Summary Basis of Decision for Kymriah

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 Kymriah is located below.

Recent Activity for Kymriah

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Kymriah

Updated: 2023-11-24

The following table describes post-authorization activity for Kymriah a product which contains the medicinal ingredient tisagenlecleucel. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs)

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

Drug Identification Number (DIN):

  • DIN 02480514 - tisagenlecleucel suspension, 2.0 x 106 to 6.0 x 108 chimeric antigen receptor (CAR) positive viable T cells, intravenous

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 272275

2023-02-08

Issued NOL 2023-06-01

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the raw material testing site and specifications, and changes to the drug substance and drug product release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 273708

2023-03-27

Issued NOL 2023-04-21

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the vector shelf‐life. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 263500

2022-04-19

Issued NOC under NOC/c Guidance 2022-12-19

Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: Kymriah is a CD19-directed genetically modified autologous T-cell immunocellular therapy indicated for the treatment of adult patients with relapsed or refractory grade 1, 2, or 3a follicular lymphoma (FL) after two or more lines of systemic therapy. The submission was reviewed and considered acceptable, and an NOC was issued under the Guidance Document: Notice of Compliance with Conditions (NOC/c). A Regulatory Decision Summary was published.

NC # 264889

2022-09-08

Issued NOL 2022-09-08

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug product release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 262508

2022-03-17

Issued NOL 2022-06-20

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the shelf‐life for the vector. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 261730

2022-02-24

Issued NOC 2022-06-06

Submission filed as a Level I – Supplement for the addition of a vector manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 254129

2021-06-23

Issued NOL 2021-10-06

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug substance and drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 253778

2021-06-15

Issued NOL 2021-10-01

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the vector manufacturing process, release and shelf life specifications, and reference control. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 235485

2020-01-24

Issued NOC 2020-12-24

Submission filed as a Level I – Supplement to update the PM with additional clinical data based on longer term follow-up of pivotal (B2202 and C2202) and supportive (B2205J) clinical trials of Kymriah in the treatment of pediatric and young adult B-cell acute lymphoblastic leukemia (B-ALL) and adult DLBCL. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box; Indications; Warnings and Precautions; Adverse Reactions; Drug Interactions; Dosage and Administration; Description; Action and Clinical Pharmacology; Special Handling Instructions; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 243706

2020-09-04

Issued NOL 2020-11-23

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update the endotoxin calculations for pediatric patients below 10 kg and to update the lower limit dose range for patients weighing a minimum of 6 kg. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 241117

2020-06-26

Issued NOL 2020-10-07

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a new manufacturing and testing site for the auxiliary materials/reagents of biological origin. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 233774

2019-11-22

Issued NOL 2020-04-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of an alternate supplier of a human plasma-derived excipient. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 230268

2019-07-31

Issued NOC 2020-03-13

Submission filed as a Level I – Supplement for changes to the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02480514) market notification

Not applicable

Date of first sale:

2019-05-24

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Information Update

Not applicable

Posted 2019-05-15

Information Update posted (Health Canada is advising Canadians about the potential health risks associated with unauthorized cell therapy treatments such as stem cell therapy), containing important safety information for healthcare professionals and the general public.

NC # 222898

2018-12-10

Issued NOL

2019-03-20

 

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change a drug product specification. The submission was reviewed and considered acceptable, and an NOL was issued.

NDS # 213698

2018-02-14

Issued NOC

2018-09-05

Submission filed for new indication. The indication authorized was Kymriah (tisagenlecleucel) is a CD19-directed genetically modified autologous T-cell immunocellular therapy 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, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma Regulatory Decision Summary published

NDS # 213547

2018-02-09

Issued NOC

2018-09-05

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Kymriah

Date SBD issued: 2019-02-08

The following information relates to the New Drug Submission for Kymriah.

Tisagenlecleucel
Suspension, 2.0 x 106 to 6.0 x 108 chimeric antigen receptor (CAR) positive viable T cells, intravenous

Drug Identification Number (DIN):

  • 02480514

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 213547

 

On September 5, 2018, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product, Kymriah.

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 Kymriah is favourable for the treatment of pediatric and young adult patients 3 to 25 years with B-cell acute lymphoblastic leukemia (ALL) who are refractory, have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, or have experienced second or later relapse.

 

1 What was approved?

 

Kymriah is classified as an antineoplastic and immunomodulating agent.

Kymriah was authorized for the treatment of pediatric and young adult patients 3 to 25 years with B-cell acute lymphoblastic leukemia (ALL) who are refractory, have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, or have experienced second or later relapse.

No formal studies have been performed in relapsed or refractory B-cell ALL pediatric patients <3 years of age.

The safety and efficacy have not been established in B-cell ALL patients ≥65 years of age.

Kymriah is contraindicated in patients with known hypersensitivity to tisagenlecleucel or to any component of the product formulation, including dimethyl sulfoxide or dextran 40.

Kymriah 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.

Kymriah (2.0 x 106 to 6.0 x 108 chimeric antigen receptor [CAR] positive viable T cells) is presented as a cell suspension. In addition to the medicinal ingredient, the suspension contains dextran, dextrose, dimethylsulfoxide, human serum albumin, plasma-Lyte A (multiple electrolytes for injection, Type 1, pH 7.4), and sodium chloride.

The recommended dose is as follows:

  • For patients 50 kg and below: 0.2 to 5.0 x 106 chimeric antigen receptor (CAR)-positive viable T cells/kg body weight.
  • For patients above 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells (non-weight based).

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

 

2 Why was Kymriah approved?

 

Health Canada considers that the benefit-risk profile of Kymriah is favourable for the treatment of pediatric and young adult patients 3 to 25 years with B-cell acute lymphoblastic leukemia (ALL) who are refractory, have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, or have experienced second or later relapse.

The disease B-cell ALL is a hematological malignancy characterized by the uncontrolled proliferation of malignant lymphoblasts in the bone marrow. This type of leukemia is a relatively rare disease, representing 75% to 80% of acute leukemias among children; approximately 60% of the cases occur in patients younger than 20 years of age whereas 23% are diagnosed at 45 years or older.

With current multi-agent treatment regimens, the cure rate among children with ALL is >80%. Most patients (>85%) with relapsed ALL will achieve a second remission but most of these patients relapse again and ultimately die of the disease. Of the available treatment options for patients with refractory or relapsed (r/r) B-cell ALL, allogeneic SCT is the only potentially curative option. However, outcomes are suboptimal, and patients need to identify a matched donor and achieve complete remission in order to be eligible for allogeneic SCT. Consequently, treatment of patients with r/r B-cell ALL after failing 2 prior regimens of therapy is challenging. Treatment with authorized agents such as clofarabine and blinatumomab results in low response rates and relatively short duration of responses.

Adoptive T-cell therapy is a new therapeutic strategy whereby T-cell receptors (TCRs) are engineered to bind to specific antigens present on tumour cells. These modified TCRs, known as chimeric antigen receptors (CARs), allow the immune system to specifically target and destroy tumour cells in a major histocompatibility complex (MHC) independent manner.

A very promising target antigen for B-cell malignancies is CD19, a cell-surface protein whose expression is restricted to B cells and their precursors. Kymriah consists of autologous T-cells that are genetically modified ex vivo via lentiviral vector transduction to express a murine CD19 antigen recognition domain that is attached via a CD8 transmembrane region to two co-stimulatory intracellular signalling domains, 4-1BB and CD3 zeta. These T cells undergo activation and expansion in an MHC independent manner. Tisagenlecleucel may offer a therapeutic alternative for patients with r/r B-cell malignancies who are either SCT ineligible or who have relapsed after SCT.

Kymriah has been shown to be efficacious in patients with r/r B-cell ALL. The market authorization was based on one pivotal, Phase II, multicentre, open-label, single-arm study (Study B2202) of 75 infused patients who were 3 to 25 years of age; as well as two supporting studies.

The results of the pivotal study and the supporting studies demonstrated improved efficacy of single-dose Kymriah therapy in pediatric and young adult patients with r/r ALL compared to authorized chemotherapeutic agents. In the pivotal study, the overall response rate was 81.3% (95% confidence interval [CI]: 70.7, 89.4), the median duration of remission had an estimated event-free probability at 6 months of 79.5% (95% CI: 65.1, 88.5), and the median overall survival was 19.5 months at a median follow-up of 10.5 months and maximum follow-up of 21 months. This overall remission rate and the proportion of durable remissions are considered substantially improved evidence of efficacy over current standard treatment options offered to this population of patients.

The risks of single-dose Kymriah therapy include frequent and often severe cytokine release syndrome (CRS), febrile neutropenia, infections, and immunoglobulinemia. In the pivotal study, CRS occurred in 77.3% of patients and 60.3% of these patients experienced severe CRS requiring admission to the intensive care unit. Neurological adverse events such as non-infectious encephalopathy and delirium may develop during episodes of CRS. Febrile neutropenia was reported in 34.7% of patients, with 73.1% of these events considered to be related to the study drug. Infections occurred in 42.7% of patients in the first 8 weeks after Kymriah infusion, 40.6% of which were suspected to be related to the infusion. Most deaths were attributed to underlying leukemia while a small proportion of deaths were due to a variety of infections, hemorrhage, and encephalopathy. No deaths were attributed to CRS. These results demonstrate that this therapy is associated with manageable, serious risks. This product should be administered only in specialized clinical settings that provide intense monitoring, appropriate supportive care, and highly trained and experienced health care personnel. If consent is given, patients will be enrolled in a registry and long-term follow-up will be maintained for at least 15 years.

Appropriate warnings and precautions are in place in the approved Kymriah Product Monograph to address the identified safety concerns. Warnings of CRS and neurological toxicities have been listed in a Serious Warnings and Precautions box in the Kymriah Product Monograph.

A Risk Management Plan (RMP) for Kymriah was submitted by Novartis Pharmaceuticals 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.

As part of the marketing authorization for Kymriah, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. See question 4. What follow-up measures will the company take?

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

Overall, Kymriah 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. The therapeutic benefits of Kymriah therapy seen in the pivotal study are positive and are considered to outweigh the potential risks.

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 Kymriah?

 

The drug submission for Kymriah was reviewed under the Priority Review Policy.

Kymriah demonstrated a statistically significant and clinically relevant improvement in efficacy or decrease in risk such that the overall benefit/risk profile is improved over existing therapies on the Canadian market for a life-threatening or debilitating disease.

 

Submission Milestones: Kymriah

Submission Milestone Date
Pre-submission meeting: 2017-10-26
Request for priority status  
Filed: 2017-12-01
Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics: 2018-01-02
Submission filed: 2018-02-09
Screening  
Screening Acceptance Letter issued: 2018-03-09
Review  
On-Site Evaluation: 2018-06-11 - 2018-06-15
Review of Risk Management Plan complete: 2018-07-03
Clinical Evaluation complete: 2018-08-22
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-08-29
Quality Evaluation complete: 2018-08-30
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2018-09-05

 

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

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

 

4 What follow-up measures will the company take?

 

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

The sponsor was reminded of the following commitments agreed upon during the review of this submission:

  1. Provide Periodic Safety Update Reports/Periodic Benefit-Risk Evaluation Reports (PSUR/PBRER) according to standard reporting requirements, beginning with a first planned report following a data lock point of February 12, 2019. Reports will be submitted every 6 months for the first 2 years, once yearly for the following 2 years, then once every 3 years unless regulatory reporting requirements are changed.
  2. Establish and oversee a controlled distribution program and educational program in Canada, aligned with the Kymriah Risk Management Plan (RMP).
  3. Establish and maintain a registry of patients receiving cellular therapy in the United States and Canada in the post-marketing setting. The registry will be conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) and will enroll patients who received Kymriah or any other CAR-T cell product. The sponsor will receive data from the CIBMTR and data will be analyzed according to study CCTL019B2401, a non-interventional study with secondary use of data.
  4. The sponsor will follow post-market adverse event reporting requirements for marketed health products in accordance with internal procedures as well as Health Canada's Division 1 and Division 8 requirements of the Food and Drug Regulations.

 

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

 

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.

The PAAT for Kymriah is found above.

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

Kymriah (tisagenlecleucel) is an autologous, immunocellular cancer therapy which involves reprogramming a patient's own T-cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. The CAR is comprised of a murine single-chain antibody fragment which recognizes CD19 (a protein common on B cells) and is fused to intracellular signalling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and anti-tumour activity while 4-1BB enhances the expansion and persistence of Kymriah. Upon binding to CD19 expressing cells, the CAR transmits a signal to promote T cell expansion, activation, target cell elimination and persistence of Kymriah.

Cellular kinetics of tisagenlecleucel in pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL) were characterized. Following infusion, tisagenlecleucel exhibited an initial rapid expansion followed by a slower bi-exponential decline.

A dedicated dose-finding study was not performed. The proposed dose for Kymriah for B-cell ALL was based on the clinical response and safety data from the pivotal study and supportive studies as well as results of correlation analyses for dose, exposure, and clinical response. There was no apparent relationship between dose and cellular kinetic parameters. Responses were observed across the dose range and there was no clinically meaningful impact of dose on safety.

Humoral immunogenicity of tisagenlecleucel was measured by the determination of anti-murine CAR19 antibodies (anti-mCAR19) in serum pre- and post-administration. The majority of patients (84.6%) tested positive for pre-dose anti-mCAR19. Treatment induced anti-mCAR19 antibodies were detected in 34.6% of patients. The pre-existing and treatment-induced anti-mCAR19 antibodies did not significantly impact cellular kinetics or clinical response. Cellular immunogenicity was assessed by quantification of intracellular interferon-gamma production in response to mCAR19 peptide stimulation. The cellular immunogenicity responses did not correlate with expansion and persistence of tisagenlecleucel and Month 3 response.

The clinical pharmacological data support the use of Kymriah for the specified indication.

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

Clinical Efficacy

The clinical efficacy of Kymriah treatment in pediatric and young adult patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) was evaluated in one pivotal, Phase II, multicentre, open-label, single-arm study (Study B2202) with 75 infused patients who were 3 to 23 years of age. All patients had leukapheresis products collected and cryopreserved prior to or during study entry.

Ninety-two patients were enrolled, 75 were infused; 17 patients discontinued prior to Kymriah infusion (3 patients due to adverse events, 7 patients due to death; 7 patients due to failure to meet one or more non-safety manufacturing quality criteria).

Eight percent of the patients infused had primary refractory disease. Sixty-one percent of patients had a prior stem cell transplant (SCT). A total of 72 out of 75 patients who received Kymriah infusion also received lymphodepleting chemotherapy after enrolment and prior to the Kymriah infusion.

The primary endpoint was the overall remission rate (ORR), defined as the sum of complete responders (CR) and complete responders with incomplete blood count recovery (CRi), confirmed at Day 28 following the date of the initial documented remission. All responses in all analyses were determined by an independent review committee (IRC).

A planned interim analysis occurred when 50 patients were infused. The ORR was 82.0% (98.9% confidence interval [CI]: 64.5, 93.3), crossed the pre-specified lower boundary for ORR of 20%, and reached statistical significance at a nominal p<0.0001 level.

The median time from Kymriah infusion to the data cut-off date was 13.11 months (range: 2.1 to 23.5). The ORR was 81.3% (95% CI: 70.7, 89.4), again meeting the pre-specified criteria for success and statistical significance at a nominal p-value of 0.0001. Pre-planned subgroup analyses all supported this overall result. All confirmed responders were negative of minimal residual disease (MRD), meeting that key secondary objective as well. The key time-to-event endpoint was duration of remission (DOR); this endpoint was also assessed by IRC.

At the time of the data cut-off date, patients had been followed for a median of 7.5 months and maximum of 19.3 months. Seventeen events had occurred and 30 patients with ongoing remissions were censored at the cut-off date. Seven patients were censored due to receiving SCT while in remission, and 6 patients received new anti-cancer therapy (including additional CD19 chimeric antigen receptor T-cell therapy) while in remission.

The median DOR and upper end of the 95% CI had not been reached while the lower end of the 95% CI was 8.6 months. The estimated event-free probability at 6 months was 79.5% (95% CI: 65.1, 88.5). Other time-to-event secondary endpoints included relapse-free survival (RFS) which was identical to the DOR; and the median event-free survival (EFS) which was not reached. The median overall survival (OS) was 19.1 months (95% CI: 19.1, not estimable) at a median follow-up of 10.5 months and maximum follow-up of 21 months. Compared to authorized single agents available for this r/r ALL population, Kymriah showed a very high overall remission rate that was durable in a substantial number of patients up to the time of data cut-off. However, the relatively short follow-up of those in remission and the loss of patients to informative censoring due to additional anti-cancer therapy while in remission are two weaknesses of this study that reduce the robustness of the evidence for durable long-term remissions.

Supportive Studies

Two supportive studies (Study B2205J and Study B2101J were submitted. Both studies used a single dose of Kymriah, included patients with a median of 3 prior lines of therapy (one of which was allogeneic SCT in 58.6% of patients), and included no patients with lymphoma.

Study B2205J was a single-arm study of children and young adults with r/r ALL aged 3 to 25 years old, a population similar to the pivotal study. Of 35 enrolled patients, 29 were infused with Kymriah. The ORR, confirmed at 28 days and assess by IRC, was 69.0% (98.95% CI: 43.6%, 88.1%). Among the 20 patients who achieved CR or CRi, 8 relapsed. Twelve patients were censored, 10 patients for remaining in remission at the time of the data cut-off date and 2 patients for receiving new anti-cancer therapy while in remission. All deaths were due to underlying ALL. Results of the other secondary endpoints were also similar to those in the pivotal study.

Study B2101J was also a single-arm study of children and young adults with r/r CD19+ B-cell malignancies. It was a dose-exploring study that required split dosing of the first dose as well as multiple dosing at later time points. The median follow-up for this planned interim analysis was 32.2 months, the longest of the three main studies. The focus of the analysis for this submission was on the 56 patients with ALL involving minimal or no central nervous system disease who received Kymriah. Similarities of this cohort with the other previously mentioned studies included heavy previous treatment (89.3% had ≥3 prior regimens) and the age range was 1-24 years. The confirmed ORR at 28 days by investigator assessment was 53/56 (94.6%; 95% CI: 85.1, 98.9), with 94.3% of responders reported as MRD negative. The median DOR was 34.4 months (95% CI: 8.0, not estimable) with a maximum follow-up of 54.8 months. The other time-to-event outcomes were similarly supportive of the pivotal study results. The requirement for split dosing and allowance for multiple total doses along with the determination of ORR by investigator, rather than conducting an independent, assessment, limited the ability to compare these results for efficacy with the pivotal and the other supportive study. However, the ORR is clearly in support of that achieved in the pivotal study and the longer follow-up for DOR gives added promise that the remissions achieved with Kymriah therapy will be durable and meaningful.

Indication

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

  • Kymriah (tisagenlecleucel) is indicated for the treatment of pediatric and young adults age 3 to 25 years with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

After evaluation of the submitted data package, Health Canada authorized Kymriah for the following indication:

  • Kymriah (tisagenlecleucel) is indicated for the treatment of pediatric and young adult patients 3 to 25 years with B-cell acute lymphoblastic leukemia (ALL) who are refractory, have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, or have experienced second or later relapse.

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

Clinical Safety

The clinical safety of Kymriah treatment in pediatric and young adult patients with r/r B-cell ALL was evaluated in one pivotal, Phase II, multicentre, open-label, single-arm study (Study B2202) with 75 infused patients who were 3 to 23 years of age. Two supportive studies provided additional safety data.

In Study B2202, all but one patient received bridging chemotherapy (83.7% of enrolled patients) and/or lymphocyte-depleting chemotherapy (LD) after enrolment and prior to infusion (96% of infused patients). Among enrolled patients who received LD, 79.5% (58/73) experienced at least 1 adverse event (AE) and 51.7% of these experiences had at least 1 maximum grade 3 (15.5%) or maximum grade 4 event (36.2%). One of these patients died before receiving an infusion of Kymriah due to a respiratory fungal infection. At least one AE was reported in 94.5% of patients following Kymriah infusion and the large majority of study infusion-related AEs (92%) were reported in the first 8 weeks post-infusion. The most common of such AEs were (all grades; proportion grade 3 or 4) cytokine release syndrome (CRS) (77.3%; 60.3%), hypogammaglobulinemia (29.3%; 10%), febrile neutropenia (26.7%; 100%), hypotension (25.3%; 68.4%), and pyrexia (25.3%; 36.8%). Admission to an intensive care unit for a median duration of 7 days was required in 60% of patients experiencing CRS. Of those patients, 80% required systemic anti-cytokine therapy (with tocilizumab), 54% required high-dose vasopressor therapy, and 28.6% required invasive assisted ventilation.

Two-thirds of the 58 patients who experienced at least one serious AE (SAE) were reported within the first 8 weeks post-infusion. Adverse events related to Kymriah were suspected in 50/58 (86.2%) of the patients and 90% of these 50 patients experienced grade 3 or 4 toxicity.

Infections occurred in 42.7% of patients within the first 8 weeks after Kymriah infusion, 40.6% of which were suspected to be related to the infusion. There were 6 deaths attributed to causes other than underlying leukemia. One death occurred due to cerebral hemorrhage in the first 30 days post-infusion while the other 5 deaths occurred later, with 3 attributed to systemic or cerebral infection, 1 due to hepatobiliary disease, and 1 death of unknown direct cause. No replication-competent lentivirus or evidence of insertional oncogenesis was detected in any post-infusion patients. The safety profile of patients who received Kymriah from the facility in the United States was similar to that observed in the European facility. The safety profile of Kymriah in the pivotal study was similar to that reported in the two supportive studies with CRS and febrile neutropenia leading the list of study-related, frequently reported higher grade events.

Appropriate warnings and precautions are in place in the approved Kymriah Product Monograph to address the identified safety concerns. Warnings of CRS and neurological toxicities have been listed in a Serious Warnings and Precautions box in the Kymriah Product Monograph.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Non-clinical studies identified and analyzed characteristics of Kymriah (tisagenlecleucel) such as effective receptor constructs, biodistribution and persistence, dose-related toxicity, human membrane protein off-target binding of CD19scFv, assessment of CD19 or CD19 mRNA expression in human brain, and lentivirus insertion site analysis.

Reports of CAR-positive T cells were detected in the spleen, lung, kidney and bone marrow and persisted in a few animals until the end of the study (Day 217 post T-cell injection). There was no indication of uncontrolled cell growth of transduced T cells, or of the preferential outgrowth of cells harbouring integration events near genes of concern. Furthermore, there was no evidence of expression of CD19 protein or CD19 mRNA in human or cynomolgus monkey brain, binding of human membrane proteins by CD19scFv, or preferential integration near genes of concern.

There are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Kymriah (tisagenlecleucel) is a suspension of autologous T cells that have been genetically modified to express a chimeric antigen receptor (CAR) specific for CD19. CD19 is a cell surface protein expressed by normal B cells, as well as B-cell lineage tumours. The T cells are isolated from a patient's peripheral blood cells collected by leukapheresis. The CAR gene is delivered to the T cells by a recombinant, replication-defective, viral vector derived from the human immunodeficiency virus (HIV). The leukapheresis material and the viral vector are considered critical starting materials for tisagenlecleucel, and are described in more detail in the Manufacturing Process and Process Controls section below. The manufacturing process for tisagenlecleucel is continuous, and therefore the information below does not delineate the tisagenlecleucel drug substance.

Characterization of the Drug Product

Multiple lots of tisagenlecleucel were assessed regarding their immunophenotypic, genotypic, and functional characteristics. Overall, tisagenlecleucel contained predominantly viable, naïve and central memory, early-differentiated non-senescent, activated helper and cytotoxic T cells of variable CD4/CD8 composition and CAR expression. The transduction efficiency was variable with, in most cases, a within-sample average of fewer than one CAR copy per cell. There was no evidence for preferential CAR gene integration near genes of concern or preferential outgrowth of cells harbouring integration sites of concern. The majority of T cell effector proteins are produced in response to an anti-CAR stimulus by a small fraction of the CAR-positive T cells. The most expressed analytes included various chemokines and cytokines that are known to play an important role in both T-cell function and tumour immunity. One of the most abundant was IFNγ, which was also consistently produced at variable levels by tisagenlecleucel in mixed lymphocyte reactions with a CD19-expressing cell line. Tisagenlecleucel was demonstrated capable of killing target cells in a cytotoxicity assay with a CD19-expressing cell line. Finally, tisagenlecleucel was demonstrated capable of proliferation by monitoring cell counts during the manufacturing process, and in a proliferation assay with a CD19-expressing cell line.

The final cellular drug product is comprised of T cells transduced with the CAR gene and non-transduced T cells. The active component in tisagenlecleucel is the CAR-gene-transduced, viable T cells. The non-transduced T cells are not considered an impurity as they could support the function of CAR-positive T cells. Non-viable cells could pose a safety risk to the patient, however, cell viability has been quite high in batches manufactured to date. B cells in the final product would be a safety concern, however, no residual B-lineage cells have been detected in any batches manufactured with the current process. The cell culture medium that is used in commercial production does not provide any growth promotion factors for B cells. Red blood cells (RBCs) could potentially be in the final product, however, the manufacturing process is designed to isolate T cells and thus no RBCs are expected to be found in the final drug product.

Manufacturing Process and Process Controls of the Drug Product

Kymriah is manufactured using a patient's autologous leukapheresis material (non-mobilized peripheral blood mononuclear cells [PBMC]) which is enriched for T cells, then transduced with a lentiviral vector encoding a CAR, expanded ex vivo to reach the final dose, harvested, and cryopreserved.

The manufacturing process is continuous, resulting in the tisagenlecleucel drug product. The cells collected by leukapheresis and supplied frozen are thawed, washed, and processed to enrich T cells and deplete other cell types. The T cells are activated, transduced with viral vector, washed, and then allowed to proliferate until the target cell number is achieved. Finally, the cells are harvested, washed, formulated, dispensed into cryobags, and frozen under controlled conditions.

Operating parameters have been based on both historical manufacturing experience and using risk based approaches. Once manufacturing begins with the thawing of the apheresis material, the drug product manufacturing commences and typically finishes within a set period of time. There are no hold times once manufacturing begins and no reprocessing steps are currently allowed in the manufacturing process.

In-process testing program, used to monitor the satisfactory performance of the manufacturing process, was adequately described, including for each step a set of applicable performance parameters with associated validated analytical methods and justified acceptance criteria.

Both the leukapheresis material collected from the patient and the viral vector used to transduce cells processed from the leukapheresis material are considered as critical starting materials for the manufacture of tisagenlecleucel.

  • The leukapheresis material is collected by a third-party specialist at designated sites. For commercial production, the sites must be approved by Novartis Pharmaceuticals Canada Inc. and a quality agreement is required to be in place prior to any leukapheresis material being used for tisagenlecleucel manufacturing. The leukapheresis material that is obtained from the patient, must meet pre-determined acceptance criteria prior to being processed at the manufacturing facility. The leukapheresis material contains T cells and various other cell types including B cells/B-lineage lymphoblasts, natural killer cells, monocytes, dendritic cells, granulocytes, erythrocytes, and platelets. Due to various factors, the composition of the cells can vary widely from patient to patient. Infectious disease testing of the donor will be performed as part of the patient leukapheresis eligibility process.
  • The viral vector is assembled in a human packaging cell line transiently co-transfected with multiple plasmids encoding the necessary genes that have been engineered to minimize the risk of generating replication-competent viruses. The viral vector is manufactured in two stages performed at distinct GMP-compliant facilities, resulting in the vector substance and vector product. At the vector product manufacturing facility, vector substance is thawed, pooled, sterilized by filtration, concentrated, dispensed into suitable containers, and cryopreserved for long-term storage and transportation. Operating parameters associated with each unit operation of the vector substance and vector product manufacturing process were described, and deemed acceptable. The consistency of the manufacturing process was confirmed through the execution at each manufacturing facility of three consecutive process validation batches under nominal manufacturing conditions. The desired quality of vector substance and vector product was defined in the provided specifications, comprising a list of tests for product characteristics indicative of identity, purity, potency and formulation properties including the associated analytical methods, and acceptance criteria that were appropriately justified. The provided batch analysis data confirmed that the manufacturing process consistently yields vector substance and vector product that conforms to the respective specifications.

Control of the Drug Product

The sponsor provided a comprehensive dataset of final drug product lots produced from leukapheresis material. Overall, the sponsor demonstrated that they were able to manufacture the tisagenlecleucel drug product batches that met the predetermined acceptance criteria.

Kymriah is an autologous cell product. Therefore it is imperative that there are processes in place that ensure that the correct final product was derived from the patient's own cells. To ensure that the correct cells are administered to the right patient, a Chain of Identity (COI) is established for transportation through a system known as CellChain that becomes linked to a unique identifier at the manufacturing facility. The systems covering COI are robust, and the risk of the wrong cells being administered to a patient is extremely low.

Stability of the Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug product were adequately supported and are considered to be satisfactory.

For the Kymriah drug product, the stability data support a 9-month shelf life when stored at ≤-120°C in vapour phase liquid nitrogen. For the infusion process, the time when the product is thawed to completion of the infusion should not exceed 30 minutes at room temperature. At 2-8°C, the in-use period is a maximum of 1 hour. At 37°C, test samples begin to show a significant drop in cell viability within one hour and therefore, 37°C is not recommended for the in-use period.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug product, Kymriah, has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

The OSEs for the facilities involved in the manufacture and testing of the vector substance and vector product were not conducted as it was determined by the review team that, although it is a critical starting material in the manufacturing process, it is not administered directly to the patient as are the CAR-T cells. The quality control system in place for vector manufacturing was deemed robust by the review team to ensure that the vector consistently met pre-determined acceptance criteria.

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

Adventitious Agents Safety Evaluation

The risk of contamination by adventitious agents, including bioburden, mycoplasma, transmissible spongiform encephalopathy (TSE) agents, and viruses was minimized by implementing an appropriate control strategy involving the validation of the manufacturing process, and/or appropriate testing of the starting materials, process intermediates, and finished product. For TSE agents, the risk is mitigated through appropriate selection of starting materials. The relevant control strategy components were covered under process validation and performance monitoring, cell substrate qualification, quality control of biological raw materials, and release specifications.

 

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