Summary Basis of Decision for Columvi

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 Columvi is located below.

Recent Activity for Columvi

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 Columvi. When the PAAT for Columvi becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Columvi

Date SBD issued: 2023-05-31

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

Glofitamab

Drug Identification Number (DIN):

  • DIN 02536552 – 1 mg/mL (2.5 mg/2.5 mL), solution, intravenous administration

  • DIN 02536560 – 1 mg/mL (10 mg/10 mL), solution, intravenous administration

Hoffmann-La Roche Limited

New Drug Submission Control Number: 265517

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: 2022-06-23

Authorization Date: 2023-03-24

On March 24, 2023, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Hoffmann-La Roche Limited for the drug product Columvi. 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 Columvi is favourable for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, diffuse large B-cell lymphoma arising from follicular lymphoma, or primary mediastinal B-cell lymphoma, who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive chimeric antigen receptor (CAR) T-cell therapy or have previously received CAR T-cell therapy.

1 What was approved?

Columvi is an antineoplastic agent. It was authorized for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, diffuse large B-cell lymphoma arising from follicular lymphoma, or primary mediastinal B-cell lymphoma, who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive chimeric antigen receptor (CAR) T-cell therapy or have previously received CAR T-cell therapy.

Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of Columvi in pediatric (younger than 18 years of age) patients have not been established. Therefore, Health Canada has not authorized an indication for pediatric use.

No differences in safety or efficacy of Columvi were observed between patients 65 years of age or older and those under 65 years of age.

Columvi (glofitamab 1 mg/mL [2.5 mg/2.5 mL and 10 mg/10 mL]) is presented as a solution. In addition to the medicinal ingredient, the solution contains L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 20, D-sucrose, and water for injection.

The use of Columvi 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 Columvi 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 Columvi approved?

Health Canada considers that the benefit-risk profile of Columvi is favourable for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, diffuse large B-cell lymphoma arising from follicular lymphoma, or primary mediastinal B-cell lymphoma, who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive CAR T-cell therapy or have previously received CAR T-cell therapy. Columvi 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.

Large B-cell lymphomas represent a clinically and molecularly heterogeneous group of mature B-cell malignancies. Eighteen entities of large B-cell lymphomas are listed in the latest, 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Among these, the most frequent entity is diffuse large B-cell lymphoma, not otherwise specified, accounting for more than 80% of the cases of large B-cell lymphomas.

The R-CHOP immunochemotherapy regimen (rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone) is the standard first-line treatment for diffuse large B-cell lymphomas, resulting in an overall cure rate of approximately 60%. Patients with treatment failure after upfront R-CHOP often have a poor outcome. For these patients, second-line treatment options include alternative chemotherapy regimens, high-dose chemotherapy with autologous stem cell transplantation, and axicabtagene ciloleucel (an anti-CD19 CAR T-cell product). For patients whose disease does not respond or relapses after two or more lines of systemic therapy, the currently available treatment options are anti-CD19 CAR T-cell products (e.g., axicabtagene ciloleucel, tisagenlecleucel), antibody-drug conjugates (e.g., polatuzumab vedotin), and monoclonal antibodies (e.g., tafasitamab). Notably, in this setting, none of the aforementioned products have demonstrated definitively that they improve overall survival over the alternative treatment options. Authorizations of these products were based primarily on exceptional response rate data and meaningful durations of response. Accordingly, there remains an unmet medical need for new treatment options for this patient population.

Glofitamab, the medicinal ingredient in Columvi, is a bispecific monoclonal antibody that binds bivalently and with high affinity to CD20 expressed on the surface of B cells and monovalently, with low affinity, to CD3 in the T-cell receptor complex expressed on the surface of T cells. By simultaneously binding CD20 on the B cell and CD3 on the T cell, glofitamab mediates the formation of an immunological synapse with subsequent potent T-cell activation and proliferation, secretion of cytokines, and release of cytolytic proteins that results in the lysis of CD20-expressing B cells.

Columvi has been shown to be efficacious in adult patients with relapsed or refractory diffuse large B-cell lymphoma who have received at least two prior lines of systemic therapy. The market authorization issued with conditions was based on efficacy and safety data from an ongoing, first-in-human, multicentre, open-label, Phase I/II dose-escalation and dose-expansion study (NP30179). Cohort D3 of this multiple-cohort study represented the primary efficacy population comprising 108 patients. Among them, there were 79 patients with diffuse large B-cell lymphoma, not otherwise specified, 17 patients with diffuse large B-cell lymphoma arising from follicular lymphoma, 6 patients with primary mediastinal B-cell lymphoma, and 6 patients with high-grade B-cell lymphoma. All patients had received at least two prior systemic therapies, 34.3% had received prior CAR T-cell therapy, and 15% had received prior autologous stem cell transplant.

Following a single pretreatment dose of 1,000 mg of obinutuzumab (an anti-CD20 monoclonal antibody) on Day 1 of the first 21-day cycle (Cycle 1), patients received 2.5 mg of Columvi on Day 8 of Cycle 1, 10 mg of Columvi on Day 15 of Cycle 1, and 30 mg of Columvi on Day 1 of Cycle 2, as per the step-up dosing schedule. Thereafter, 30 mg of Columvi was administered on Day 1 of every subsequent 21-day cycle for up to 12 cycles or until disease progression or unmanageable toxicity occurred.

The primary efficacy outcome of the study was the complete response rate (CRR) among patients enrolled in Cohort D3. The CRR was assessed by an independent review committee (IRC) using the Lugano classification criteria for the response assessment of non-Hodgkin lymphoma. With a median follow-up of 9.0 months, the study demonstrated a CRR in Cohort D3 of 35.2% (95% confidence interval [CI]: 26.2, 45.0), i.e., 38 of the 108 patients achieved complete remission. With respect to the different large B-cell lymphoma histologic subtypes, the CRR rate was consistent between patients with diffuse large B-cell lymphoma, not otherwise specified, patients with diffuse large B-cell lymphoma arising from follicular lymphoma, and patients with primary mediastinal B-cell lymphoma. However, no complete responses and one partial response were observed in patients with high-grade B-cell lymphoma. It is also notable that no complete responses were observed among 10 patients with double-hit lymphoma (harbouring rearrangements of MYC and BCL2 genes), which is considered high-grade B-cell lymphoma. Due to the small sample sizes, it is difficult to interpret the results by histological subtype. Health Canada considered that there was insufficient evidence of efficacy to include patients with high-grade B-cell lymphoma within the intended patient population for Columvi.

The safety profile of Columvi was evaluated based on data from the primary safety population including 152 patients who received at least one dose of study treatment (obinutuzmab pretreatment followed by a step-up dosing regimen of Columvi) and were within the scope of the target population in the proposed indication. The median number of treatment cycles was 4 (range: 1 to 12 cycles).

Treatment-emergent adverse events were experienced by 98% of patients treated with the Columvi step-up regimen (2.5/10/30 mg). Adverse events of Grade 3 or higher severity occurred in 55.9% of patients in the primary safety population. The most frequently reported adverse events of Grade 3 or higher severity (occurring in at least 5% of patients) were neutropenia (23.7%), anemia (6.6%), thrombocytopenia (5.9%), and hypophosphatemia (5.9%). Serious adverse events occurred in 45.5% of patients. The most frequently reported serious adverse events were cytokine release syndrome (20.4%), sepsis (3.9%), coronavirus disease 2019 (COVID-19) pneumonia (3.3%), tumour flare (3.3%), COVID-19 (2.0%), anemia (2.0%), and pleural effusion (2.0%). Seven patients died due to a treatment-emergent adverse event. The reported Grade 5 adverse events (i.e., adverse events that resulted in death) were COVID-19 pneumonia (3 patients), sepsis (2 patients), COVID-19 (1 patient), and delirium (1 patient).

Cytokine release syndrome is the most important adverse event associated with T-cell engaging products, including Columvi. Overall, 94 patients (61.8%) experienced cytokine release syndrome, the severity of which was graded as per the American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading scheme. Most instances (57.9%) were Grade 1 or Grade 2 in severity. However, 20.4% of patients experienced cytokine release syndrome that was considered a serious adverse event. Given the need for appropriate monitoring and prompt management, the risk of cytokine release syndrome was highlighted in a Serious Warnings and Precautions box of the Columvi Product Monograph.

Other important adverse events, which have been addressed in the Warnings and Precautions section of the Columvi Product Monograph are neurologic adverse events, tumour lysis syndrome, tumour flare, infusion-related reactions, and serious infections.

A Risk Management Plan (RMP) for Columvi was submitted by Hoffmann-La Roche Limited 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 Columvi Product Monograph meet 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 Columvi was accepted.

Overall, Columvi as a single agent administered according to a step-up dosing regimen after a fixed, single pretreatment dose of obinutuzumab has demonstrated promising efficacy and an acceptable safety profile for the intended patient population. In accordance with the Notice of Compliance with Conditions (NOC/c) Guidance, safety monitoring will be ongoing. Further evaluation of the benefit-risk profile of Columvi will take place upon the submission of the results from a Phase III, open-label, multicentre, randomized study evaluating the efficacy and safety of glofitamab in combination with gemcitabine plus oxaliplatin versus rituximab in combination with gemcitabine plus oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma.

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 Columvi?

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 Columvi. Upon assessment of the presented information, Health Canada determined that the eligibility criteria were met for the NDS to be filed and reviewed under the NOC/c Guidance. There was promising clinical evidence that the drug would provide effective treatment in the setting of relapsed or refractory diffuse large B-cell lymphoma, a serious and life-threatening disease with a significant unmet medical need.

The review of the NDS led to the decision to issue a market authorization for Columvi under the NOC/c Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness presented 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.

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

Submission Milestones: Columvi

Submission Milestone

Date

Pre-submission meetings

2021-03-23 

2022-03-08

Advance Consideration under the Notice of Compliance with Conditions Guidance accepted

2022-04-25

New Drug Submission filed

2022-06-23

Screening

Screening Acceptance Letter issued

2022-07-25

Review

Review of Risk Management Plan completed

2023-01-31

Labelling review completed

2023-02-03

Biostatistics evaluation completed

2023-02-06

Non-clinical evaluation completed

2023-02-06

Clinical/medical evaluation completed

2023-02-06

Quality evaluation completed

2023-02-07

Notice of Compliance with Conditions Qualifying Notice issued

2023-02-09

Review of Response to Notice of Compliance with Conditions Qualifying Notice

Response filed (Letter of Undertaking)

2023-02-23

Clinical/medical evaluation completed

2023-03-20

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

2023-03-24

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations and in the Notice of Compliance with Conditions (NOC/c) Guidance. The sponsor has agreed to provide confirmatory evidence of efficacy of Columvi in the setting of relapsed/refractory diffuse large B-cell lymphoma. Specifically, the sponsor is expected to submit the results of a Phase III, open-label, multicentre, randomized study evaluating the efficacy and safety of glofitamab in combination with gemcitabine plus oxaliplatin versus rituximab in combination with gemcitabine plus oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma.

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

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 Columvi. 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

Glofitamab, the medicinal ingredient in Columvi, is a bispecific monoclonal antibody that simultaneously binds to CD20 on B cells and CD3 on T cells and induces T-cell mediated killing of CD20-expressing B cells.

The pharmacokinetic properties of glofitamab were evaluated in Study NP30179 in patients with relapsed or refractory diffuse large B-cell lymphoma (described in the Clinical Efficacy section).

Non-compartmental analyses showed that the maximum observed plasma concentration (Cmax) of glofitamab was reached at the end of the intravenous infusion and thereafter the concentrations declined biexponentially. Glofitamab exhibited linear and dose-proportional pharmacokinetics over the dose range of 0.005 mg to 30 mg.

A two-compartment population pharmacokinetic model included both time-independent and time-varying clearance parameters (to account for accumulation during the therapeutic cycle). The population pharmacokinetic model diagnostics (i.e., the evaluation of the goodness-of-fit plots and shrinkage values) indicated that the model may be associated with bias, which could mask the identification of associations. Therefore, conclusions based on the model should be interpreted with caution.

In the covariate analysis, no clinically meaningful covariates for exposure were identified, although body weight had statistically significant effects on the model parameters for clearances and volumes. The exposure-response analysis, using exposure estimates from the population pharmacokinetic model, suggested that the efficacy (i.e., complete response rate, overall response rate) was significantly correlated with exposure and that the risk of cytokine release syndrome (of Grade 2 or higher severity) increased significantly with the increasing average receptor occupancy observed within 24 hours of the first dose of glofitamab. This finding helped confirm the validity of the recommended dosing regimen, which incorporates step-up dosing of glofitamab to mitigate the risk of cytokine release syndrome.

A minimal physiologically based pharmacokinetic model, employed to investigate the effects of glofitamab-induced interleukin 6 expression on hepatic cytochrome P450 (CYP450) enzymes and the subsequent effects on the metabolism of drugs, suggested a moderate suppressive effect on some CYP enzymes. Despite the uncertainty associated with the simulations from this modelling exercise, a precautionary statement has been included in the Drug-Drug Interactions section of the Columvi Product Monograph to recommend monitoring patients who concomitantly receive CYP450 substrates with a narrow therapeutic index (e.g., warfarin, cyclosporine).

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

Clinical Efficacy

The efficacy of Columvi in adult patients with relapsed or refractory diffuse large B-cell lymphoma who have received at least two prior lines of systemic therapy is supported by data from an ongoing, first-in-human, multicentre, open-label, Phase I/II dose-escalation and dose-expansion study (NP30179). Cohort D3 of this multiple-cohort study represented the primary efficacy population comprising 108 patients. Among them, there were 79 patients with diffuse large B-cell lymphoma, not otherwise specified, 17 patients with diffuse large B-cell lymphoma arising from follicular lymphoma, 6 patients with primary mediastinal B-cell lymphoma, and 6 patients with high-grade B-cell lymphoma. Most patients (69.4%) were male, with a median age of 66 years. The majority of patients (63.9%) had extranodal disease, whereas 41.7% had bulky disease. All patients had received at least two prior systemic therapies, 34.3% had received prior chimeric antigen receptor (CAR) T-cell therapy, and 15% had received prior autologous stem cell transplant.

Following a single pretreatment dose of 1,000 mg of obinutuzumab (an anti-CD20 monoclonal antibody) on Day 1 of the first 21-day cycle (Cycle 1), patients received 2.5 mg of Columvi on Day 8 of Cycle 1, 10 mg of Columvi on Day 15 of Cycle 1, and 30 mg of Columvi on Day 1 of Cycle 2, as per the step-up dosing schedule. Thereafter, 30 mg of Columvi was administered on Day 1 of every subsequent 21-day cycle for up to 12 cycles or until disease progression or unmanageable toxicity occurred. Patients received premedication including an antipyretic, an antihistamine, and a glucocorticoid.

The primary efficacy outcome of the study was the complete response rate (CRR) among patients enrolled in Cohort D3. The CRR was assessed by an independent review committee (IRC) using the Lugano classification criteria for the response assessment of non-Hodgkin lymphoma.

Key secondary endpoints were the overall response rate, the duration of complete response, and duration of response. The submitted data included evaluations of progression-free survival, overall survival, and patient-reported outcomes; however, these were considered of limited value given the single-arm study design.

With a median follow-up of 9.0 months, the study demonstrated a CRR in Cohort D3 of 35.2% (95% confidence interval [CI]: 26.2, 45.0), i.e., 38 of the 108 patients achieved complete remission. Consistency was observed between the IRC-assessed CRR and the investigator-assessed CRR of 33.3%. Inclusion of 7 additional patients from cohorts D2 and D3, who were identified to be within the scope of the sought indication, did not significantly change the CRR. Similarly, among patients in Cohort D5 who had reached the first response assessment, the CRR was 33.3%; however, the response assessment had not been conducted for all patients in this cohort at the time of the clinical data cut-off.

With respect to the different large B-cell lymphoma histologic subtypes, the CRR rate was consistent between patients with diffuse large B-cell lymphoma, not otherwise specified, patients with diffuse large B-cell lymphoma arising from follicular lymphoma, and patients with primary mediastinal B-cell lymphoma, However, no complete responses and a single partial response were observed in patients with high-grade B-cell lymphoma. Also notable, no complete responses were observed among 10 patients with double-hit lymphoma (harbouring rearrangements of MYC and BCL2 genes) which is considered high-grade B-cell lymphoma. Due to the small sample sizes, it is difficult to interpret the results by histological subtype. Health Canada considered that there was insufficient evidence of efficacy to include patients with high-grade B-cell lymphoma within the intended patient population for Columvi.

The overall response rate, which was a key secondary endpoint evaluated in cohort D3, was 50% (95% CI: 40.22, 59.78). The IRC-assessed duration of complete response among the 38 complete responders was estimated to be 14.4 months (95% CI: non-estimable [NE], NE). At 3, 6, and 9 months, the estimated event-free probabilities were 96.9%, 93.2%, and 83.8%, respectively. Of note, the median duration of complete response estimate is immature, and it is likely to change with an additional follow-up. The IRC-assessed duration of response among the 54 responders (patients with a complete response and patients with a partial response) was 14.4 months (95% CI: 7.3, NE), but it is also expected to change with a longer follow-up.

Overall, the submitted efficacy results are considered promising for the target patient population. To confirm the clinical benefit of Columvi, the sponsor will provide the results from a Phase III, open-label, multicentre, randomized study evaluating the efficacy and safety of glofitamab in combination with gemcitabine plus oxaliplatin versus rituximab in combination with gemcitabine plus oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma. The primary efficacy objective of the Phase III study is to demonstrate that glofitamab in combination with gemcitabine plus oxaliplatin is associated with improved overall survival when compared to rituximab in combination with gemcitabine plus oxaliplatin.

Indication

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

Columvi (glofitamab for injection) is 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, not otherwise specified, including diffuse large B-cell lymphoma arising from follicular lymphoma, high-grade B-cell lymphoma, and primary mediastinal B-cell lymphoma, who cannot receive CAR T-cell therapy, or have previously received CAR T-cell therapy.

Health Canada revised the proposed indication to exclude patients with high-grade B-cell lymphoma from the intended patient population for Columvi, given the insufficient evidence of efficacy to support the use of Columvi in these patients (as elaborated in the Clinical Efficacy section). Accordingly, Health Canada approved the following indication:

Columvi (glofitamab for injection) is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, diffuse large B-cell lymphoma arising from follicular lymphoma, or primary mediastinal B-cell lymphoma, who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive CAR T-cell therapy or have previously received CAR T-cell therapy.

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

Clinical Safety

The assessment of the safety profile of Columvi was based on data derived from the pivotal study (Study NP30179, described in the Clinical Efficacy section). The primary safety population included 152 patients who received at least one dose of study treatment (obinutuzmab pretreatment followed by a step-up dosing regimen of Columvi) and were within the scope of the target population in the proposed indication. Patients from Cohort D3 comprised the majority of these patients (107 patients), while the remainder were enrolled in Cohort D2 (7 patients) and Cohort D5 (38 patients). The median number of treatment cycles was 4 (range: 1 to 12 cycles).

Treatment-emergent adverse events were experienced by 98% of patients treated with the Columvi step-up regimen (2.5/10/30 mg). Adverse events of Grade 3 or higher severity occurred in 55.9% of patients in the primary safety population. The most frequently reported adverse events of Grade 3 or higher severity (occurring in at least 5% of patients) were neutropenia (23.7%), anemia (6.6%), thrombocytopenia (5.9%), and hypophosphatemia (5.9%). Serious adverse events occurred in 45.5% of patients. The most frequently reported serious adverse events were cytokine release syndrome (20.4%), sepsis (3.9%), coronavirus disease 2019 (COVID-19) pneumonia (3.3%), tumour flare (3.3%), COVID-19 (2.0%), anemia (2.0%), and pleural effusion (2.0%). Seven patients died due to a treatment-emergent adverse event. The reported Grade 5 adverse events (i.e., adverse events that resulted in death) were: COVID-19 pneumonia (3 patients), sepsis (2 patients), COVID-19 (1 patient), and delirium (1 patient).

Cytokine release syndrome is the most important adverse event associated with T-cell engaging products, including Columvi. Overall, 94 patients (61.8%) experienced cytokine release syndrome, the severity of which was graded as per the American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading scheme. Most instances (57.9%) were Grade 1 or Grade 2 in severity. However, as previously mentioned, 20.4% of patients experienced cytokine release syndrome that was considered a serious adverse event. The vast majority of the adverse events of cytokine release syndrome had resolved by the clinical cut-off date, at which point there were 2 ongoing cases. Overall, cytokine release syndrome was considered manageable. Of the 94 cases, 7 patients were admitted to the intensive care unit, 2 patients required mechanical ventilation, 1 patient required high-flow oxygen, and no patients required management with multiple vasopressors. Thirty-one patients received tocilizumab, 27 patients received corticosteroids, and 16 patients were treated with both tocilizumab and corticosteroids. Given the need for appropriate monitoring and prompt management, the risk of cytokine release syndrome was specifically addressed in a Serious Warnings and Precautions box of the Columvi Product Monograph.

Neurologic adverse events, which have been observed with other bispecific T-cell engaging products and CAR T-cell products, were reported in 36.2% of patients in the primary safety population. In 6.6% of patients in the primary safety population, neurologic adverse events occurred concurrently with cytokine release syndrome. The most frequently reported neurologic adverse event was Grade 1 or Grade 2 headache (9.2%). Preferred terms for nervous system and psychiatric disorders (as per the Medical Dictionary for Regulatory Activities, MedDRA) were surveyed by Health Canada for terms associated with immune effector cell-associated neurotoxicity syndrome. In the primary safety population, preferred terms indicative of immune effector cell-associated neurotoxicity syndrome included confusional state (3 cases), somnolence (2 cases), tremor (2 cases), agitation (1 case), delirium (1 Grade 5 case), and seizure (1 case). Patients with relapsed or refractory diffuse large B-cell lymphoma treated with other dosing regimens of Columvi also experienced such events, in addition to events of depressed level of consciousness and disturbance in attention. Based on these findings, Health Canada recommended the addition of a warning for neurological adverse events in the Warnings and Precautions section of the Columvi Product Monograph.

Other important adverse events, which have also been addressed in the Warnings and Precautions section of the Columvi Product Monograph are tumour lysis syndrome, tumour flare, infusion-related reactions, and serious infections.

Further evaluation of Columvi will take place upon the submission of the results of a Phase III, open-label, multicentre, randomized study evaluating the efficacy and safety of glofitamab in combination with gemcitabine plus oxaliplatin versus rituximab in combination with gemcitabine plus oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma.

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

7.2 Non-Clinical Basis for Decision

Glofitamab, the medicinal ingredient in Columvi, is a bispecific monoclonal antibody that binds bivalently and with high affinity to CD20 expressed on the surface of B cells and monovalently, with low affinity, to CD3 in the T-cell receptor complex expressed on the surface of T cells. By simultaneously binding to CD20 on the B cell and CD3 on the T cell, glofitamab mediates the formation of an immunological synapse with subsequent potent T-cell activation and proliferation, secretion of cytokines, and release of cytolytic proteins that results in the lysis of CD20-expressing B cells.

Glofitamab displayed potent and dose-dependent antitumour activity in in vivo mouse models of diffuse large B-cell lymphoma. Tumour regression was observed regardless of the immune cell infiltration prior to treatment. Glofitamab-activated T cells express activation and exhaustion markers, secrete cytokines and cytotoxic granules, and proliferate. Importantly, the activity of glofitamab is specific and occurs only in the presence of simultaneous binding to CD20-expressing target cells and CD3-expressing T cells. Glofitamab maintains potent antitumour efficacy even when obinutuzumab, step-up dosing, and steroids are combined as additional measures to mitigate cytokine release, which is associated with the administration of glofitamab.

The clearance of glofitamab was rapid and dose-dependent, with decreased values at higher dose levels. The dose-dependent pharmacokinetics is consistent with target-mediated drug disposition via binding to CD20 on B cells. Low-affinity binding to CD3 does not contribute significantly to the observed target-mediated drug disposition. Rapid clearance persisted following B-cell depletion by obinutuzumab.

Glofitamab is pharmacologically active in cynomolgus monkeys, as demonstrated in vitro and in vivo. Given the high clearance, marked immunogenicity, and dose-limiting cytokine release in cynomolgus monkeys, several measures were undertaken to achieve higher exposure and better tolerability. These approaches included step-up dosing, every-other-day dosing, or pretreatment with obinutuzumab (in single-dose toxicity studies).

Key non-clinical findings, identified in single- and repeat-dose toxicity studies up to 4 weeks in duration, were related to the mechanism of action of glofitamab and included transient post-dose cytokine release, primarily limited to the first dose, and changes secondary to cytokine release. Animals with severe cytokine release after a single glofitamab dose of 100 µg/kg without obinutuzumab pretreatment had epithelial degeneration/single-cell necrosis in the exocrine pancreas and stomach mucosa or erosions in the gastrointestinal tract and mixed-cell and/or neutrophilic infiltrates in some organs. These findings were likely secondary to cytokine release and cytokine-induced immune cell activation. Pretreatment with obinutuzumab resulted in the attenuation of cytokine release, allowing administration of glofitamab at a dose ten times higher than the dose that resulted in severe cytokine release syndrome. This higher dose of glofitamab led to a maximum serum concentration observed (Cmax) of 3.74 times the human Cmax at the recommended clinical dose of 30 mg.

No reproductive toxicity studies have been conducted with glofitamab. Based on the low placental transfer of antibodies during the first trimester, the mechanism of action and available data on glofitamab, and the data on the anti-CD20 antibody class, the risk for teratogenicity is low. However, prolonged B-cell depletion can lead to an increased risk of opportunistic infections, which may cause fetal loss. Transient cytokine release associated with the administration of glofitamab may also be harmful to pregnancy.

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

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

7.3 Quality Basis for Decision

Characterization of the Drug Substance

Glofitamab, the medicinal ingredient in Columvi, is a novel recombinant bispecific humanized monoclonal antibody based on a human immunoglobulin G1 (IgG1) framework. Glofitamab is composed of two different heavy chains and two different light chains and has a molecular mass of approximately 194 kDa. The molecule contains two fragment antigen-binding (Fab) domains directed against the human CD20 protein expressed on the surface of B cells and one Fab domain directed against the human CD3 epsilon (CD3ɛ) subunit of the T-cell receptor complex expressed on the surface of T cells. Hence, glofitamab binds bivalently to CD20 and monovalently to the CD3 epsilon (CD3ɛ) subunit of the T-cell receptor. By simultaneously binding to CD20 on the B cell and CD3 on the T cell, glofitamab mediates the formation of an immunological synapse with subsequent potent T-cell activation and proliferation, secretion of cytokines, and release of cytolytic proteins that results in the lysis of CD20-expressing B cells.

The fragment crystallizable (Fc) region of the molecule contains a modification (“PG LALA” mutation) which abrogates its binding to complement (C1q) and Fc gamma receptors (FcγR). This molecular change prevents FcγR-mediated co-activation of innate immune effector cells including natural killer cells, monocytes/macrophages, and neutrophils without affecting functional binding to the neonatal Fc receptor (FcRn).

Detailed characterization studies were performed to provide assurance that glofitamab consistently exhibits the desired characteristic structure and biological activity. Glofitamab is a heterogeneous protein that has the primary structure, post-translational modifications, and other characteristics of a recombinant IgG1 derived from Chinese hamster ovary (CHO) cells.

The product- and process-related 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

Glofitamab is produced using a genetically engineered CHO cell line. The antibody is expressed as a secreted product of the CHO cells.

The production of glofitamab starts with the thaw of a single vial of the working cell bank. The cell substrate biomass is expanded by sequential subcultivation into a progressively larger volume of medium to generate sufficient inoculum volume for the fed-batch production bioreactor. When set criteria are reached, the cell culture fluid from the production bioreactor is harvested by centrifugation and filtration. Multiple batches of harvested cell culture fluid can be produced from a single vial of working cell bank.

A single batch of harvested cell culture fluid is subsequently purified through chromatography steps, filtration steps, and additional steps for removal and inactivation of potential viral contaminants. The drug substance is concentrated and conditioned to the final concentration and composition, and filtered into sterile, ethylene vinyl acetate single-use bags. The bags are stored frozen at or below-30 °C.

The commercial drug product manufacturing process consists of drug substance thawing, optional pooling of multiple drug substance batches and their mixing, dilution of the drug substance solution and its mixing, bioburden-reduction filtration, in-line sterile filtration, aseptic filling of vials, stoppering, capping/crimping, and visual inspection. Both vial configurations of Columvi (2.5 mg of glofitamab in 2.5 mL of solution and 10 mg of glofitamab in 10 ml of solution) are manufactured using the same process and equipment.

Operating parameters associated with each manufacturing process step were adequately described and justified in the submission. The performance of the manufacturing process is routinely monitored by in-process testing of relevant process intermediates against justified limits.

The commercial drug substance and drug product manufacturing processes were validated by manufacturing several consecutive process performance qualification batches and by ancillary validation studies. Overall, the validation data demonstrate that the commercial manufacturing processes are capable of consistently producing drug substance batches and drug product batches of acceptable quality.

Control of the Drug Substance and Drug Product

The quality of the drug substance and drug product is ensured by suitable specifications for identity, purity, potency, and relevant characteristics of the dosage form. The corresponding analytical methods were adequately validated or qualified and established at each testing site. A two-tiered in-house reference standard program has also been implemented. The acceptance criteria were appropriately justified.

Columvi 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 are adequately supported and are considered satisfactory.

The stability data support the proposed shelf life of 24 months for Columvi, when it is stored protected from light at 2 °C to 8 °C. The prepared infusion solution should be used immediately. If not used immediately, the infusion solution can be stored in the refrigerator at 2 °C to 8 °C for up to 64 hours and at 25 °C for up to 4 hours prior to administration, followed by a maximum infusion duration of 8 hours.

The compatibility of the drug product with the container closure system was demonstrated through long-term stability studies and extractables/leachables studies.

Facilities and Equipment

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

An on-site evaluation of the drug substance manufacturing facility was not recommended, given that a pre-licence inspection conducted by the Paul Ehrlich Institute, an agency of the German Federal Ministry of Health, did not identify any major issues and supported the suitability of this site to manufacture Columvi drug substance. The inspection report was provided to Health Canada upon request and leveraged as a mitigating factor in the overall risk assessment of the facility.

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

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

Adventitious Agents Safety Evaluation

The manufacturing process of glofitamab incorporates adequate control measures to prevent contamination and maintain microbial control.

Thorough testing of the master cell bank, working cell bank, and pre-harvest cell culture fluid provides confirmation that the cell substrate and starting materials for the drug substance manufacturing process are free of detectable adventitious agents (bacteria, fungi, mycoplasma, and viruses). The cell culture process includes in-process tests to monitor for bioburden, mycoplasma, and viruses. Scaled-down viral clearance studies demonstrate that the downstream purification process is capable of inactivating or removing model viruses with a broad range of biochemical and biophysical properties.

No animal-derived and human-derived raw materials are used in the cell line development, cell bank preparation, and manufacture of the drug substance and drug product. In addition, the excipients used in the drug product formulation are not of animal or human origin.