Summary Basis of Decision for Tzield

Clinical Pharmacology

Teplizumab, the medicinal ingredient in Tzield, binds to cluster of differentiation 3 (CD3; a cell surface antigen present on T lymphocytes) and delays the onset of Stage 3 type 1 diabetes in adult and pediatric patients 8 years of age and older with Stage 2 type 1 diabetes. The mechanism of action may involve partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T lymphocytes. Teplizumab leads to an increase in the proportion of regulatory T cells and of exhausted cluster of differentiation 8 (CD8)-positive T cells in peripheral blood.

Trough serum concentrations of teplizumab at baseline and at days 10, 11 and 13 were determined in 42 patients who received the full 14-day regimen in Study TN-10, the pivotal study described in the Clinical Efficacy section. Pharmacokinetic parameters were estimated by population pharmacokinetic modelling analysis. During the 14-day course of treatment with teplizumab, the total lymphocyte count (pharmacodynamic parameter) started to decrease after the first dose, with a nadir on the 5th day of dosing, and fully recovered by Week 6. Anti-drug antibodies were detected in 72% of patients 8 years to less than 18 years of age and in 33% of patients 18 years of age and older. There was insufficient data to assess the impact of anti-drug antibodies on the pharmacokinetics, efficacy, and safety of teplizumab for the indication sought.

Tzield is not bioequivalent to the drug product that was used in Study TN-10. A pharmacokinetic bridging study (Study 31-004) showed about 50% lower exposure (as measured by the area under the concentration-time curve extrapolated to infinity [AUC_inf]) for Tzield compared to the study drug product. The difference was found to be smaller, i.e., 27% lower exposure (AUC_inf), in a pharmacokinetic/pharmacodynamic sub-study of Study PRV-031-001 conducted in patients with newly diagnosed type 1 diabetes. To match the exposure of the study drug product, the total dose of Tzield was adjusted from the 9 mg/m² that was used in Study TN-10 to approximately 11 mg/m² using population pharmacokinetic modelling and a simulation approach. This adjusted dose of Tzield was predicted to have a similar safety and efficacy profile to that observed in Study TN-10. Using a simulation-based dose regimen is justified by the fact that it is scientifically unnecessary and ethically inappropriate to conduct an additional study due to the special patient population being targeted by this drug product, and because the recommended matching pharmacokinetics using an adjusted dosage regimen is expected to ensure a similar exposure achieved between Tzield and the study drug product. The slightly higher dose of Tzield is expected to compensate for uncertainties in the clinical response related to differences in exposure between the Tzield and the study drug product.

Overall, the clinical pharmacology data support the use of Tzield for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Tzield was assessed in Study TN-10, a pivotal, Phase II, multicentre, double-blind, randomized, placebo-controlled study in 76 patients aged 8 years and older with Stage 2 type 1 diabetes. Stage 2 type 1 diabetes was defined as having dysglycemia on an oral glucose tolerance testing and two or more pancreatic islet autoantibodies (glutamic acid decarboxylase 65 autoantibodies, insulin autoantibody, insulinoma-associated antigen 2 autoantibody, zinc transporter 8 autoantibody, or islet cell autoantibody) on two tests, the most recent of which being less than 6 months prior to study entry.

Patients were randomized to receive Tzield (44 patients) or placebo (32 patients) by intravenous infusion for 14 days with a dose escalation. Dosing was based on body surface area. The Day 1 dose was 51 mcg/m²; the Day 2 dose was103 mcg/m²; the Day 3 dose was 207 mcg/m²; the Day 4 dose was 413 mcg/m²; and the dose from days 5 to 14 was 826 mcg/m². Of note, the doses in Study TN-10 were lower than those proposed in the Product Monograph for Tzield as the study used a different formulation of the drug product that was shown to have a higher bioavailability compared to Tzield. The recommended dose regimen for Tzield includes the same dose escalation scheme, but at doses ranging from 65 mcg/m² to 1,030 mcg/m².

In terms of patient demographics, 55.3% were male, 97.4% were White, 94.7% were from sites in the United States, and the mean age was 19 years (range 8.5 to 49.5 years, with 72% being under 18 years of age).

The primary efficacy endpoint in Study TN-10 was the time from randomization to the development of Stage 3 type 1 diabetes. As a time-to-event study, the duration of follow-up varied across the population based on the time from enrollment to the time when the target number of 40 Stage 3 type 1 diabetes diagnosis events was reached. Median follow-up duration was 27.5 months in the Tzield arm and 17.8 months in the placebo arm. At data cutoff, 43 patients had received a Stage 3 type 1 diabetes diagnosis, including 20 (45%) patients in the Tzield arm and 23 (72%) patients in the placebo arm. After adjustment for baseline imbalances in two autoantibodies with the potential to have affected the results, time from randomization to Stage 3 type 1 diabetes diagnosis was 50 months in the Tzield arm and 26 months in the placebo arm, for an estimated delay in time to diagnosis of 24 months and a hazard ratio of 0.48 (95% confidence interval: 0.25, 0.95). Supportive evidence was provided by maintenance or increases from baseline of C-peptide in the Tzield arm compared to decreases from baseline in the placebo arm, which indicated a potentially greater preservation of beta cell function in patients treated with Tzield.

Indication

The New Drug Submission for Tzield was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Tzield (teplizumab) is indicated:

• to delay the onset of Stage 3 type 1 diabetes in adult and pediatric patients 8 years of age and older with Stage 2 type 1 diabetes.

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

Clinical Safety

The clinical safety of Tzield was characterized in randomized controlled studies, which included the pivotal Study TN-10 described in the Clinical Efficacy section, and multiple studies in patients with newly diagnosed Stage 3 type 1 diabetes. Data from 1,018 patients who participated in five of these studies were pooled into a safety database. In total, 791 of these patients had received Tzield.

The most common treatment-emergent adverse events in patients treated with Tzield were lymphopenia (79.9% Tzield versus [vs] 46.9% controls), leukopenia (63.3% Tzield vs 21.6% controls), neutropenia (39.6% Tzield vs 21.6% controls), and rash (34.5% Tzield vs 10.2% controls). Treatment-emergent adverse events leading to withdrawal of study treatment were observed in 14.3% of patients treated with Tzield compared with 3.7% of patients treated with controls. More than 50% of these events were due to laboratory abnormalities (mainly increased alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) and were stipulated as discontinuation criteria in the study protocols. Laboratory-related adverse events of increased ALT and AST generally occurred during the first week of dosing and were slightly more frequent in the Tzield group compared to the control groups (ALT [26.5% Tzield vs 22.5% controls] and AST [28.1% Tzield vs 20.4% controls]). These increases were likely due to cytokine effects on the liver and typically resolved by the end of the treatment course.

Treatment-emergent serious adverse events were reported in 12.4% of patients treated with Tzield compared to 8.2% of patients treated with controls. The most common treatment-emergent serious adverse events reported in at least 2.0% of patients were related to metabolic disorders (e.g., diabetic ketoacidosis, hyperglycemia, hypoglycemia [4.2% Tzield vs 2.0% controls]) and infections (mainly gastroenteritis [3.5% Tzield vs 2.0% controls]).

Comparable rates of infections were reported between groups (53.0% Tzield vs 52.7% controls) with the most commonly reported infections being upper respiratory infections (19.0% Tzield vs 17.6% controls), nasopharyngitis (11.1% Tzield vs 9.4% controls), and pharyngitis (5.1% Tzield vs 4.5% controls). The rate of primary Epstein-Barr virus infections does not appear to be increased with Tzield (1.9% Tzield vs 3.6% controls). While there were more cases of Epstein-Barr virus reactivation with Tzield (3.9% Tzield vs 1.2% controls), the majority of patients were asymptomatic and the cases were associated with transient viremia.

Cytokine release syndrome was reported in 5.8% of patients who received Tzield and in 1.2% of patients who received controls. In patients who received Tzield, approximately 90% of cases of cytokine release syndrome were mild to moderate in severity, with 80% these of patients completing the treatment course.

Uncertainty remains regarding the potential impact of patient characteristics (e.g., age, autoantibody profile, race, etc.) as this could not be adequately assessed in the pivotal study due to the small sample size (76 patients).

Appropriate warnings and precautions are in place in the approved Product Monograph for Tzield to address the identified safety concerns, including risk mitigation strategies such as appropriate patient selection, premedication, laboratory monitoring, and discontinuation guidance.

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

The sponsor demonstrated that teplizumab cross-reactivity with cluster of differentiation 3 (CD3)-positive T cells is limited to humans, chimpanzees, gorillas, and other species that are not established experimental species. Therefore, the non-clinical data was limited to a single study in chimpanzees and repeat-dose and reproductive and developmental toxicity studies using a surrogate antibody-targeting mouse CD3. The relevance of the surrogate antibody-targeting mouse CD3 was established through in vitro studies showing similar dissociation constants for the respective antigens, with variation in on-rates and off-rates.

In a primary pharmacodynamic study in non-obese diabetic mice aged 9 to 13 weeks with insulin autoantibodies, the overall incidence of type 1 diabetes progression was reduced from 64% to 30% following a 5-day dosing regimen with the surrogate antibody. Additionally, a delayed onset by approximately 5 weeks was observed compared to the control group when evaluated at 31 weeks of age.

Potential risks that were identified in the non-clinical studies included an increased incidence of post-implantation loss and complete litter loss following exposure to the surrogate antibody; immunological effects, including a reduced immunological response in weaned offspring; and the potential for transfer of teplizumab to breast milk following administration during lactation or following gestational exposure. These risks were captured appropriately in the Product Monograph for Tzield.

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

Characterization of the Drug Substance

Teplizumab is a recombinant humanized immunoglobulin G1 (IgG1) kappa subclass monoclonal antibody which binds to the cluster of differentiation 3 (CD3)ε chain of the T cell receptor (TCR) complex on human T lymphocytes. Binding of teplizumab to the TCR-CD3 complex elicits partial activation of T cells, which leads to deactivation (anergy) and functional exhaustion, eventually leading to the removal of the autoreactive T cells responsible for beta cell destruction, while simultaneously enabling regulatory T cells to restore immune tolerance.

The drug substance was well characterized in terms of primary and higher order structure, carbohydrate and disulfide structure, mass, size and charge heterogeneity, and biological function.

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

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

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

The drug substance is produced in Chinese hamster ovary (CHO) cells using a single-use production bioreactor. The upstream manufacturing process is followed by downstream purification using affinity capture chromatography, low pH viral inactivation and neutralization, anion exchange chromatography, nanofiltration, ultrafiltration/diafiltration, and finally formulation of the bulk drug substance. The drug substance is then frozen and stored.

The Tzield drug product manufacturing process consists of drug substance thawing, pooling, final formulation, bioburden reduction, sterile filtration, aseptic filling, visual inspection, packaging, and storage. No major changes were implemented for the drug product manufacturing process during development.

The drug substance and drug product manufacturing processes were validated. During validation, all process parameters, in-process controls, release testing results, characterization results, and stability results met the pre-defined acceptance criteria. The impurity clearance was successfully demonstrated, and all hold times, sterile filtration and aseptic processes and shipping were successfully validated. These validations demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Release and stability specifications and in-process controls ensure the consistent and reproducible production of the drug substance and the drug product. A two-tier reference standard program has been established, and the in-house analytical methods were appropriately validated.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

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

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life is acceptable when Tzield is stored between 2 °C to 8 °C and protected from light.

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

The design, operations, and controls of all facilities and equipment involved in the production are considered suitable.

An on-site evaluation of the facility involved in the manufacture and testing of the drug substance was not warranted since the facility was recently evaluated and obtained a satisfactory rating. Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.

Adventitious Agents Safety Evaluation

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

The excipients used in the drug product formulation are not of animal or human origin.