-arm, open-label, pivotal Phase I/II trial ZUMA-1, in patients with relapsed or refractory large B-cell lymphoma.

Eligible patients had received two or more lines of systemic therapy, and had refractory disease to the most recent therapy or relapse within one year of receiving autologous hematopoietic stem cell transplant (HSCT). Prior therapies must have included anti-CD20 antibody therapy and an anthracycline-containing regimen.

Exclusion criteria included prior allogeneic HSCT or CD19-targeting CAR T-cell therapy, central nervous system (CNS) lymphoma or a history of other CNS disorders (e.g. seizures or cerebrovascular ischemia), thrombolic events within the last six months, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, significant hematological disorders, inadequate kidney, liver, heart, or lung function, and active serious infection or active autoimmune disease requiring systemic immunosuppression.

Prior to treatment with Yescarta, patients completed a lymphodepleting conditioning regimen, in which 500 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine were administered on the 5th, 4th, and 3rd days before receiving Yescarta. Yescarta was administered as a single intravenous infusion, at a target dose of 2 × 106 CAR-positive viable T cells/kg of body weight, with a maximum dose of 2 × 108 CAR-positive viable T cells. Bridging chemotherapy was not allowed. This dosing regimen was examined in seven patients in Phase I of the trial, and one case of dose-limiting toxicity was detected. All patients were hospitalized for the administration of Yescarta, and for at least seven days afterwards.

Yescarta was administered to a greater number of patients in Phase II. At the data cut-off point, 111 patients had undergone leukapheresis, 103 patients had completed the conditioning regimen, and 101 patients were infused with Yescarta. Of the ten patients who underwent leukapheresis but did not receive Yescarta, two patients had spontaneous remissions, and eight patients died due to progressive disease or serious adverse events.

Among the patients who received Yescarta and had histologically confirmed disease, 75 patients had diffuse large B-cell lymphoma (DLBCL; primarily of the not otherwise specified [NOS] subtype), four patients had primary mediastinal large B-cell lymphoma (PMBCL), and 16 patients had DLBCL arising from follicular lymphoma, according to the 2008 World Health Organization (WHO) lymphoma classification. Forty-seven patients had tumours that were evaluable for genetic abnormalities. Seven of these patients had high-grade B-cell lymphoma based on the 2016 update of the WHO lymphoma classification.

The objective response rate (ORR), the primary efficacy endpoint, was 72%. Fifty-one percent (51%) of patients achieved complete remission, and 21% of patients achieved partial remission. The median follow-up time was 15.1 months. The ORR was calculated by an independent review committee using the 2007 revised International Working Group (IWG) response criteria for malignant lymphoma; an internationally recognized standard.

The median time to response was one month, and the median duration of response was 14 months. Patients who achieved complete remission had a longer duration of response, compared to patients who experienced partial remission. The ORRs in subgroups of patients (by demographics or disease characteristics) were generally consistent.

As a historical control, the sponsor conducted a retrospective pooled analysis of outcomes in patients with refractory DLBCL, referred to as SCHOLAR-1. Information for this analysis was retrieved from databases of two large randomized clinical trials and three different treatment centres. Patients were chosen to align with the key disease characteristics of patients in ZUMA-1.

The ORR in SCHOLAR-1 was 26% (compared to 72% in ZUMA-1), with 7% of patients experiencing complete remission. The median overall survival was 6.3 months. The evidence gained through this analysis is not equivalent to that which could have been provided by a control group within the ZUMA-1 trial. However, the improvement in ORR observed in ZUMA-1 compared to SCHOLAR-1 is substantial, and unlikely to be caused by differences in patient populations and disease characteristics.

Overall, the ORR and the complete remissions observed in response to treatment with Yescarta are considered clinically meaningful for a patient population in which effective treatment options are limited.

Indication

The New Drug Submission for Yescarta was filed by the sponsor with the following indication, which Health Canada subsequently approved:

Yescarta is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for:

  • The treatment of adult patients with relapsed or refractory 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, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

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

Clinical Safety

The clinical safety of Yescarta was evaluated in the pivotal ZUMA-1 trial, which is described in detail in the Clinical Efficacy section. Patient safety was assessed in 108 patients who received Yescarta at the recommended doses in both Phase I and Phase II of ZUMA-1. The median duration of follow-up in this population was 15.4 months.

The most common non-hematological adverse reactions, reported in at least 20% of patients, were cytokine release syndrome (CRS; 93%), encephalopathy (58%), fatigue (43%), decreased appetite (41%), fever (40%), headache (40%), diarrhea (35%), nausea (31%), tremor (31%), tachycardia (29%), cough (29%), unspecified pathogen infection (28%), hypotension (27%), vomiting (23%), dizziness (21%), constipation (20%), and edema (20%).

Serious adverse reactions occurred in 55% of patients. The most frequently reported reactions were encephalopathy (18%), lung infection (7%), pyrexia (7%), pneumonia (6%), confusional state (5%), febrile neutropenia (5%), aphasia (4%), atrial fibrillation (4%), cardiac arrest (4%), urinary tract infection (4%), acute kidney injury (3%), agitation (3%), ejection fraction decreased (3%), hypotension (3%), hypoxia (3%), neutropenia (3%), somnolence (3%), atrial flutter (2%), and delirium (2%). Seventeen patients (17%) required admission to the intensive care unit (ICU).

The most common adverse reactions classified as Grade 3 or higher (≥10% of patients) were encephalopathy (30%), unspecified pathogen infection (19%), and cytokine release syndrome (12%). Collectively, these were reported in 65% of patients.

Grade 5 (fatal) adverse events occurred in four patients. These were anoxic brain injury (secondary to cardiac arrest which occurred in the setting of CRS), hemophagocytic lymphohistiocytosis (HLH), intracranial hemorrhage in the setting of thrombocytopenia, and pulmonary embolism.

Cytokine release syndrome is a known adverse reaction to CAR T-cell therapy. It occurred in 93% of patients in ZUMA-1, with 12% of patients experiencing Grade 3 CRS or higher. The signs of CRS most often observed in this trial (in at least 10% of patients) were fever (76%), hypotension (41%), tachycardia (21%), hypoxia (21%), and chills (19%).

Cytokine release syndrome can cause end organ dysfunction, and has been associated with various serious adverse events. These include, but are not limited to cardiac arrhythmias (including atrial fibrillation/flutter and ventricular tachycardia), hypoxia, hypotension, cardiac arrest, cardiac failure, renal insufficiency or failure, abnormal liver enzymes, increased blood bilirubin, coagulopathy, capillary leak syndrome, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Neurologic toxicities were observed in 65% of ZUMA-1 patients, with 31% of patients experiencing Grade 3 or higher events. The most common manifestations of neurologic toxicities (occurring in over 10% of patients) were encephalopathy (37%), tremor (31%), confusional state (27%), aphasia (18%), and somnolence (17%). Serious adverse reactions occurring in patients treated with Yescarta include encephalopathy, aphasia, delirium, and seizures. Fatal and serious cases of cerebral edema occurred in patients treated with Yescarta in other clinical trials.

Cytokine release syndrome and neurologic toxicities were generally reversible in ZUMA-1, but required close monitoring and prompt intervention to prevent life-threatening complications or death. Monitoring and management strategies were developed to address these risks, including the use of the anti-interleukin-6 (anti-IL6) antibody tocilizumab and/or corticosteroids, and supportive therapies for end organ dysfunction.

Cytokine release syndrome and neurologic adverse reactions are listed in the Serious Warnings and Precautions box of the Yescarta Product Monograph, along with the instruction that Yescarta should be administered by experienced healthcare professionals at specialized treatment centres. Yescarta is available through a controlled distribution plan. This plan requires health professionals to be trained in handling and administration of Yescarta, and in monitoring and management of serious adverse reactions related to treatment. Under this plan, the clinical settings in which Yescarta is administered must have access to emergency equipment and an appropriate intensive care facility.

Several factors may impact the safety and efficacy of Yescarta. The demographics or disease characteristics of patients in the post-market setting may not have been fully represented in the patient population of ZUMA-1. It is unclear whether safety and efficacy would be consistent in these cases. They may also be affected by the use of bridging chemotherapy, which was not allowed in ZUMA-1, or by a change in the conditioning regimen. Additionally, while serious CRS was generally managed successfully with tocilizumab in ZUMA-1, the dosing regimen may not be optimal for all patients and may evolve over time. The sponsor is expected to address these factors in ongoing and future clinical trials with Yescarta, as well as in the post-market setting.

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

7.2 Non-Clinical Basis for Decision

Yescarta is an autologous product, consisting of genetically modified human T cells. Due to the highly individualized nature of the treatment, there are no in vitro assays, ex vivo models, or in vivo models that can be applied to accurately examine the toxicological characteristics of the product.

Traditional toxicology, carcinogenicity, and genotoxicity studies were not performed. Additionally, the effects of Yescarta on fertility, reproduction, and development were not studied, but the risk of fetal toxicity cannot reasonably be discounted. It is unknown whether Yescarta is excreted in human milk, and caution is advised for patients who are planning to nurse.

As the production of Yescarta involves genetic modification of the patient's own cells, there is a theoretical risk of secondary malignancies developing as a result of therapy. The sponsor is expected to further characterize this risk in a planned prospective observation study, to be conducted post-market.

The key non-clinical uncertainties and precautionary recommendations are addressed in the Yescarta product Monograph. Considering the intended use of Yescarta, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

7.3 Quality Basis for Decision

Yescarta is a suspension of autologous (patient-derived) T cells, isolated from peripheral blood cells by leukopheresis, and genetically engineered ex vivo to express a CAR directed against the B-cell antigen CD19. The CD19 protein is expressed on the surface of all B cells, including B cell lineage tumours. A vector encoding the anti-CD19 CAR gene is introduced into the patient's T cells, and the anti-CD19 CAR may then be expressed on the cell surface. Although the vector is considered to be 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, axicabtagene ciloleucel, marketed under the brand name Yescarta. Following the infusion of Yescarta 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

The replication-incompetent retroviral vector, PG13-CD19-H3, is used to introduce the anti-CD19 CAR gene into the patient's T cells to generate the final drug product, Yescarta. The vector is a critical starting material, as it encodes the gene for a CAR specific for CD19; a target antigen expressed on the surface of B cells.

The vector was characterized, including vector structure and function, as well as vector impurities. The vector sequence covering the full transgene sequence was verified. Additionally, the gene product, the anti-CD19 CAR, was confirmed to be expressed and functional through an interferon gamma (IFNγ) production test. T cells produce IFNγ following antigen recognition, and it is therefore a widely accepted indicator of T cell activation.

Vector quality was tested using validated methods, and stability and release specifications for the vector were appropriately established.

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

The vector manufacturing process includes cell expansion, harvest, filtration, fill, and storage steps. The manufacturing process has been validated, and in-process controls have been appropriately established.

The manufacturing process for the axicabtagene ciloleucel drug product was based on the commercial process identified as CLP 2.2. Revisions were made during process development to remove human serum albumin from the growth medium and to minimize the risk of contamination by adding more closed steps to the process.

Fresh apheresis product is obtained from the patient at a qualified clinical site, and transported cold to the manufacturing site. The apheresis product is treated to enrich the number of lymphocytes. T cells within this culture are activated and transduced with the retroviral vector encoding the anti-CD19 CAR T cell transgene, producing axicabtagene ciloleucel. The cells undergo expansion, are formulated into a buffer, and then frozen in a controlled rate freezer to reach the vapour phase of nitrogen (below -150ºC). The frozen axicabtagene ciloleucel is packed and returned to the clinical site to be infused back into the patient. The final drug product consists primarily of genetically modified CD3+ T cells, with limited numbers of modified natural killer (NK) and natural killer T (NKT) cells.

The axicabtagene ciloleucel manufacturing process was validated using 15 apheresis products from healthy donors. Additionally, extensive process characterization studies were carried out on over 127 lots from healthy donors to define process parameter ranges and identify critical process parameters. The data indicate that axicabtagene ciloleucel can be manufactured at a consistent high level of quality, from fresh or frozen apheresis starting material.

The final release specifications were based on critical product quality attributes. Critical attributes were identified through a product risk analysis conducted with 142 lots from the ZUMA-1 trial and subsequent clinical lots of axicabtagene ciloleucel. Specifications were established for appearance, identity, dose, potency, purity, and safety.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the axicabtagene ciloleucel with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Yescarta is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Consistency lot testing was not conducted for Yescarta, 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 in Canada on a quarterly basis, or on a monthly basis if the number of released lots meets or exceeds one lot per week. 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

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. Yescarta must be frozen in the vapour phase of liquid nitrogen (≤-150ºC) until the patient is ready for treatment, and is stable for up to 18 months at this temperature. Once thawed, the product is stable for up to three hours. Thawed product must not be refrozen.

Facilities and Equipment

An On-Site Evaluation (OSE) was conducted at the drug product manufacturing site. Two observations were noted, and both were considered resolved at the end of the quality review process. The manufacturing process, quality assurance, and quality control measures observed during the OSE were consistent with the information provided in the submission. The manufacturing site was issued a compliant rating.

Adventitious Agents Safety Evaluation

The master and working cell banks involved in the manufacturing of the vector drug substance were tested according to International Council for Harmonisation (ICH) guidelines, and found to be free of contamination from bacteria, fungi, mycoplasma, and adventitious viruses.

All vector harvests are tested for sterility. Safety testing is conducted on the last harvest to confirm that the entire batch of product remains free of adventitious agents, particularly mycoplasma, in vitro viruses, and replication-competent retroviruses (RCR). All vector lots that had been tested at the time of review were negative for adventitious agents and met the relevant specifications.

The supernatant from cells containing the retroviral vector are subject to a biosafety testing program, consistent with current guidelines from the ICH, the Food and Drug Administration (FDA), and the World Health Organization (WHO). Additionally, the cell bank prepared using cells at the limit of in vitro cell age used for manufacturing (the end of production [EOP] cell bank) was tested for the presence of RCR and other adventitious agents according to ICH guidelines, and passed all safety tests.

Patient apheresis material and each lot of human serum albumin (HSA) used in the manufacturing process were screened for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis viruses B and C, and other potential human pathogens.

Certification letters were provided by the sponsor for HSA, lactobionic acid, human holo-transferrin, recombinant human insulin, and fetal bovine serum, as they are of human or animal origin. These letters served as attestations that these materials were obtained from approved sources, appropriate for their intended use, and do not pose a risk for bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE).

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