Regulatory Decision Summary for Avtozma

The purpose of this submission is to seek market authorization for Avtozma (tocilizumab, CT-P47), a proposed biosimilar to Actemra which has been on the Canadian market since 2010.

Avtozma (tocilizumab) is a proposed biosimilar biologic drug to the Canadian Reference Biologic Drug (CRBD) Actemra. The Sponsor sought all indications and presentations as for the CRBD on the basis of biosimilarity.

The main clinical studies submitted in the dossier were two Phase 1 comparative bioavailability studies performed in healthy subjects (Studies CT-P47 1.1 and CT-P47 1.2) and a Phase 3 study performed in patients with moderate to severe rheumatoid arthritis (RA; Study CT-P47 3.1). In all clinical studies, EU-RoActemra was nominated as the reference biologic drug. 

Study CT-P47 1.1 was a Phase 1, randomized, double-blind, two-arm, parallel group, single-dose study to compare the pharmacokinetics and safety of two subcutaneous injection formulations of tocilizumab (CT-P47 and EU-RoActemra) in healthy subjects. Each subject received a single 162 mg dose in a 1:1 ratio by subcutaneous injection of either CT-P47 or EU-RoActemra. Study CT-P47 1.2 was a Phase 1, randomized, double-blind, three-arm, parallel group, single-dose study to compare the pharmacokinetics and safety of three intravenous infusion formulations of tocilizumab (CT-P47, EU-RoActemra, and US-licensed Actemra) in healthy subjects. Each subject received a single 8 mg/kg dose in a 1:1:1 ratio by intravenous infusion of either CT-P47, EU-RoActemra, and US-licensed Actemra.

Taken together, the comparative bioavailability studies demonstrated pharmacokinetic (PK) comparability between Avtozma and EU-RoActemra; the point estimate for Avtozma and EU-RoActemra geometric least square mean ratio for the maximum concentration (C_max) and the 90% confidence intervals (CI) for the area under the concentration versus time curve to the time of the last quantifiable concentration (AUC_0-last) were within the comparability margins of 80.0% to 125.0%.

Study CT-P47 3.1 was a randomized, active-controlled, double-blind study to compare efficacy, pharmacokinetics, safety and immunogenicity of IV formulation (8 mg/kg) of CT-P47 to EU-RoActemra when co-administered with methotrexate (MTX) in patients with moderate to severe RA up to 52 weeks. The primary efficacy endpoint was the mean change in baseline in Disease Activity Score using 28 joint counts (Erythrocyte-Sedimentation Rate), abbreviated to DAS28 (ESR) at Week 12. The 95% CI of the treatment difference between CT-P47 and EU-RoActemra was contained within the equivalence margin of -0.6 to +0.6. No imbalance in safety profile was observed between CT-P47 and EU-RoActemra and consistent C_trough exposures were observed following multiple dosing. No consistent imbalances in immunogenicity were observed between CT-P47 and EU-RoActemra.

Overall, the pharmacokinetic, efficacy, and safety results evaluated as part of this submission provide sufficient clinical support for the establishment of biosimilarity between Avtozma and the CRBD Actemra.

The Risk Management Plan (RMP) Canadian Specific Addendum (CSA) version 1.0 (dated 19 February 2024) and EU-RMP version 1.0 (dated 23 January 2024) were submitted as part of this New Drug Submission (NDS). Based on the information provided, the Avtozma CSA RMP and EU-RMP, which align with the latest Actemra EU-RMP, were found satisfactory by the Marketed Health Product Directorate (MHPD).

The chemistry and manufacturing information submitted for Avtozma has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

The labelling material submitted met all applicable regulations and guidance.

Therefore, a Notice of Compliance (NOC) was recommended.

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