Summary Basis of Decision for Abecma

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 Abecma is located below.

Recent Activity for Abecma

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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.

The following table describes post-authorization activity for Abecma, a product which contains the medicinal ingredient idecabtagene vicleucel. 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 Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2024-01-05

Drug Identification Number (DIN):

DIN 02516233 – idecabtagene vicleucel, 275 to 520 × 106 chimeric antigen receptor (CAR)-positive T cells, suspension, intravenous administration

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

DIN 02516233 cancelled (pre market)

Not applicable

Discontinuation date: 2023-11-14

The manufacturer notified Health Canada that sale of the drug has been discontinued pre market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.

NC # 277034

2023-07-05

Issued NOL 2023-10-05

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process, such as a change in process flow or procedures. The submission was reviewed and considered acceptable, and an NOL was issued.

PBRER-C # 275972

2023-06-02

Filed 2023-08-18

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C for the period 2022-09-26 to 2023-03-25. The information was reviewed and found acceptable.

PBRER-C # 270307

2022-12-01

Filed 2023-08-18

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C for the period 2022-03-26 to 2022-09-25. The information was reviewed and found acceptable.

NC # 275214

2023-05-11

Issued NOL 2023-07-31

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug substance release or shelf‐life specifications involving replacement of an analytical procedure and relaxation of an acceptance criterion. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 274034

2023-04-04

Issued NOL 2023-07-20

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in a cell bank/seed bank qualification protocol, a change in the controls (in‐process tests and/or acceptance criteria) applied during the drug substance manufacturing process or on intermediates, and the qualification of a new lot of reference standard against the approved reference standard. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 269443

2022-11-04

Issued NOL 2023-01-23

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product release or shelf‐life specifications, involving replacement of an analytical procedure. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 267921

2022-09-16

Issued NOL 2022-12-07

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process and a change in the controls (in‐process tests and/or acceptance criteria) applied during the drug substance manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.

PBRER-C # 264839

2022-06-03

Filed 2022-10-13

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C for the period 2021-09-26 to 2022-03-25. The information was reviewed and found acceptable.

NC # 261504

2022-02-14

Issued NOL 2022-06-01

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug substance manufacturing process involving a change in the auxiliary materials/reagents of biological origin. The submission was reviewed and considered acceptable, and an NOL was issued.

PSUR-C # 259018

2021-11-24

Filed 2022-02-16

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C for the period 2021-03-26 to 2021-09-25. The information was reviewed and found acceptable.

NC # 258314

2021-11-03

Issued NOL 2022-02-01

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process, such as a change in process flow or procedures. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 257886

2021-10-22

Issued NOL 2022-01-17

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug substance release or shelf‐life specifications involving minor changes to an approved analytical procedure. The submission was reviewed and considered acceptable, and an NOL was issued.

NDS # 244266

2020-09-22

Issued NOC under NOC/c Guidance 2021-05-26

NOC issued under the NOC/c Guidance for New Drug Submission.
Summary Basis of Decision (SBD) for Abecma

Date SBD issued: 2021-11-22

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

Idecabtagene vicleucel

Drug Identification Number (DIN):

  • DIN 02516233 - 275 to 520 × 106 chimeric antigen receptor (CAR)-positive T cells, suspension, intravenous administration

Celgene Inc.

New Drug Submission Control Number: 244266

 

On May 26, 2021, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Celgene Inc. for the drug product Abecma. 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 Abecma is favourable for the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and who are refractory to their last treatment.

Authorization was based on overall response rate, complete response rate, and durability of response from a single-arm clinical study. An improvement in progression-free survival or overall survival has not yet been established.

 

1 What was approved?

 

Abecma, an antineoplastic agent, was authorized for the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and who are refractory to their last treatment.

Authorization was based on overall response rate, complete response rate, and durability of response from a single-arm clinical study. An improvement in progression-free survival or overall survival has not yet been established.

Abecma is not authorized for use in pediatric patients (<18 years of age), as no data are available to Health Canada for this population.

In the single-arm Phase II study for Abecma (KarMMa), 45 of the 128 patients (35%) treated with Abecma were 65 years of age or older. No clinically important differences were observed in the safety or effectiveness of Abecma between these patients and patients younger than 65 years of age.

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

Abecma 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.

Abecma (275 to 520 × 106 CAR-positive T cells, target dose of 450 × 106 CAR-positive T cells) is presented as a cell suspension in one or more patient-specific single infusion bags. In addition to the medicinal ingredient, the suspension contains CryoStor CS10, magnesium chloride, potassium chloride, sodium acetate trihydrate, sodium chloride, sodium gluconate, and water for injection.

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

 

2 Why was Abecma approved?

 

Health Canada considers that the benefit-risk profile of Abecma is favourable for the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and who are refractory to their last treatment.

Authorization was based on overall response rate, complete response rate, and durability of response from a single-arm clinical study. An improvement in progression-free survival or overall survival has not yet been established.

Abecma 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.

Multiple myeloma is a largely incurable blood cancer characterized by the proliferation of malignant plasma cells, both within the bone marrow and at localized extramedullary sites (plasmacytomas). It accounts for 1% of all cancers, and 10% of hematologic malignancies. Although it is considered a single disease, multiple myeloma is a collection of several different cytogenetically distinct plasma cell malignancies that becomes progressively more difficult to treat over time. Patients who failed (refractory) or whose disease has come back after an initial response to treatment (relapse) comprise a relapsed and refractory multiple myeloma (RRMM) population for whom limited effective treatment options are available.

Abecma, a chimeric antigen receptor (CAR) T-cell therapy, was developed to recognize the B cell maturation antigen (BCMA). Abecma (idecabtagene vicleucel) is a genetically modified autologous immunotherapy consisting of human T cells transduced with lentiviral vector (LVV) encoding a CAR that recognises B-cell maturation antigen (BCMA). The BCMA is highly expressed on plasma and multiple myeloma cells and plays a key role in proliferation and survival.

The clinical efficacy and safety of Abecma were evaluated primarily in the pivotal Phase II study, KarMMa, which enrolled 140 patients with RRMM. Screening and leukapheresis were carried out during the pre-treatment phase, along with bridging therapy if needed. During the treatment phase, patients underwent lymphodepleting chemotherapy (LDC) for 5 days, followed by the infusion of Abecma. Abecma was infused in 128 patients, with 124 patients receiving a dose between 275 × 106 and 520 × 106 CAR-positive T cells, with a target dose of 450 × 106 CAR-positive T cells. Patients were hospitalized for 14 days after infusion to monitor and manage adverse events. The post-treatment phase was ongoing at the time of review.

The primary efficacy endpoint on study was the overall response rate (ORR), which was determined by an Independent Response Committee (IRC) according to guidelines established by the International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. The key secondary endpoint was the combined stringent complete response (sCR) and complete response (CR) rates. The very good partial response rate and the duration of response were considered important secondary endpoints.

Bridging therapy was administered to the majority of patients (88%) while individualized CAR-positive T cells were being prepared. Patients were restaged after bridging therapy. Six of the 128 patients who received treatment with Abecma no longer had measurable disease after bridging therapy and were therefore excluded from the final efficacy analyses. Of the 122 remaining patients who had measurable disease, 74% had a partial response or better, and 32% had a sCR or CR. The overall median duration of response was 11 months, which increased to 19 months for patients who achieved a sCR or CR. For patients who responded to therapy (partial response or better), the median time to response was 1 month from the Abecma infusion (range: 0.5 to 2.9 months).

Safety data were obtained primarily from the 128 patients who received treatment with Abecma during this study. The median duration of follow-up was 13.3 months.

The most common adverse reactions (reported in ≥20% of patients) included cytokine release syndrome (CRS), infections (pathogen unspecified), musculoskeletal pain, diarrhea, fatigue, nausea, viral infections, upper respiratory tract infection, encephalopathy, pyrexia, cough, decreased appetite, headache, edema, and hypogammaglobulinemia (increased risk of infection). Serious adverse reactions occurred in 67% of patients, and included CRS (17%), general physical health deterioration (13%), pneumonia (9%), and febrile neutropenia (7%). The most common Grade 3 or 4 adverse reactions (reported in ≥10% of patients) were febrile neutropenia (16%) and infections (pathogen unspecified; 15%).

The safety profile of Abecma is similar to those of other authorized CAR T-cell therapies, and includes the risks of CRS, neurologic toxicities, and hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS). As a result, patients were monitored carefully during the study. Fatal or life-threatening CRS events, severe or life-threatening neurologic toxicities, and cases of HLH/MAS were observed during the study. Several treatments were readily available to manage these adverse events as needed. These risks have been highlighted in a Serious Warnings and Precautions box in the Abecma Product Monograph.

A Risk Management Plan (RMP) for Abecma was submitted by Celgene 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 Abecma Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Abecma was accepted.

Overall, Abecma has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Abecma Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Abecma will be ongoing. Further evaluation will take place upon the submission of 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 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 Abecma?

 

The new drug submission (NDS) for Abecma was accepted for review under the Priority Review Policy. The pivotal study (KarMMa) was conducted in patients with relapsed and refractory multiple myeloma (RRMM), a population for whom treatment options are limited. Based on the full review of the submission, Health Canada determined that the Notice of Compliance with Conditions (NOC/c) pathway was more appropriate for this NDS rather than the Priority Review pathway, as the pivotal study results were found to be promising rather than substantial. The sponsor is expected to submit results from the ongoing Phase III study, KarMMa-3, to confirm the clinical benefit of Abecma in patients with RRMM.

 

Submission Milestones: Abecma

Submission Milestone Date
Pre-submission meeting 2020-04-02
Request for priority status filed 2020-06-26
Request for priority status approved by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics 2020-07-21
New drug submission filed 2020-09-22
Screening  
Screening Acceptance Letter issued 2020-10-19
Review  
Quality Evaluation complete 2021-04-16
Non-Clinical Evaluation complete 2021-04-09
Clinical/Medical Evaluation complete 2020-04-15
Review of Risk Management Plan complete 2021-04-06
Labelling Review complete 2021-04-14
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued 2021-04-16
Review of Response to NOC/c-QN:  
Response filed (Letter of Undertaking) 2021-04-30
Clinical/Medical Evaluation complete 2021-05-17
Labelling Review complete 2021-05-17
Notice of Compliance (NOC) issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance 2021-05-26

 

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

 

4 What follow-up measures will the company take?

 

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

In addition to 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 following reports:

Confirmatory studies

The sponsor is expected to submit the report for the final analysis of the KarMMa-3 study, a randomized, open-label, Phase III study comparing the safety and efficacy of Abecma to the safety and efficacy of standard treatment regimens in patients with relapsed and refractory multiple myeloma (RRMM). Continued authorization might be contingent on Abecma demonstrating a favourable benefit-risk profile compared to standard regimens in the treatment of patients with RRMM in the confirmatory trial.

Additional studies

The sponsor has committed to submitting an interim report for the KarMMa-2 study, a multi-cohort, open-label, Phase II study. This study is designed to assess the preliminary efficacy and safety of Abecma in patients with RRMM and patients with high-risk multiple myeloma having progressed within one year of initial treatment.

Additionally, the sponsor has committed to submitting status reports detailing the progress of ongoing confirmatory trials, in line with the NOC/c Guidance. Status reports are to be submitted annually, within 60 calendar days of the anniversary of market authorization or a date agreed upon at the time of issuance of market authorization.

Post-market safety monitoring

Periodic Safety Update Reports (PSURs) or Periodic Benefit-Risk Evaluation Reports (PBRERs) for NOC/c products are to be submitted every six months for the initial two years of market authorization, and on an annual basis thereafter.

Additionally, the sponsor has committed to conducting a post-marketing, prospective, observational study to evaluate the long-term safety of Abecma and the risks of secondary malignancies in patients with RRMM. A minimum of 1,000 patients are to be enrolled in this study, and will be required to be followed for 15 years after receiving a single dose of Abecma infusion.

The sponsor is expected to comply with the requirements for reporting on specific issues of concern, reporting adverse drug reactions occurring in Canada and internationally, and risk management measures as described in the NOC/c Guidance.

 

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

 

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.

The PAAT for Abecma is found above.

At this time, no PAAT is available for Abecma. 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

Abecma (idecabtagene vicleucel) is a chimeric antigen receptor (CAR)-positive T-cell therapy targeting the B cell maturation antigen (BCMA). The BCMA is expressed on the surface of normal and malignant plasma cells where it plays important roles in proliferation and survival. The CAR construct includes an anti-BCMA single-chain variable fragment (scFv)-targeting domain for antigen specificity, a transmembrane domain, a CD3-zeta T cell activation domain, and a 4-1BB costimulatory domain. Antigen-specific activation of Abecma results in CAR-positive T-cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

A population pharmacokinetics (popPK) analysis was conducted based on data from the Phase II pivotal study, KarMMa (described in Clinical Efficacy). The model-predicted data were generally consistent with the observed data. Statistically significant exposure-response relationships were observed for the overall response rate (ORR), very good response rate, and complete response rate (CR). A significant exposure-response relationship was also identified for cytokine release syndrome (CRS) that required treatment with tocilizumab or corticosteroids, but not for neurologic toxicities or cytopenias.

The cellular expansion kinetics of idecabtagene vicleucel are characterized by an increase in cell expansion parameters (the maximum plasma concentration [Cmax], exposure as measured by the area under the plasma concentration-time curve [AUC] from 0-28 days [AUC0-28days], and the exposure as measured by the AUC from 0-3 months [AUC0-3M]) across the target dose levels. A high degree of variability was observed between subjects.

The results of the popPK model do not provide strong support for considering body weight in decisions regarding dose individualization for idecabtagene vicleucel. Age, race, ethnicity, sex, and anti-drug antibody (ADA) status were not found to influence CAR-positive T-cell expansion. Additionally, no association was observed between the number of prior anti-multiple myeloma therapies and the cell expansion parameters. The benefit-risk balance was considered favourable across the exposure range associated with doses of 300 × 106 CAR-positive T cells and 450 × 106 CAR-positive T cells, based on the exposure-response relationships for efficacy and safety.

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

Clinical Efficacy

Evidence of the clinical efficacy of Abecma was provided primarily by the results of the pivotal Phase II study, KarMMa (BB2121-MM-001). The results of a global non-interventional retrospective study and a Phase I dose escalation study were also submitted for review to support the data from the pivotal study.

Pivotal Study

The pivotal study, KarMMa, was conducted in patients with relapsed and refractory multiple myeloma (RRMM). The patients enrolled in the study had a median age of 61 years, which is young for a population of RRMM patients. Additionally, 94% of patients had undergone a prior autologous stem cell transplantation (ASCT). Due to neurologic toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, patients with neurological conditions or a history of central nervous system (CNS) pathology were not included in the study. Due to the low median age and the prior ASCT treatments received by the majority of patients, this study patient population may not represent the greater population of patients with RRMM in Canada who could be treated with this therapy.

The study began with a pre-treatment phase, consisting of screening and leukapheresis, as well as bridging therapy if needed. The treatment phase involved lymphodepleting chemotherapy (LDC) and Abecma infusion. The LDC period began five days before the infusion date of Abecma, and consisted of daily intravenous infusions of cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) for three days. Following infusion of Abecma, patients were hospitalized for 14 days to monitor and manage adverse events due to the potential for cytokine release syndrome (CRS) and neurotoxicity. The post-treatment phase was ongoing at the time of review and continued for either a minimum of 24 months after Abecma infusion or until documented disease progression, whichever was longer.

Out of 140 patients who underwent leukapheresis, 128 patients received Abecma. Four patients received a low dose of 150 × 106 CAR-positive T cells and were excluded from the efficacy analyses. The remaining 124 patients received a dose between 275 × 106 to 520 × 106 CAR-positive T cells, with a target dose of 450 × 106 CAR-positive T cells. Efficacy was assessed by an Independent Response Committee Review according to the International Myeloma Working Group criteria.

The primary efficacy endpoint was the overall response rate (ORR). The key secondary endpoint was the combined stringent complete response (sCR) and complete response (CR) rates. The very good partial response (VGPR) rate and the duration of response were considered important secondary endpoints.

Bridging therapy was administered to the majority of patients (88%) while individualized CAR-positive T cells were being prepared. Patients were restaged after bridging therapy. Six of the 128 patients had non-measurable disease after bridging therapy and were therefore excluded from the final analysis. Of the 122 remaining patients who had measurable disease, 74% had a partial response or better, and 32% had a sCR or CR. The median overall duration of response was 11 months, which increased to 19 months for patients who achieved a sCR or CR. For patients who responded to therapy (partial response or better), the median time to response was 1 month from the Abecma infusion (range: 0.5 to 2.9 months).

Supportive Studies

The Phase I dose escalation study, CRB-401, was a two-part, non-randomized, open-label, single-arm study conducted in patients with RRMM. Based on observations during Part A, in which multiple dose levels were evaluated, the 150 × 106 and 450 × 106 doses were recommended to be used in Part B. The two doses were further evaluated in Part B, and patients who received the higher dose of 450 × 106 CAR T cells had higher ORRs (89.5%) than those who received 150 × 106 CAR T cells (50%).

Indication

Sponsor’s proposed indication

Health Canada-approved indication

Abecma (idecabtagene vicleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for:

• the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

Abecma (idecabtagene vicleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for:

• the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and who are refractory to their last treatment.

The indication was revised to more accurately reflect the patient population in the pivotal study. Authorization was based on ORR, complete response rate, and durability of response from a supportive single-arm clinical study. An improvement in progression-free survival or overall survival has not yet been established.

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

Clinical Safety

Safety data were obtained primarily through the pivotal Phase II study, KarMMa, which is described in the Clinical Efficacy section. Out of the 128 patients who received treatment with Abecma during this study, 124 patients received the recommended dose (275 × 106 to 520 × 106 CAR-positive T cells), and four patients received a lower dose (150 × 106 CAR-positive T cells). The median duration of follow-up was 13.3 months.

The most common adverse reactions (reported in ≥20% of patients) included cytokine release syndrome (CRS), infections (pathogen unspecified), musculoskeletal pain, diarrhea, fatigue, nausea, viral infections, upper respiratory tract infection, encephalopathy, pyrexia, cough, decreased appetite, headache, edema, and hypogammaglobulinemia (increased risk of infection).

Serious adverse reactions occurred in 67% of patients, and included CRS (17%), general physical health deterioration (13%), pneumonia (9%), and febrile neutropenia (7%). The most common Grade 3 or 4 adverse reactions (reported in ≥10% of patients) were febrile neutropenia (16%) and infections (pathogen unspecified; 15%).

The safety profile of Abecma is similar to those of other authorized CAR T-cell therapies, and includes the risks of CRS, neurologic toxicities, and hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS). These risks have been highlighted in a Serious Warnings and Precautions box in the Abecma Product Monograph.

In the KarMMa study, treatment with Abecma was delayed for patients with active uncontrolled infections, active inflammatory disorders, or unresolved serious adverse reactions from prior therapies. Fatal or life-threatening CRS events occurred during the study. Patients were monitored carefully for cases of CRS, and several treatments for CRS (tocilizumab, anti-interleukin-6 receptor monoclonal antibodies, and corticosteroids) were readily available for use as needed.

Neurologic toxicities, which may be severe or life-threatening, occurred during the study, either concurrently with CRS, after the resolution of CRS, or in the absence of CRS. Clinical manifestations of neurologic toxicity include headache, confusion, delirium, language disturbance, seizures, and acute cerebral edema. Tocilizumab or corticosteroids were used as supportive care for these neurological toxicities.

Cases of HLH/MAS were also observed. Clinical features included persistent high-grade fevers, hepatosplenomegaly, lymphadenopathy, hemorrhagic manifestations, and sepsis-like conditions.

Other important toxicities identified during the study included hypogammaglobulinemia, hypersensitivity reactions, serious infections (including fatalities), viral reactivation, and prolonged cytopenias. Immunogenicity was also reported, but there were no observed effects of anti-drug antibodies on the efficacy of Abecma.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

In the non-clinical studies, idecabtagene vicleucel (the medicinal ingredient in Abecma) demonstrated sensitive, specific, and potent activity against B-cell maturation antigen (BCMA)-positive multiple myeloma tumour cells. The data supported the hypothesis that primary human multiple myeloma should be recognized and killed by idecabtagene vicleucel, as this chimeric antigen receptor (CAR)-positive T-cell therapy secretes cytokines, proliferates, and induces cytotoxic activities. In non-obese diabetic and severe combined immune deficiency gamma (NSG) mice bearing human multiple myeloma, a single dose of idecabtagene vicleucel at or above the minimum effective dose eliminated multiple myeloma tumours with relatively high BCMA expression, typically within 20 days following administration. The minimal effective dose in mice represents a human effective dose of 2.05 × 108 CAR-positive T cells for a 100 kg human.

Repeat-dose studies were not conducted, as idecabtagene vicleucel is intended to be administered as a single-dose intravenous infusion. The expression of BCMA proteins was essentially limited to the cell surface of plasma cells in normal tissues, neoplastic plasma cells in multiple myeloma, and lymphocytes in lymphoma. There was no observed evidence of secondary pharmacodynamic effects associated with nonspecific, cross-reactive, or “off-target/off-tumor” binding of the anti-BCMA CARs. Specific “on-target/on-tumor” toxicity, manifested as cytokine release syndrome (CRS) and/or tumour lysis syndrome (TLS), was not observed in the mice. The absence of CRS/TLS in immunodeficient mice, however, does not inform about the potential of such a response in humans. Specific “on-target/off-tumor” cytolysis of normal (healthy) BCMA-positive plasma cells is expected to occur in humans, but nonspecific, cross-reactive or “off-target/off-tumor” toxicity is unlikely to occur. The results indicated no unique tumorigenic risks related to the idecabtagene vicleucel manufacturing process. No safety issues were identified, including clonal dominance or immortalization, which would prohibit the use of idecabtagene vicleucel in humans.

Due to the nature of this product, traditional toxicity, fertility, and pharmacokinetic studies with Abecma were not conducted.

In vitro expansion studies with CAR-positive T cells from healthy donors and patients showed no evidence for transformation and/or immortalisation of T cells. A genomic insertion site analysis of the lentiviral vector was performed on Abecma samples, including patient lots, and there was no evidence for preferential integration near genes of concern or preferential outgrowth of cells harboring integration sites of concern.

Overall, the non-clinical studies support a favourable efficacy and safety profile of idecabtagene vicleucel for the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Abecma Product Monograph. Considering the intended use of Abecma, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Abecma Product Monograph to address the identified safety concerns.

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

 

 

7.3 Quality Basis for Decision

 

Abecma is a suspension of autologous (patient-derived) T cells, enriched from leukapheresis material and genetically engineered ex vivo to express a CAR directed against the BCMA. The BCMA is expressed on the surface of mature B cells, and its overexpression is associated with multiple myeloma. A viral vector is used to introduce the genetic information encoding the anti-BCMA CAR into the patient's T cells, which is then expressed on the cell surface. The manufacturing process is continuous, without a distinction between the drug substance and drug product. The leukapheresis material collected from the patients (for autologous use) and the vector encoding the anti-BCMA CAR are the two critical starting materials involved in the manufacturing process. The autologous T cells expressing the anti-BCMA CAR correspond to the drug substance, idecabtagene vicleucel. The final drug product, consisting of idecabtagene vicleucel and the excipients, is marketed under the brand name Abecma. Following the infusion of Abecma into the patient, the anti-BCMA CAR on the T cells engages with BCMA on the surface of B cells. This activates the T cells and initiates a signalling cascade that ultimately results in the elimination of BCMA-expressing cells.

Characterization of the Drug Substance

Multiple lots of idecabtagene vicleucel were characterized regarding the transgene integration into host genome, transgene sequence integrity, CAR expression, CAR structure and functionality, phenotype and activation status, cytokine production, and cytotoxic activity. Abecma comprises primarily CD4+ and CD8+ T cell populations. Only transduced cells are capable of increased proliferation, cytokine secretion, and cytolytic activity in the presence of BCMA, and demonstrate cell trafficking and migration capability relevant to the proposed mechanism of action.

The lentiviral vector (LVV) is a critical starting material used to manufacture idecabtagene vicleucel. Multiple lots of LVV were characterized regarding the virus particle size, protein profile, and the ability to transduce target cells. The LVV is used to introduce the anti-BCMA CAR expression cassette into the patient’s T cells (from the leukapheresis material).

The process-derived and product-related impurities of idecabtagene vicleucel and the LVV were characterized and are controlled through appropriate sourcing and testing of materials, validated clearance by the manufacturing process and in-process testing, and release testing of the finished product.

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

The LVV manufacturing process steps include host cell expansion, transient transfection, harvesting, purification, sterilizing filtration, and aseptic filling. The manufacturing process and required materials have been validated, and in-process controls have been appropriately established.

Leukapheresis material is obtained from the patient at a qualified clinical site and transported to the manufacturing site. The peripheral blood mononuclear cells (PBMCs) are isolated from the leukapheresis material through washing, buffer exchange, and red blood cell lysis. The T cells then undergo transduction with the LVV, which encodes the anti-BCMA CAR, and expansion, producing idecabtagene vicleucel. The expanded cells undergo harvesting, formulation, aseptic filling, cryopreservation under controlled conditions, and storage in the vapour phase of liquid nitrogen (≤-130 °C).

The frozen idecabtagene vicleucel product is packed in a validated shipping container and returned under validated conditions to the clinical site to be infused back into the patient. Appropriate chain-of-custody and chain-of-identity procedures are maintained from the collection of leukapheresis material at a qualified apheresis site to the administration of Abecma at a clinical site.

The proposed processing times and in-process hold conditions were supported by data which demonstrated the biochemical and microbiological integrity of process intermediates. Results from multiple Process Performance Qualification (PPQ) campaigns demonstrated consistency of the manufacturing process under nominal operating conditions.

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 idecabtagene vicleucel with the excipients and primary packaging is supported by the provided stability data.

Control of the Drug Substance and Drug Product

Batch release and stability specifications were established to define the acceptable quality of idecabtagene vicleucel drug product and LVV. The specifications include product characteristics selected based on process and product understanding gained from product development and manufacturing experience. The associated analytical methods were validated according to International Conference on Harmonisation (ICH) guidelines, and acceptance criteria were appropriately justified.

Batch analysis data were provided for batches of idecabtagene vicleucel drug product. The data demonstrate that the respective manufacturing processes consistently generate product whose quality meets the applicable specifications.

Abecma 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 Abecma, as the product is autologous and therefore highly individualized to each patient.

Abecma has been assigned to Lot Release Evaluation Group 4. 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

Abecma may be stored for up to 12 months in the vapour phase of liquid nitrogen (≤-130 °C). The proposed shelf life and storage conditions for Abecma were adequately supported by the provided stability data and are considered satisfactory.

Each bag of Abecma must be completely infused within one hour from start of thaw. The proposed in-use period was supported by available stability data for material subjected to simulated administration conditions.

Facilities and Equipment

Conducting an in-person on-site evaluation (OSE) of the Abecma manufacturing site was not feasible due to limitations resulting from the coronavirus disease 2019 (COVID-19) pandemic.

Instead of an OSE, a Virtual Evaluation of Process and Facility (VEPF) was conducted according to conditions mutually agreed upon by Health Canada and the sponsor.

Boardroom sessions, facility tours, and witnessing of unit operations were all conducted virtually. Overall, the VEPF greatly enhanced the information provided in the submission. Some observations were made during the VEPF, which were resolved during the review period. The manufacturing site was issued a compliant rating.

Adventitious Agents Safety Evaluation

Viral safety of Abecma and LVV is ensured by selecting materials that are free from potential pathogens. Furthermore, LVV is subject to release testing for adventitious viruses using crude harvest samples from untransfected control cultures. Host cell banks are qualified for use in LVV manufacture based on extensive testing that includes a panel of viruses. Plasmids used to manufacture LVV originate from bacterial cell banks qualified based on extensive testing that includes lytic phage. Ancillary materials of biological origin used in the manufacture of Abecma, LVV, host cell banks, and plasmids are released for use based on relevant documented viral safety assessments and testing by audited suppliers

None of the excipients used to formulate Abecma are of animal or human origin. The biologic raw materials used during the manufacture of Abecma, LVV, host cell banks, and plasmids originate from sources with no or minimal risk of bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE), based on considerations that include animal species, tissue, and country of origin. The relevant supporting documents have been provided to support the traceability and biological safety of all materials.

 

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