Summary Basis of Decision for Tecvayli

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)

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

Recent Activity for Tecvayli

The 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle. At this time, no PAAT is available for Tecvayli. When the PAAT for Tecvayli becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Tecvayli

Date SBD issued: 2023-09-20

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

Teclistamab

Drug Identification Number (DIN):

  • DIN 02539756 - 30 mg/3.0 mL (10 mg/mL), solution, subcutaneous injection

  • DIN 02539764 - 153 mg/1.7 mL (90 mg/mL), solution, subcutaneous injection

Janssen Inc.

New Drug Submission Control Number: 269369

Submission Type: New Drug Submission (New Active Substance) - Notice of Compliance with Conditions

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): L01 Antineoplastic agents

Date Filed: 2022-11-02

Authorization Date: 2023-07-26

On July 26, 2023, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Janssen Inc. for the drug product Tecvayli. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

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 Tecvayli is favourable for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-cluster of differentiation 38 (CD38) monoclonal antibody, and who have demonstrated disease progression on the last therapy.

1 What was approved?

Tecvayli, an antineoplastic, monoclonal antibody, was authorized for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-cluster of differentiation 38 (CD38) monoclonal antibody, and who have demonstrated disease progression on the last therapy.

Tecvayli is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available for this population.

Of the 165 patients who were treated with Tecvayli at the recommended dose in the pivotal MajesTEC-1 study, 48% were 65 years of age or older, and 15% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Tecvayli (30 mg/3.0 mL and 153 mg/1.7 mL teclistamab) is presented as a solution. In addition to the medicinal ingredient, the solution contains ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate, glacial acetic acid, polysorbate 20, sodium acetate trihydrate, sucrose, and water for injection.

The use of Tecvayli is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Tecvayli Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Tecvayli approved?

Health Canada considers that the benefit-risk profile of Tecvayli is favourable for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-cluster of differentiation 38 (CD38) monoclonal antibody, and who have demonstrated disease progression on the last therapy. Tecvayli was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

In Canada, multiple myeloma (MM) is a serious, incurable disease representing approximately 1.6% of new cancers with about 3,800 new cases and 1,600 deaths from MM annually. Multiple myeloma is a cancer of plasma cells. The malignant plasma cells produce clonal immunoglobulin, invade bone marrow, and destroy adjacent bone tissue. While novel therapies have improved care for patients with MM, relapsed or refractory MM remains challenging to manage, especially following several prior lines of anti-myeloma therapy. All patients with this disease eventually relapse and/or become refractory to existing treatments. With each successive relapse, symptoms return, quality of life worsens, and the chance and duration of response to subsequent treatment typically decreases.

Patients with relapsed or refractory disease who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, have limited treatment options. Treatments that may be considered for these patients include anti-myeloma agents that have not been used in earlier lines of treatment.

Tecvayli (teclistamab) is a bispecific antibody that targets both the cluster of differentiation 3 (CD3) receptor expressed on the surface of T cells and the B-cell maturation antigen (BCMA) expressed on the surface of malignant MM cells and some B-lineage cells. With its dual binding sites, teclistamab is able to draw CD3+ T cells in close proximity to BCMA+ MM cells, resulting in T-cell activation and subsequent lysis and death of BCMA+ cells.

Tecvayli has been shown to be efficacious in adult patients with relapsed or refractory MM. The market authorization with conditions was based on the data from one single-arm, open-label, multicentre, pivotal study (MajesTEC-1). The primary efficacy cohort supporting the authorized indication consisted of 110 adult patients with relapsed or refractory MM who had received at least three prior lines of anti-myeloma therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Most patients were refractory to their last prior line of myeloma therapy. Patients received initial step-up doses of 0.06 mg/kg and 0.3 mg/kg Tecvayli administered subcutaneously followed by the treatment dose of 1.5 mg/kg actual body weight once weekly until disease progression or unacceptable toxicity.

The efficacy results were based on overall response rate (ORR) as determined by the Independent Review Committee assessment using International Myeloma Working Group (IMWG) 2016 criteria. The ORR was 61.8% (95% Confidence Interval [CI]: 52.1%, 70.9%), with 28.2% of patients achieving a complete response or better. The median duration of response (DOR) was not estimable. At a follow-up analysis (which included 15 additional patients who enrolled after the primary analysis), the ORR was 62.4% (95% CI: 53.3%, 70.9%), and the median DOR was 14.9 months (95% CI: 14.9 months, not estimable). These efficacy results demonstrated promising evidence of clinical benefit for Tecvayli. The survival benefit of Tecvayli therapy has not been established and is to be confirmed in an ongoing Phase III clinical study (MajesTEC-3).

As part of the MajesTEC-1 study, the safety of Tecvayli was evaluated in 165 adult patients with relapsed or refractory MM who received Tecvayli. Adverse reactions that were reported in 20% or more of patients included: hypogammaglobulinemia; cytokine release syndrome; neutropenia; musculoskeletal pain; fatigue; thrombocytopenia; injection site reaction; upper respiratory tract infection; lymphopenia; diarrhea; pneumonia; nausea; pyrexia; headache; cough; constipation; and pain. Serious adverse reactions that were reported in 2% or more of patients included: pneumonia; coronavirus disease 2019 (COVID-19); cytokine release syndrome; sepsis; pyrexia; musculoskeletal pain; acute kidney injury; diarrhea; cellulitis; hypoxia; febrile neutropenia; and encephalopathy. Fatal adverse events regardless of causality were reported in 18 patients (10.9%), including fatal infections in 15 patients (9.1%; of whom, 12 patients [7.3%] had fatal COVID-19 infections). These safety findings and the applicable risk mitigation measures are described in the Tecvayli Product Monograph.

The identified serious safety concerns include cytokine release syndrome and serious or life-threatening neurological toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS). These are all listed in a Serious Warnings and Precautions box in the Tecvayli Product Monograph.

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

The submitted inner and outer labels, package insert and Patient Medication Information section of the Tecvayli Product Monograph met the necessary regulatory labelling, plain language and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike-sound‑alike-attributes. Upon review, the proposed name Tecvayli was accepted.

Overall, the therapeutic benefits of Tecvayli therapy seen in the pivotal study are promising. Tecvayli has an acceptable safety profile based on the non-clinical data, the clinical studies and in the context of the authorized use. The identified safety issues can generally be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Tecvayli Product Monograph to address the identified safety concerns.

Based on the evidence reviewed under the NOC/c Guidance, the anticipated benefit of Tecvayli outweighs the potential risks and remaining uncertainties of the clinical evidence for the treatment of adult patients with relapsed or refractory MM who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy. The clinical benefit of Tecvayli is to be confirmed in the ongoing Phase III clinical MajesTEC-3 study. As described within the framework of the NOC/c Guidance, safety monitoring of the use of Tecvayli will be ongoing. Further evaluation will take place upon the submission of data from the requested studies after they become available.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Tecvayli?

The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the New Drug Submission (NDS) for Tecvayli. Promising evidence of clinical effectiveness was presented demonstrating that Tecvayli has the potential to provide a significant increase in efficacy such that the overall benefit-risk profile is improved over existing therapies for a serious, life-threatening or severely debilitating disease that is not adequately managed by a drug marketed in Canada. Subsequent review led to the decision to issue the sponsor market authorization under the NOC/c Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit (described in the What follow-up measures will the company take? section).

The NDS for Tecvayli was reviewed under Project Orbis, an initiative of the United States Food and Drug Administration (FDA) Oncology Center of Excellence. The project is an international partnership designed to give cancer patients faster access to promising cancer treatments. The submission for Tecvayli was classified as a Project Orbis Type C submission, where the FDA had already issued a positive decision and subsequently shared its completed review documents with Health Canada.

The Canadian regulatory decision on the Tecvayli NDS was made independently. The review of the NDS was based on a critical assessment of the data package submitted to Health Canada and of the reviews completed by the United States FDA as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Method 3 was used for the review of the clinical efficacy and safety, as well as the non-clinical components of the submission. Method 2 was used for the review of the quality and clinical pharmacology datasets.

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

Submission Milestones: Tecvayli

Submission Milestone

Date

Pre-submission meeting

2022-08-23

Advance Consideration under the Notice of Compliance with Conditions Guidance accepted

2022-10-17

New Drug Submission filed

2022-11-02

Screening

Screening Acceptance Letter issued

2022-12-01

Review

Review of Risk Management Plan completed

2023-05-18

Quality evaluation completed

2023-06-13

Non-clinical evaluation completed

2023-06-15

Clinical/medical evaluation completed

2023-06-15

Biostatistics evaluation completed

2023-06-15

Labelling review completed

2023-06-19

Notice of Compliance with Conditions Qualifying Notice issued

2023-06-19

Review of Response to Notice of Compliance with Conditions Qualifying Notice:

Response filed (Letter of Undertaking)

2023-06-23

Clinical/medical evaluation completed

2023-07-17

Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate under the Notice of Compliance with Conditions Guidance

2023-07-26
4 What follow-up measures will the company take?

In addition to the requirements outlined in the Food and Drugs Act and Regulations and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide the results from the confirmatory Phase III MajesTEC-3 study. This randomized study compares Tecvayli in combination with subcutaneously administered daratumumab (Tec-Dara) versus daratumumab subcutaneous (SC), pomalidomide, and dexamethasone, or daratumumab SC, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma. The clinical study report will include results from the primary analysis of progression-free survival and an analysis of overall survival that will permit a meaningful evaluation of the overall survival benefit of Tecvayli-based therapy versus the control treatment. The sponsor will also provide the clinical study report of an updated analysis of the Phase I/II MajesTEC-1 study (described in the Clinical Basis for Decision section). The updated analysis will further characterize the safety and efficacy of Tecvayli including but not limited to patients in Cohort A, Cohort C and those who met the protocol-defined criteria and received a less frequent dose of Tecvayli. This analysis will be conducted two years after the initial dose of the last patient in Phase II.

As part of the marketing authorization for Tecvayli, Health Canada requested and the sponsor agreed to several additional commitments to be addressed post market. These commitments include (but are not limited to):

  • Addition of hepatotoxicity as an important potential risk.

  • Additional routine pharmacovigilance activities for the important identified risks of cytokine release syndrome and neurologic toxicity, and the important potential risk of hepatotoxicity.

  • Developing and implementing additional risk minimization activities (i.e., Patient Card and healthcare professional training) for the important identified risks of cytokine release syndrome and neurologic toxicity.

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

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 life cycle.

At this time, no PAAT is available for Tecvayli. 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

As outlined in the What steps led to the approval of Tecvayli? section, the review of the clinical component of the New Drug Submission for Tecvayli was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration (FDA) as a Project Orbis Type C submission. The clinical review of the efficacy and safety components of the New Drug Submission for Tecvayli was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Method 2 was used for the clinical pharmacology dataset.

One pivotal clinical study (MajesTEC-1) along with population pharmacokinetic analysis were submitted in support of Tecvayli. The MajesTEC-1 study is a single-arm, open-label, Phase I/II, multicentre study evaluating Tecvayli in adult patients with relapsed or refractory multiple myeloma (MM). The study excluded patients who had stroke, seizure, allogeneic stem cell transplant within the past 6 months, an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or higher, known central nervous system involvement or clinical signs of meningeal involvement of MM, active or documented history of autoimmune disease (with the exception of vitiligo), Type 1 diabetes, and prior autoimmune thyroiditis. Patients received initial step-up doses of 0.06 mg/kg and 0.3 mg/kg Tecvayli administered subcutaneously, followed by a dose of 1.5 mg/kg actual body weight once weekly thereafter until disease progression or unacceptable toxicity. The median duration between the first and second step-up dose was 2.9 days (range: 2-7 days). The median duration between the second step-up dose and the initial treatment dose was 3.9 days (range: 2-9 days).

Clinical Pharmacology

Teclistamab is a full-size, immunoglobulin G4 proline, alanine, alanine (IgG4-PAA) bispecific antibody that targets the cluster of differentiation 3 (CD3) receptor expressed on the surface of T cells and B-cell maturation antigen (BCMA) expressed on the surface of malignant MM and healthy B-lineage cells and plasma cells. With its dual binding sites, teclistamab draws CD3+ T cells in close proximity to BCMA+ cells, resulting in T-cell activation and subsequent lysis and death of BCMA+ cells. This is mediated by the secretion of perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. This effect occurs without regard to T-cell receptor specificity or reliance on major histocompatibility complex (MHC) Class 1 molecules on the surface of antigen-presenting cells.

The pharmacokinetics of teclistamab was evaluated in the pivotal MajesTEC-1 study (described earlier in the Clinical Basis for Decision section). Teclistamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose range of 0.08 mg/kg to 3 mg/kg (0.05 to 2.0 times the recommended dose). Based on the population pharmacokinetic analysis, covariates including age, sex, race ethnicity, body weight, mild or moderate renal impairment, and mild hepatic impairment were not associated with clinically important differences in teclistamab pharmacokinetics. Based on the exposure-efficacy analysis, the overall response rate increased with the increase of teclistamab exposure and approached plateau at the exposure in patients treated with the recommended dose. No clear association was found between the exposure to teclistamab and the safety findings, based on the exposure-safety analysis. Overall, the clinical pharmacology evaluation supports the recommended dose for teclistamab.

No drug interaction studies have been performed with Tecvayli. The initial release of cytokines associated with the start of Tecvayli treatment could suppress cytochrome P450 (CYP) enzymes, which could in turn increase the exposure to and the toxicity of concomitantly administered CYP substrates with a narrow therapeutic index. This finding is described in the Product Monograph for Tecvayli.

The clinical pharmacology data support the use of Tecvayli for the recommended indication. For further details, please refer to the Tecvayli Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Tecvayli in treating adult patients with relapsed or refractory multiple myeloma (MM) was evaluated in the pivotal Phase I/II MajesTEC-1 study (described earlier in the Clinical Basis for Decision section). The primary efficacy cohort consisted of 110 adult patients with relapsed or refractory MM. The median age of these patients was 66.0 years (range: 33-82 years), with 16% of patients 75 years of age or older. Fifty-six percent of patients were male and 44% were female. Ninety-one percent were White, 5% were Black, and 3% were Asian.

The median time since initial diagnosis of MM to enrollment was 6.4 years (range: 1.1 to 22.7 years). Patients had received a median of five prior lines of therapy (range: 2-14) with all patients having received at least three prior lines of therapy. Eighty-one percent of patients had received prior stem cell transplantation. All patients had received prior therapy with a proteasome inhibitor, an immunomodulatory agent, and an anti-cluster of differentiation 38 (CD38) monoclonal antibody, and 76% were triple-class refractory (refractory to each of these therapies). Ninety-two percent of patients were refractory to the last prior line of myeloma therapy.

Efficacy results were based on overall response rate (ORR) as determined by the Independent Review Committee assessment using International Myeloma Working Group 2016 criteria. The ORR was 61.8% (95% Confidence Interval [CI]: 52.1%, 70.9%) with 28.2% of patients achieving a complete response or better. With a median follow-up of 8.8 months, the median duration of response (DOR) was not estimable (NE; 95% CI: 9 months, NE). After a median follow-up of 14.1 months at a follow-up analysis (which included 15 additional patients who enrolled since the primary analysis), the ORR was 62.4% (95% CI: 53.3%, 70.9%), and the median DOR was 14.9 months (95% CI: 14.9 months, NE).

These efficacy results are considered promising evidence of clinical benefit for Tecvayli. The survival benefit of Tecvayli has not been established and is to be confirmed in the ongoing Phase III MajesTEC-3 study. As part of the marketing authorization, the sponsor has agreed to provide the final clinical study report from this study as well as a clinical study report of an updated analysis of the Phase I/II MajesTEC-1 study. The additional data from these reports will further characterize the clinical benefit of Tecvayli.

Indication

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

Tecvayli (teclistamab injection) is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

Health Canada approved the following indication:

Tecvayli (teclistamab injection) is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.

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

Clinical Safety

The safety of Tecvayli was evaluated in 165 adult patients with relapsed or refractory MM in the pivotal MajesTEC-1 study (described earlier in the Clinical Basis for Decision section). All 165 patients received Tecvayli administered subcutaneously at the recommended dose. Adverse reactions that were reported in 20% or more of patients included: hypogammaglobulinemia, cytokine release syndrome, neutropenia, musculoskeletal pain, fatigue, thrombocytopenia, injection site reaction, upper respiratory tract infection, lymphopenia, diarrhea, pneumonia, nausea, pyrexia, headache, cough, constipation, and pain. Serious adverse reactions reported in 2% or more of patients included: pneumonia, coronavirus disease 2019 (COVID-19), cytokine release syndrome, sepsis, pyrexia, musculoskeletal pain, acute kidney injury, diarrhea, cellulitis, hypoxia, febrile neutropenia, and encephalopathy. Fatal adverse events regardless of causality were reported in 18 patients (10.9%), including fatal infections in 15 patients (9.1%; of whom, 12 patients [7.3%] had fatal COVID-19 infections).

Dose interruptions of Tecvayli due to adverse reactions were reported in 65% of patients. The most frequent adverse reactions (occurring in 5% or more of patients) leading to dose interruptions were neutropenia, COVID-19, pneumonia, cytokine release syndrome, and pyrexia. Permanent discontinuation of Tecvayli due to adverse reactions occurred in two patients (1.2%), both due to infections.

Cytokine release syndrome and neurologic toxicity (including immune effector cell-associated neurotoxicity syndrome [ICANS]) were serious, potentially life-threatening adverse reactions of Tecvayli. In the MajesTEC-1 study, most of these events were Grade 1 or 2, and were manageable through risk mitigation measures including screening for risk factors, pre-medications, step-up dosing, close monitoring (including hospitalization), prompt initiation of treatment based on severity, and Tecvayli dose delay. These safety findings and the applicable risk mitigation measures are described in a Serious Warnings and Precautions box in the Product Monograph for Tecvayli.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). In the MajesTEC-1 study, 238 patients treated with subcutaneous Tecvayli monotherapy were evaluated for antibodies to teclistamab using an electrochemiluminescence-based immunoassay. One patient (0.4%) developed neutralizing antibodies to teclistamab of low titre. The impact of ADAs on the pharmacokinetics, pharmacodynamics, safety, and efficacy of Tecvayli could not be characterized, however, it is unlikely to be significant, given the generally low incidence of the ADAs.

Overall, in the context of the proposed use and taking into consideration the promising efficacy results, the safety profile of Tecvayli is considered acceptable given the serious and life-threatening nature of relapsed or refractory MM. The risks associated with Tecvayli and the appropriate risk management strategies have been adequately addressed and communicated in the Tecvayli Product Monograph. As part of the marketing authorization, the sponsor has agreed to provide the final clinical study reports of the Phase III MajesTEC-3 study and the updated analysis of Phase I/II MajesTEC-1 study. These data will help to further characterize the safety profile of Tecvayli.

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

7.2 Non-Clinical Basis for Decision

As outlined in the What steps led to the approval of Tecvayli? section, the review of the non-clinical component of the New Drug Submission for Tecvayli was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. The review of the non-clinical component of the New Drug Submission for Tecvayli was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The non-clinical studies included both in vitro and in vivo data demonstrating that teclistamab binds to B‑cell maturation antigen (BCMA) receptors as well as T cells. The studies showed that upon T-cell binding, T cells were activated, released cytokines, and induced killing of BCMA-expressing cells. This mechanism of action was demonstrated in a humanized animal model of multiple myeloma.

Single- and repeat-dose toxicity studies were also performed in a non-human primate model using doses up to six-fold greater than the proposed treatment dose of 1.5 mg/kg. Overall, there were no significant teclistamab-related toxicological findings in the cynomolgus monkeys within the dose range from 0.1 to 10 mg/kg. Although the toxicological profile of teclistamab appeared to be minimal in non-human primates, these results should be interpreted with caution as animal models cannot fully predict teclistamab-related adverse reactions that may occur in humans.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Tecvayli Product Monograph. In view of the intended use of Tecvayli, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

7.3 Quality Basis for Decision

As outlined in the What steps led to the approval of Tecvayli? section, the review of the quality component of the New Drug Submission for Tecvayli was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. The review of the quality component of the New Drug Submission for Tecvayli was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that teclistamab consistently exhibits the desired characteristic structure and biological activity.

The drug substance and drug product manufacturing process have been optimized and scaled up during development. The changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

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

Teclistamab is produced through the controlled Fab-arm exchange (FAE) of two parental monoclonal antibodies: an anti-B-cell maturation antigen (BCMA) antibody, and an anti-cluster of differentiation 3 (CD3) receptor antibody. During the FAE reaction, the heavy chain and linked light chain pair (half antibody) of one parental antibody is exchanged with a heavy chain and linked light chain pair of the other parental antibody, resulting in the heterodimerization of the parental half antibodies and the formation of a teclistamab molecule consisting of an anti-BCMA Fab arm and an anti-CD3 receptor Fab arm.

Drug Substance

The teclistamab drug substance is manufactured using recombinant deoxyribonucleic acid (DNA) technology. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process for the drug substance involves multiple stages. In the first stage, the two parental antibodies are manufactured using a Chinese hamster ovary (CHO) cell line in separate but parallel processes. For each parental antibody, the process begins with the thawing of a single working cell bank vial which then goes through a series of cell growth, harvesting, and purification steps, resulting in a concentrated pool of drug substance intermediates for each antibody. The drug substance intermediates are filtered, bottled, and frozen until further processing to form the bispecific antibody.

Separate process characterization and process validation studies are performed for each drug substance intermediate and for the final drug substance.

The manufacturing process for the teclistamab drug substance starts with the thawing and pooling of each parental antibody separately. The individual parental antibody pools are then combined prior to reduction, diafiltration, and oxidation reactions to obtain the heterodimer antibody. The heterodimer antibody undergoes a series of viral inactivation, chromatography, viral filtration, and purification steps. It is then filled into containers. The final drug substance contains a target of 90 mg/mL teclistamab and is frozen.

Drug Product

The manufacturing process for the drug product starts with thawing the drug substance batches, pooling the drug substance batches, and mixing (i.e., the compounding stage). The drug product solution is then sterile-filtered and aseptically filled into vials. For the 10 mg/mL drug product, the 90 mg/mL drug substance pool is diluted with formulation buffer to 10 mg/mL during the compounding stage. The drug product is then stored at 5 °C ± 3 °C.

Tecvayli is supplied as a sterile solution in 30 mg/3.0 mL (10 mg/mL; for step-up dose) and 153 mg/1.7 mL (90 mg/mL; for treatment dose) single-use vials with blue- or orange-coloured caps, respectively.

The materials used in the manufacture of the drug substance and drug product are considered suitable and/or meet standards appropriate for their intended use. The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits. The proposed drug product manufacturing process is able to consistently manufacture Tecvayli drug product of acceptable quality. Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of teclistamab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

An integrated control strategy has been developed for Tecvayli based on critical quality attributes, risk assessments, process characterization studies, and overall experience gained throughout development. The control strategy includes control of raw materials and components/consumables as well as facility and equipment controls. Furthermore, suitable process parameter limits, in-process testing limits, as well as release and stability specifications have been established to ensure consistent manufacture and quality of parental antibody intermediates, drug substance, and drug product.

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with ICH guidelines. The drug substance and drug product specifications were set using compendial guidelines, product and process knowledge, prior experience with other antibody products, and statistical analyses of release and stability data.

A risk assessment was conducted for the presence of nitrosamine impurities. No risks were identified for the presence of N-nitrosamine impurities in Tecvayli. Accordingly, no confirmatory testing or mitigation plans are required.

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

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. The proposed 18-month shelf life is acceptable for both the 10 mg/mL and 90 mg/mL Tecvayli drug products when stored between 5 °C ± 3 °C, protected from light.

The compatibility of the drug product with the container closure system was demonstrated through long-term stability studies and extractables/leachables studies. The container closure system met all validation test acceptance criteria.

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.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.

All sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The teclistamab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Materials of biological origin are properly sourced and tested. The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens. The excipients used in the drug product formulation are not of animal or human origin.

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