Regulatory Decision Summary for Tzield (teplizumab)

This New Drug Submission (NDS) was filed to obtain market authorization for Tzield (teplizumab) for the delay of Stage 3 type 1 diabetes onset in patients aged 8 years and older with Stage 2 type 1 diabetes. The submission was filed under the Health Canada’s Priority Review Policy.

A pivotal, randomized, double-blind, placebo-controlled study (TN-10) of patients in Stage 2 type 1 diabetes aged 8 years or older was submitted to support the efficacy and safety of Tzield (teplizumab). In this trial, those assigned to Tzield (n = 44) had a delay to Stage 3 type 1 diabetes diagnosis of approximately 24 months compared to those that received placebo (n = 32). The safety of teplizumab was characterized by randomized controlled trials, including one main study in pre-symptomatic diabetic individuals (Stage 2) as described above, and in multiple studies in patients with newly diagnosed T1D (Stage 3). In total, data from 1,018 patients from five studies were pooled into a safety database and of these, 791 received teplizumab. Overall, the drug was well-tolerated. The most common adverse reactions were lymphopenia, rash, and leukopenia. Laboratory abnormalities leading to drug discontinuation included transaminase elevations, hematologic parameters (lymphopenia, neutropenia, anemia, and thrombocytopenia) and cytokine release syndrome. The above risks were described sufficiently in the Product Monograph with risk mitigation strategies including appropriate patient selection, premedication, laboratory monitoring, and discontinuation guidance.

The to-be-marketed drug product, manufactured by AGC Biologics, was not used in the pivotal trial TN-10 and was found not to be bioequivalent to the Eli Lilly manufactured drug product used in the pivotal Study TN-10. The dose regimen proposed, based on simulation results of a population PK modelling, is expected to compensate for the lower exposure associated with the to-be-marketed drug product (from AGC) compared with the drug product used in the pivotal trial (from Eli Lilly).

The non-clinical pharmacological effect of teplizumab was demonstrated using a surrogate antibody in a diabetic mouse model. Compared to the control group, the test article reduced the onset of type 1 diabetes from 64% to 33% and delayed onset by approximately 5 weeks when evaluated at 31 weeks of age. The surrogate antibody was associated with increased incidence of post-implantation loss and complete litter loss, and immunological effects including reduced adaptive immunological responses in weaned offspring of female mice dosed during gestation.

There is residual uncertainty due to the small sample size in the clinical trial (n = 76 total) and the potential impact of patient characteristics that were unable to be adequately assessed in the small sample set (e.g., impact of age, autoantibody profile, race, etc.).

Routine pharmacovigilance will be conducted by the sponsor and additional pharmacovigilance activities have also been proposed to further characterize the risks presented in the Risk Management Plan.

Overall, the benefit-risk profile was favourable for Tzield for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

The chemistry and manufacturing information submitted for Tzield has demonstrated that the drug substance and drug product have been well characterized and can be consistently manufactured to meet the approved specifications.

The Risk Management Plan (RMP) for Tzield (teplizumab) was submitted to Health Canada as part of the New Drug Submission (NDS; Control No. 289990). The RMP is designed to describe known and potential safety issues, to present the monitoring plan and, when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP is considered to be acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures for Tzield. This includes providing information in the product monograph and identifying populations and areas where more data are needed. Results related to the safety and effectiveness of Tzield from ongoing and planned studies will be submitted in Periodic Benefit Risk Evaluation Reports as they become available.

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