Summary Basis of Decision for Kimmtrak

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 Kimmtrak is located below.

Recent Activity for Kimmtrak

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

The following table describes post-authorization activity for Kimmtrak, a product which contains the medicinal ingredient tebentafusp. 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 that are found in PAATs.

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

Updated: 2023-06-30

Drug Identification Number (DIN):

DIN 02527588 - tebentafusp 100 μg (mcg)/0.5 mL, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02527588) market notification Not applicable Date of first sale: 2022-08-23 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 258717 2021-11-19 Issued NOC 2022-06-07 NOC issued for the New Drug Submission.
Summary Basis of Decision (SBD) for Kimmtrak

Date SBD issued: 2022-10-03

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

Tebentafusp

Drug Identification Number (DIN):

DIN 02527588 - tebentafusp 100 µg (mcg)/0.5 mL, solution, intravenous administration

Immunocore Ireland Ltd.

New Drug Submission Control Number: 258717

On June 7, 2022, Health Canada issued a Notice of Compliance to Immunocore Ireland Limited for the drug product Kimmtrak.

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 Kimmtrak is favourable for the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

1 What was approved?

Kimmtrak, an antineoplastic agent, was authorized for the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

Kimmtrak is not authorized for use in pediatric (i.e., younger than 18 years of age) patients, as its safety and effectiveness have not been established in this population.

Among the 410 patients with metastatic uveal melanoma treated with Kimmtrak, 175 (43%) were 65 years of age and older and 38 (9%) were 75 years of age and older. Evidence from clinical studies suggests that the use of Kimmtrak in the geriatric (65 years of age and older) population is associated with no overall differences in safety or effectiveness as compared to the population younger than 65 years of age.

Kimmtrak (tebentafusp 100 μg [mcg]/0.5 mL) is presented as a solution. In addition to the medicinal ingredient, the solution contains citric acid monohydrate, disodium hydrogen phosphate, mannitol, polysorbate 20, trehalose, and water for injection.

The use of Kimmtrak 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 Kimmtrak 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 Kimmtrak approved?

Health Canada considers that the benefit-risk profile of Kimmtrak is favourable for the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

Uveal melanoma is a rare and highly malignant subset of melanoma. It is the most commonly occurring intraocular malignancy in adults. The Melanoma Network of Canada estimates that 200 people are diagnosed with uveal melanoma in Canada each year, which equates to an annual incidence of 5.3 per million individuals based on the Canadian population of 38 million. Uveal melanoma arises exclusively from melanocytes of the uvea, and it is biologically, clinically, and genetically distinct from cutaneous melanoma. It has a low tumour mutational burden, which limits natural antitumour immunity and makes the disease less sensitive to immune checkpoint inhibitors.

Uveal melanoma is a life-threatening disease with no effective therapy available once it metastasizes. Despite local therapy (radiation and surgery), up to 50% of patients develop systemic metastases, predominantly to the liver (approximately 90% of patients) and less commonly to the lungs and bones. Once patients develop metastatic uveal melanoma, the prognosis and outcomes are dismal, with a median survival of 12 months or less. There has been no treatment with a survival benefit for patients with metastatic uveal melanoma for decades.

Tebentafusp, the medicinal ingredient in Kimmtrak, is a bispecific glycoprotein 100 (gp100) peptide-HLA-A*02:01-directed (cluster of differentiation 3) CD3 T-cell engager. Glycoprotein 100 is only expressed in melanocytes and tumours derived from melanocytes. Tebentafusp is composed of a T-cell receptor (TCR) fused to an antibody fragment with specificity for the CD3 receptor on polyclonal T cells. The TCR has specificity for a gp100-derived peptide fragment (YLEPGPVTA) presented by human HLA-A*02:01 on the cell surface. In vitro, tebentafusp was shown to bind to HLA-A*02:01-positive uveal melanoma cells and activate polyclonal T cells to release inflammatory cytokines and cytolytic proteins, which resulted in direct lysis of uveal melanoma tumour cells.

The market authorization of Kimmtrak was based on efficacy and safety data from the pivotal, randomized, open-label, multicentre study, IMCgp100-202, conducted in 378 HLA-A*02:01-positive adult patients with metastatic uveal melanoma. Patients were randomized in a 2:1 ratio to receive Kimmtrak (252 patients) or the investigator’s choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (126 patients). Randomization was stratified by lactate dehydrogenase level at study entry. Kimmtrak was administered by intravenous infusion at a dose of 20 μg on Day 1, 30 μg on Day 8, 68 μg on Day 15, and 68 μg weekly thereafter. The median duration of treatment exposure was 23 weeks in the Kimmtrak arm and 9 weeks in the investigator’s choice arm. All patients were followed up for a median period of 14.1 months. Across both treatment arms, patients stopped treatment for disease progression, unless the patient was otherwise deriving benefit, or for unacceptable toxicity. The primary efficacy endpoint of the study was overall survival.

The study demonstrated a statistically significant improvement in overall survival in patients treated with Kimmtrak compared to those treated with the investigator’s choice of therapy (hazard ratio of 0.51; 95% confidence interval [CI]: 0.37, 0.71; p < 0.0001). These results indicate that the relative risk of death was reduced by 49% (ranging from 29% to 63%) in the Kimmtrak arm when compared with the investigator’s choice arm. The estimates (median time in months) for overall survival were 21.7 months (95% CI: 18.6, 28.6) for the Kimmtrak arm and 16 months (95% CI: 9.7, 18.4) for the investigator’s choice arm. The findings for the primary efficacy endpoint of overall survival are considered clinically meaningful.

Among the Kimmtrak-treated patients, the most frequently reported adverse reactions (occurring in at least 30% of patients) were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common laboratory abnormalities (occurring in at least 50% of patients) were decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate. Few patients exited the study due to drug-related adverse events (2.4% of patients in the Kimmtrak arm and 2% of patients in the investigator’s choice arm). No drug-related deaths occurred.

The key safety concern associated with Kimmtrak is the risk of cytokine release syndrome, which can be serious or life-threatening. Grade 2 or higher events of cytokine release syndrome occurred in 77% of patients who received Kimmtrak in the pivotal study. Therefore, a Serious Warnings and Precautions section in the Kimmtrak Product Monograph highlights the risk of cytokine release syndrome and specifies the need for monitoring patients for at least 16 hours following the first three infusions of Kimmtrak. Furthermore, the management of cytokine release syndrome, acute skin reactions, and elevated liver enzymes is addressed in the Warnings and Precautions section and the Dosage Adjustment section, with specific instructions for monitoring and dose modifications, and criteria for treatment discontinuation. 

A Risk Management Plan (RMP) for Kimmtrak was submitted by Immunocore Ireland 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 Kimmtrak 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 Kimmtrak was accepted.

Overall, the survival benefit demonstrated with Kimmtrak in HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma is considered to outweigh the potential risks. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Kimmtrak Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has 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 Kimmtrak?

The sponsor requested a priority review status for the New Drug Submission (NDS) for Kimmtrak. Following review of the information in the submitted clinical assessment package, Health Canada determined that the sponsor’s request fulfilled the criteria set out in the Priority Review Policy. Specifically, the sponsor presented substantial evidence of clinical effectiveness to demonstrate that Kimmtrak provides an effective treatment for HLA-A*02:01-positive patients with metastatic uveal melanoma, a serious, life-threatening and severely debilitating disease for which no drug is presently marketed in Canada.

Additionally, the sponsor requested participation in the Project Orbis, an initiative of the United States Food and Drug Administration (FDA) Oncology Center of Excellence. The project is an international partnership of drug regulatory agencies designed to give cancer patients faster access to promising treatments. It provides a framework for concurrent submission and review of oncology products among international partners. The submission for Kimmtrak was classified as a Project Orbis Type B (Modified Orbis) submission. This type of Project Orbis submissions refers to marketing applications submitted to Project Orbis partners more than 30 days after filing with the FDA and it allows Project Orbis partners to receive FDA review reports, exchange or receive requests for clarification, and observe and participate in some multicountry meetings.

During the review, Health Canada collaborated with the FDA, Australia’s Therapeutic Goods Administration (TGA) and the United Kingdom’s Medicines and Healthcare product Regulatory Agency (MHRA). The Canadian regulatory decision on the Kimmtrak submission was made independently of the Project Orbis partners’ decisions and was based on the Canadian review.

During the review of the non-clinical and clinical data for Kimmtrak, Health Canada used the foreign reviews completed by the Project Orbis partners as added references, in accordance with Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. For the review of the quality component of the NDS, Method 2 was applied, i.e., the foreign review completed by FDA was critically assessed, while the data package submitted to Health Canada was referred to as necessary.

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

Submission Milestones: Kimmtrak

Submission Milestone Date
Request for priority status filed 2021-09-16
Request for priority status approved by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics 2021-09-27
Pre-submission meeting 2021-10-27
New Drug Submission filed 2021-11-19
Screening  
Screening Acceptance Letter issued 2021-12-13
Review  
Biostatistics evaluation completed 2022-02-25
Non-clinical evaluation completed 2022-05-01
Clinical/medical evaluation completed 2022-05-01
Quality evaluation completed 2022-05-18
Review of Risk Management Plan completed 2022-05-25
Labelling review completed 2022-05-26
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2022-06-07
4 What follow-up measures will the company take?

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

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

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 Kimmtrak is found above.

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

6 What other information is available about drugs?

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

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

Clinical Pharmacology

Tebentafusp, the medicinal ingredient in Kimmtrak, is a bispecific fusion protein composed of a soluble T-cell receptor (TCR) fused to a single-chain variable fragment (scFv) of an anti-cluster of differentiation 3 (anti-CD3) antibody. The TCR domain of tebentafusp targets a peptide fragment of glycoprotein 100 (gp100), a melanocyte lineage-specific antigen expressed in normal melanocytes and overexpressed on melanocytic tumours, when presented by human leukocyte antigen (HLA)-A*02:01 on the cell surface. When the TCR domain binds to the gp100 peptide presented by the HLA:A*02:01 on the melanoma cell surface and the anti-CD3 scFv binds to CD3 on the surface of local T cells, an immune synapse is formed resulting in redirection, proliferation, and activation of polyclonal T cells regardless of the specificity of their native TCR. These activated polyclonal T cells produce inflammatory cytokines and cytolytic proteins, which kill the target tumour cells directly and augment the local tumour-directed immune response.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of tebentafusp have not been fully characterized.

Following a single-dose administration, the pharmacokinetics of tebentafusp appears linear and dose proportional over a dose range of 20 μg to 68 μg. The geometric mean clearance of tebentafusp is 16.4 L/day (coefficient of variation [CV]: 24.5%) and the median terminal half-life is 7.5 hours (range: 6.8-7.5 hours).

The metabolic pathway of tebentafusp has not been characterized. As a protein, tebentafusp is expected to be catabolized into small peptides and amino acids.

No clinically significant differences in the pharmacokinetics of tebentafusp were identified based on weight (43 to 163 kg), sex (48% female), age (23 to 91 years), mild or moderate renal impairment based on creatinine clearance estimated by the Cockcroft-Gault formula (30 to 89 mL/min), or mild hepatic impairment. Tebentafusp has not been studied in patients with severe renal impairment or in patients with moderate or severe hepatic impairment.

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

Clinical Efficacy

The efficacy of Kimmtrak in HLA-A*02:01-positive adult patients with metastatic uveal melanoma was evaluated in the randomized, open-label, multicentre study, IMCgp100-202. Patients were excluded if they received prior systemic therapy for metastatic or advanced uveal melanoma or localized liver-directed therapy. Prior surgical resection of oligometastatic disease was permitted. Patients who had clinically significant cardiac disease or impaired cardiac function and those with the presence of symptomatic or untreated brain metastases were excluded.

There were 378 patients randomized in a 2:1 ratio to receive Kimmtrak (252 patients) or the investigator’s choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (126 patients). Randomization was stratified by lactate dehydrogenase (LDH) level at study entry (LDH level higher than the upper limit of the normal range [ULN] or LDH level lower than or equal to the ULN). Kimmtrak was administered by intravenous infusion at a dose of 20 μg on Day 1, 30 μg on Day 8, 68 μg on Day 15, and 68 μg weekly thereafter. The median duration of treatment exposure was 23 weeks in the Kimmtrak arm and 9 weeks in the investigator’s choice arm. All patients were followed up for a median period of 14.1 months. Across both treatment arms, patients stopped treatment for disease progression, unless the patient was otherwise deriving benefit, or for unacceptable toxicity.

The primary efficacy endpoint of the study was overall survival. Progression-free survival per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 was one of the secondary endpoints. 

The study population was considered representative of the Canadian patient population. The median age was 64 years (ranging from 23 to 92 years). Fifty percent of patients were female and 87% were Caucasian. The baseline Eastern Cooperative Oncology Group performance status score was 0 in 73%, 1 in 21% or 2 in 0.3% of patients. Thirty-six percent of patients had elevated LDH levels and 94% had liver metastases.

The study demonstrated a statistically significant improvement in overall survival in patients treated with Kimmtrak compared to those treated with the investigator’s choice of therapy, with a hazard ratio (HR) of 0.51 (95% confidence interval [CI]: 0.37, 0.71; p < 0.0001). This finding indicates that the relative risk of death was reduced by 49% (ranging from 29% to 63%) in the Kimmtrak arm when compared with the investigator’s choice arm. The estimates (median time in months) for overall survival were 21.7 months (95% CI: 18.6, 28.6) for the Kimmtrak arm and 16 months (95% CI: 9.7, 18.4) for the investigator’s choice arm. The findings for the primary efficacy endpoint of overall survival are considered clinically meaningful. The HR for the secondary endpoint of progression-free survival was 0.73 (95% CI: 0.58, 0.94; p = 0.00139). The findings for progression-free survival underestimated the magnitude of the overall survival benefit observed in the Kimmtrak group, but they are considered supportive of the results for the primary efficacy endpoint.

Indication

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

  • Kimmtrak is a bispecific gp100-targeted T-cell receptor fusion protein indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

Following a minor revision, Health Canada approved the following indication:

  • Kimmtrak (tebentafusp) is indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

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

Clinical Safety

The safety of Kimmtrak was evaluated in study IMCgp100-202 (described in the Clinical Efficacy section). The median duration of exposure was 23 weeks in patients treated with Kimmtrak and 9 weeks in patients who received the investigator’s choice of treatment (pembrolizumab, ipilimumab, or dacarbazine).

Among the Kimmtrak-treated patients, the most frequently reported adverse reactions (occurring in at least 30% of patients) were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting.

Serious adverse reactions occurred in 28% of patients who received Kimmtrak. Serious adverse reactions occurring in at least 2% of patients were cytokine release syndrome (10%), rash (4.5%), pyrexia (2.4%), and hypotension (2%). One patient (0.4%) experienced a fatal adverse reaction (pulmonary embolism).

Few patients exited the study due to drug-related adverse events (2.4% of patients in the Kimmtrak arm and 2% of patients in the investigator’s choice arm). No drug-related deaths occurred.

The most common laboratory abnormalities (occurring in at least 50% of patients) were decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate.

The key safety concern associated with Kimmtrak is the risk of cytokine release syndrome, which can be serious or life-threatening. Cytokine release syndrome events of Grade 2 or higher were reported in 77% of patients who received Kimmtrak in study IMCgp100-202. Therefore, a Serious Warnings and Precautions section in the Kimmtrak Product Monograph highlights the risk of cytokine release syndrome and specifies the need for monitoring patients for at least 16 hours following the first three infusions of Kimmtrak. Furthermore, the management of cytokine release syndrome, acute skin reactions, and elevated liver enzymes is addressed in the Warnings and Precautions section and the Dosage Adjustment section, with specific instructions for monitoring and dose modifications, and criteria for treatment discontinuation. 

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which may have the potential to neutralize the biological activity of the drug). Treatment-emergent anti-tebentafusp antibodies were detected in 29% of patients receiving Kimmtrak across all doses in study IMCgp100-202. The median time to onset of ADA formation was 6 to 9 weeks after the first dose of Kimmtrak. The ability of these binding ADAs to neutralize tebentafusp is unknown. In the ADA-positive patients, the median titer of ADAs across the 67 treatment cycles was 8,192. In patients with ADA titers greater than 8,192, the exposure of tebentafusp (as measured by the area under the concentration-time curve from time zero through Day 7 [AUC0-7 days]) decreased by 97%, the tebentafusp clearance increased, and the terminal half-life decreased to 10-14 minutes. Exploratory analyses with limited data suggest that formation of anti-tebentafusp antibodies does not appear to have a clinically significant effect on the frequency or severity of hypersensitivity-related adverse reactions and on the efficacy of the drug.

The safety profile of Kimmtrak is considered acceptable for the intended patient population.

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

7.2 Non-Clinical Basis for Decision

Tebentafusp, the medicinal ingredient in Kimmtrak, is a bispecific fusion protein that consists of a soluble, affinity-enhanced T-cell receptor (TCR) fused to an anti-cluster of differentiation 3 (anti-CD3) single-chain variable fragment.

The TCR domain binds a glycoprotein 100 (gp100) peptide (peptide fragment derived from the melanoma-associated antigen gp100, position 280-288, YLEPGPVTA)-human leukocyte antigen (HLA)-A*02:01 complex. Glycoprotein 100 is a type 1 transmembrane glycoprotein that is enriched in melanosomes (the melanin-producing organelles in melanocytes).

In vitro, tebentafusp bound to HLA-A*02:01-positive uveal melanoma cells and activated polyclonal T cells to release inflammatory cytokines and cytolytic proteins, which resulted in direct lysis of uveal melanoma tumour cells.

Tebentafusp is a human-specific protein and there are no relevant animal species in which the non-clinical toxicology of tebentafusp could be evaluated. No long-term carcinogenicity, genotoxicity, or reproductive and developmental toxicity studies have been conducted with tebentafusp.

In view of the intended use of Kimmtrak, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

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

7.3 Quality Basis for Decision

Characterization of the Drug Substance

The medicinal ingredient in Kimmtrak, tebentafusp, is a bispecific glycoprotein 100 (gp100) peptide-HLA-A*02:01-directed (cluster of differentiation 3) CD3 T-cell engager. It is composed of a soluble, affinity-enhanced T-cell receptor (TCR) fused to a single-chain variable fragment (scFv) of an anti-CD3 antibody.

Tebentafusp consists of an alpha chain and a beta chain subunit, which are linked by an inter-chain disulfide bond. The beta subunit of the TCR is fused to the scFv via a short linker (herein, the beta-scFv component is referred to as tebentafusp beta chain). Tebentafusp has a predicted molecular mass of 76,145 Da.

Detailed characterization studies were performed to provide assurance that tebentafusp consistently exhibits the desired characteristic structure and biological activity. Product- and process-related impurities were also characterized and found to be within established limits.

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

Tebentafusp is a heterodimeric protein manufactured by the refolding of alpha and beta chain polypeptides, which are produced in separate genetically engineered Escherichia coli lines as intracellular, insoluble inclusion bodies. Following steps that lead to the release of free alpha and beta polypeptide chains and to refolding of the chains into the correct protein structure, the correctly folded protein is purified, formulated, and stored at or below -60 °C. There is no reprocessing of the drug substance.

The drug product is essentially the same as the tebentafusp drug substance in its formulation composition. Hence, the drug product manufacturing process consists of pooling and homogenization, sterile filtration, and filling into glass vials.

The control strategy of the manufacturing process involves control of materials, in-process controls of product quality attributes, control of process parameters, release and stability specifications, and facility and equipment controls. Appropriate process parameters have been implemented and critical process parameters have been identified. This multi-level control strategy, as part of the overall process performance and product quality monitoring system, assures consistent manufacture of acceptable product and mitigates risk of failures in process performance.

Process validation data provided from consecutive drug substance and drug product batches manufactured at the commercial scale showed consistent process performance attributes and consistent product quality profiles across the process validation batches. All predefined limits and acceptance criteria for process parameters and controls were met, and all results for release and stability testing were within specifications. The data support the conclusion that the manufacturing process is well controlled and able to consistently yield a drug substance and drug product of acceptable quality.

Control of the Drug Substance and Drug Product

The release and stability specifications for the drug substance and drug product include assays for identity, quantity, biological activity, purity, impurities, and safety, and compendial requirements. All release and stability acceptance criteria were met for the drug substance and drug product batches manufactured thus far, and data were consistent across all batches. The in-house analytical methods were appropriately validated in accordance with relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The methods are considered suitable for their intended use. Additionally, the process, release, and stability data support the release and stability specifications for the critical quality attributes of the drug substance and drug product. Of note, in response to a request by Health Canada, the drug substance and drug product specifications were aligned with those approved by the United States Food and Drug Administration (FDA).

A two-tiered reference standard system was developed for the control of the drug substance in accordance with ICH guidelines. The reference standards were well characterized and an appropriate program is in place to qualify future primary and working reference material.

A risk assessment was conducted for the presence of nitrosamine impurities. The nitrosamine risk assessment showed that the risk of formation or introduction of nitrosamine impurities in the current manufacturing processes of the drug substance and drug product is negligible.

Kimmtrak 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 to be satisfactory.

The proposed shelf life of 36 months for Kimmtrak, when stored at 2 °C to 8 °C and protected from light, is considered acceptable. Kimmtrak must not be frozen or shaken.

The in-use storage time for the prepared Kimmtrak infusion bag is up to 4 hours at room temperature (15 °C to 30 °C) from the time of preparation, including the duration of the infusion. If not used immediately, the Kimmtrak infusion bag must be stored in a refrigerator at 2 °C to 8 °C and used within 24 hours from the time of preparation, which includes the storage time in the refrigerator, the time allowed for equilibration of the infusion bag to room temperature, and the duration of the infusion.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria. The proposed packaging and components are considered acceptable.

Facilities and Equipment

While recommended as per a risk assessment score determined by Health Canada, an on-site evaluation of the drug substance manufacturing facility could not be conducted due to the coronavirus disease (COVID-19) pandemic travel restrictions. Therefore, the suitability of the drug substance manufacturing facility was evaluated by reviewing the pre-license inspection documentation provided by the FDA. This documentation was considered sufficient to support the final quality review recommendation.

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 Kimmtrak incorporates adequate control measures to prevent contamination and maintain microbial control.

Bioburden and endotoxin contamination are controlled through the manufacturing process design and appropriate in-process testing. In addition, bioburden, endotoxin levels, and sterility are evaluated as part of routine release testing.

The use of prokaryotic expression systems pose negligible risks of propagating and transmitting viruses to patients from the final product; therefore, no viral inactivation and removal steps are included in the manufacturing process of tebentafusp. However, bacteriophage (a type of virus that specifically infects bacteria) contamination presents a risk to the manufacturing process and, indirectly, a risk for patients, as it could result in product supply issues. During the review, it was noted that although the master cell banks, working cell banks, end-of-production cell banks and cells at the limit of in vitro cell age used for production were tested for bacteriophage contamination and were shown to be microbiologically pure and free of bacteriophages, there was no control strategy for monitoring bacteriophage contamination in the routine cultures. Therefore, the sponsor was requested to monitor free and lysogenic bacteriophages in the next three commercial batches of tebentafusp alpha and beta chain cultures, and commit to submitting to Health Canada the finalized report of the monitoring results, along with any updates of the control strategy for bacteriophage monitoring.

No raw materials of human or animal origin are used in the manufacturing of tebentafusp. Relevant statements were provided to establish that contact materials do not pose a risk of contamination with bovine spongiform encephalopathy or transmissible spongiform encephalopathy agents. The excipients used in the drug product formulation are not of animal or human origin.

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