Regulatory Decision Summary for Enzeevu

The purpose of this new drug submission (NDS) is to seek market authorization for Afqlir/Enzeevu (aflibercept injection), a proposed biosimilar to the Canadian reference biologic drug Eylea, which has been authorized in Canada since 2012 (marketed by Bayer Inc).

During review, the Biologic and Radiopharmaceutical Drugs Directorate (BRDD) Labelling Division deemed that the original brand name “Afqlir” implied unique and superior effectiveness compared to other products in the class. As a result, the sponsor proposed “Enzeevu” as the brand name for the Canadian market, which was deemed acceptable.

The sponsor, Sandoz Canada Inc., is seeking all the adult indications for Enzeevu currently held by Eylea. These indications include treatment of neovascular age-related macular degeneration (wet AMD), visual impairment due to macular edema secondary to central retinal vein occlusion (CRVO), visual impairment due to macular edema secondary to branch retinal vein occlusion (BRVO), diabetic macular edema (DME), and myopic choroidal neovascularization (CNV).

Enzeevu (aflibercept injection) is a proposed biosimilar biologic drug to the Canadian Reference Biologic Drug (CRBD) Eylea. The sponsor sought all adult indications presentations currently held by the CRBD on the basis of biosimilarity.

The main clinical study submitted in the dossier was a Phase 3 study (Study CSOK583A12301) performed in adult patients with wet AMD. In this clinical trial, EU Eylea was nominated as the reference biologic drug. A Phase 1 comparative bioavailability study was not performed due to the invasiveness of the intravitreal injection. Instead, a subset of patients in the Phase 3 study was evaluated for pharmacokinetics.

Study CSOK583A12301 was a Phase 3, 52-week multicentre, randomized, double-masked, 2-arm parallel study designed to compare efficacy, safety and immunogenicity of Enzeevu to Eylea, in patients with AMD. The investigational products were administered by intravitreal injection at a 2 mg/0.05 mL dose. Subjects received either Enzeevu or Eylea once every 4 weeks at three subsequent visits (baseline, week 4 and week 8), thereafter once every 8 weeks until the last dose at Week 48. The primary efficacy endpoint was the change from baseline in best corrected visual area (BCVA) at Week 8. The 95% confidence interval (CI) of the difference in BCVA from baseline at Week 8 between Eylea and Enzeevu was contained within the equivalence margin of ± 3.5 letters.

A consistent safety profile was observed between Enzeevu and Eylea. Systemic pharmacokinetics were also consistent between Enzeevu and Eylea based on descriptive analyses in a limited number of patients. No consistent imbalances in immunogenicity were observed between Enzeevu and Eylea.

Two supportive human factor studies (CSOK583A12303 and CSOK583A12304) were also submitted in the dossier. Data from these studies support the safe use of the vial and PFS presentations in subjects with nAMD who had previously received IVT treatment with Eylea.

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

The Enzeevu EU-Risk Management Plan (RMP) v1.2 and the Canadian Addendum v1.0 were submitted to Health Canada as part of the Enzeevu New Drug Submission (NDS) (Control 290401). 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, having identified appropriate pharmacovigilance activities and risk minimization measures for Enzeevu, thereby aligning with the reference product, Eylea.

The chemistry and manufacturing information submitted for Enzeevu has demonstrated that the drug substance and drug products have been well characterized, are highly similar to the reference biological product (Eylea), and can be consistently manufactured to meet the approved specifications.

The labelling material submitted met all applicable regulations and guidance. 

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