Summary Basis of Decision for Eydenzelt

Eydenzelt was developed as a biosimilar of the reference biologic drug, Eylea. The weight of evidence of similarity between a biosimilar and the reference biologic drug is provided by structural and functional studies. Biosimilars are manufactured to the same regulatory standards as other biologic drugs. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity to the reference biologic drug.

As the review of the New Drug Submission (NDS) was nearing completion, a major quality issue was identified concerning insufficient controls for the prefilled syringe (PFS) presentation to ensure product sterility during manufacture and shipping, including consistent stopper positioning and bent stoppers. Furthermore, a large number of minor quality concerns were identified. Accordingly, Health Canada issued a Notice of Deficiency (NOD) for the NDS on October 31, 2024. The sponsor filed a response to the NOD on December 18, 2024. To address the major objection, the sponsor proposed changing the manufacturing and assembly sites for the PFS presentation and implemented an enhanced control strategy to ensure correct stopper positioning. Additional quality changes were implemented to address minor quality concerns. Upon review of the submitted information, Health Canada issued a Notice of Compliance for Eydenzelt.

Comparative Structural and Functional Studies

The biosimilarity evaluation was conducted as a pairwise analytical assessment using Eydenzelt and Eylea authorized in the European Union (EU-Eylea). Health Canada considers EU-Eylea a suitable proxy for Eylea authorized in Canada, as it meets all of the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

The similarity assessment is based on data from an extensive range of qualified analytical methods to compare the protein content, sequence, higher order structure, glycans, charge and size variants, post-translational modifications, potency, target binding, and thermal stability and degradation profiles for Eydenzelt and the reference biologic product using side-by-side and independent testing evaluated throughout the shelf-life of the products. Multiple lots of Eydenzelt were included in the assessments, representing both clinical and commercial material, and were compared against EU-Eylea lots.

The studies conducted established a high degree of similarity in the primary, secondary and tertiary structure, as well as the purity, biological activity, stability, and forced degradation profiles of the medicinal ingredients in the biosimilar and its reference biologic drug. Some minor analytical differences in biochemical attributes were observed, however, overall, the provided data support that the products are similar, and the observed differences were not clinically meaningful, and are not expected to impact safety or efficacy. Taken together, these studies suggest a high degree of similarity between Eydenzelt and Eylea.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that aflibercept (the medicinal ingredient in Eydenzelt) consistently exhibits the desired characteristic structure and biological activity.

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 and acceptable limits. 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).

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

The drug substance is manufactured using recombinant deoxyribonucleic acid technology in a mammalian cell expression system (Chinese hamster ovary cells). The manufacture is based on a master and working cell bank (WCB) system, where the master and WCBs have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of the drug substance begins with the thawing of a single WCB vial followed by cell expansion to inoculate a production bioreactor that uses a fed-batch process. The harvested cell culture fluid is purified through a series of chromatography steps, viral inactivation and filtration, ultrafiltration/diafiltration, polysorbate addition, and final filtration prior to filling into bottles. It is then stored frozen. The drug substance is thawed in a controlled temperature thawing room prior to shipment at 2 to 8 °C to the drug product manufacturing facilities.

The vial and prefilled syringes (PFS) presentations of the drug product are manufactured at different facilities, however, the manufacturing processes consist of the same basic steps. For both presentations, the manufacturing process starts with drug substance pooling and mixing followed by bioburden and sterile filtration, aseptic filling, inspection, and storage. The PFS process requires additional assembly steps, sealing into blister packs, and sterilization of the external syringe surface, with shipping to the assembly and sterilization sites.

The drug product is supplied in a glass vial or a PFS as a clear to slightly opalescent and colourless to very pale brownish-yellow, sterile, single-dose, preservative-free solution intended for intravitreal administration. Both presentations are formulated to contain aflibercept, L-histidine, L-histidine monohydrochloride, sodium chloride, trehalose, and polysorbate 20 at pH 6.2 in a deliverable volume of 0.05 mL (50 µL) of solution. The vial presentation is provided as a kit that also contains a filter needle (5 µm) for use in administration of the product, and the PFS is packaged into a thermoformed blister tray. 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 aflibercept with the excipients is supported by the stability data provided.

Process validation was conducted with the manufacture at the commercial scale of several drug substance batches and several batches of both the vial and PFS drug product presentations. All process parameters and in-process controls met their respective predefined operating ranges and acceptance criteria or action limits. Batch release data were consistent between process validation batches and were within the release specification limits. Data from ancillary validation studies (in-process hold times, impurity clearance, resin and membrane lifetimes, filters, extractables and leachables testing, sterility assurance, filling, shipping, and other supporting activities and equipment) also support the consistent manufacture of Eydenzelt drug substance and drug products. Together, the process validation data demonstrate that the commercial-scale manufacturing processes are capable of consistently producing drug substance and drug product batches that meet the predefined specifications.

The materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. The in-process controls and specification testing for the drug substance and drug product were established and appropriately justified based on a comprehensive set of data, including: manufacturing experience, product characterization, non-clinical and clinical experience, product and process knowledge, analytical method performance, acceptable safety levels, and international guidelines and pharmacopoeia. These controls ensure the safety, identity, strength, potency, and purity of the drug substance. The in-house analytical methods were validated and in compliance with ICH guidelines and compendial methods complied with pharmacopeial standards.

During review of the submission, unresolved deficiencies were identified for the PFS presentation that were related to stopper positions and bent ribs of stoppers. In summary, the control strategies in place at the initially proposed PFS drug product manufacturing and assembly sites were not sufficient to ensure the quality and safety of each PFS released to the Canadian market, and a Notice of Deficiency (NOD) was issued. In response to the NOD, the sponsor transferred the manufacturing processes for the unassembled and assembled and blistered PFS to new sites, and implemented an enhanced control strategy to address the major objection of the NOD; i.e., inconsistent stopper positioning. The enhanced control strategy was developed in accordance with ICH Q8 (R2) and consists of established ranges for process inputs (parameters) and outputs (in-process tests), as well as in-process stopper position checks at three points throughout syringe manufacture and assembly to ensure that stoppers are correctly positioned to maintain sterility throughout manufacture and shipping procedures.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

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

Stability of the Drug Substance and Drug Product

Given the recency of the change in manufacturing sites, limited stability data were available for the PFS drug product manufactured at the proposed facilities. However, comparability to PFS lots manufactured at the original site was suitably demonstrated and the previously reviewed stability data were leveraged and support the proposed shelf life. Based on the stability and comparability data submitted, the proposed shelf life and storage conditions for the drug substance and both drug product presentations were adequately supported and are considered to be satisfactory. The proposed shelf life of 24 months when stored at 2 to 8 °C, with up to 24 hours at room temperature (23 to 27 °C), is considered acceptable for the vial presentation of the drug product. The proposed shelf life of 18 months when stored at 2 to 8 °C, with up to 24 hours at room temperature (23 to 27 °C), is considered acceptable for the prefilled syringe presentation of the drug product.

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 facilities involved in the manufacture and testing of the drug substance was deemed not feasible and a virtual assessment of the facilities was considered. During the course of the review, no major issues were identified which could have been addressed via a virtual assessment and it was determined that the submission contained sufficient detail to support the drug substance manufacturing site. Therefore, a virtual assessment was not conducted.

Based on a risk assessment score determined by Health Canada, on-site evaluations of the drug product manufacturing facilities were not deemed necessary.

All sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The aflibercept manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure 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. Viral clearance studies, as per ICH Q5A, support the clearance capacity of the process.

Raw materials of animal and recombinant deoxyribonucleic acid origin used in the manufacturing process are adequately tested to ensure absence of adventitious agents. The biologic raw materials used during drug substance and drug product production originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens and are compliant with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3). Fetal bovine serum, which was used during cell bank development, is compliant with the European Pharmacopoeia general chapter 1483, Products with risk of transmitting agents of animal spongiform encephalopathies. In addition, applicable Certificates of Origin and Certificates of Suitability were provided that support the safety of these materials. The excipients used in the drug product formulation are not of animal or human origin.

For biosimilars, the degree of similarity to the reference biologic drug at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty. According to the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs, where similarity is well established by structural and functional studies, and where extensive in vitro mechanistic studies are indicative of similarity, non-clinical in vivo studies may not be necessary.

The results from the analytical similarity assessment (see Comparative Structural and Functional Studies) demonstrated a high degree of similarity between Eydenzelt and Eylea. There were no residual uncertainties identified that needed to be resolved by additional comparative non-clinical in vivo pharmacodynamic, pharmacokinetic, and toxicology studies.

Data from one 12-week repeat-dose study in cynomolgus monkeys were included in the submission. In this study, male and female monkeys were administered 2 mg/eye of Eydenzelt or Eylea (the reference drug product) by intravitreal injection every 4 weeks. Each single dose was considered to be representative of an estimated two-fold increase in the intended clinical dose based on species differences in vitreous volume.

No toxicologically significant findings were noted in either treatment group, and no distinct toxicities were observed in the Eydenzelt or Eylea groups. At the end of the study period, mean plasma concentrations in the Eydenzelt group were approximately 60% higher than those in the Eylea group. Furthermore, males had an approximately 40% higher exposure compared to females within their respective treatment groups. Notable differences in vitreous humour concentrations and associated vitreous humour to plasma concentration ratios were observed when comparing males and females and between the Eydenzelt and Eylea groups. Potential differences in toxicokinetics remain uncertain due to low animal numbers and high sample variability. Consistent with Health Canada guidance on the assessment of biosimilars, in vivo studies to evaluate biosimilarity are generally not required. As such, the submitted study is considered only supportive in nature.

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

The purpose of the clinical program for a biosimilar is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the biologic drug and availability of a relevant and sensitive pharmacodynamic endpoint determine the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacokinetics and Pharmacodynamics

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of proangiogenic factors. These factors act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. Vascular endothelial growth factor acts via two receptor tyrosine kinases, VEGF receptor 1 and 2 (VEGFR-1 and VEGFR-2), which are present on the surface of endothelial cells. Placental growth factor binds only to VEGFR-1, which is also present on the surface of leukocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularization and excessive vascular permeability. This is believed to contribute to vision loss in a variety of ocular diseases.

Aflibercept (the medicinal ingredient in Eydenzelt) acts as a soluble decoy receptor that binds VEGF-A and PlGF with higher affinity than their natural receptors. In doing so, it can inhibit the binding and activation of these cognate VEGF receptors.

Pharmacokinetic data were collected from a subset of patients who participated in the pivotal comparative clinical Phase III Study CT-P42 3.1 (described in the Comparative Clinical Efficacy, Safety, and Immunogenicity section below). In total, 23 (6.6%) patients with diabetic macular edema (11 from the Eydenzelt arm and 12 from the Eylea arm) provided data for assessment of systemic exposure (i.e., free aflibercept). Plasma concentrations of free aflibercept from Eydenzelt and Eylea treatment arms were measured at Week 0 and Week 16 for peak concentrations (C_max) following monthly intravitreal injections dosed at 2 mg/0.05 mL. Overall, the plasma level of aflibercept was low following intravitreal administration and no significant differences in systemic exposure of aflibercept were observed between Eydenzelt and the reference product Eylea.

Comparative Clinical Efficacy, Safety, and Immunogenicity

In the Phase III, randomized, double-masked, parallel-group, multicentre Study 3.1, the comparative clinical efficacy, safety, immunogenicity, and pharmacokinetics of Eydenzelt against its reference biologic, Eylea, were evaluated in patients with diabetic macular edema (DME). As per the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs, a biosimilar need only be tested in one of the authorized indications of the reference biologic drug, provided adequate justification for extrapolation of the indication is provided. In total, 348 adult patients with DME were randomized in a 1:1 ratio to treatment with Eydenzelt or Eylea. Treatment (2 mg [0.05 mL solution]) was administered by intravitreal injection at Week 0, followed by every 4 weeks for 5 doses, and every 8 weeks thereafter, as per the labelled posology for Eylea in DME patients. The study was ongoing at the time that the submission was filed.

The enrolled patients had a mean age of 62.7 years (range: 25 to 86 years), 58.3% were male, 41.7% were female, 64.4% were White, and 35.6% were Asian. The majority of patients (93.1%) had type 2 diabetes mellitus. Baseline hemoglobin A1c (HbA1c) was 8% or lower for 65.8% of patients and over 8% for 33.6% of patients. The mean duration of diabetes mellitus was 13.8 years while the mean duration of DME was 0.72 years. At baseline, 75.6% of patients had bilateral DME. The majority of patients (91.1%) had not received any prior treatment for DME in the study eye. A small proportion (8.6%) had undergone laser photocoagulation, and 1.1% had received prior medications.

The primary endpoint was therapeutic equivalence of Eydenzelt to Eylea in the change in best-corrected visual acuity (BCVA) from baseline to Week 8, as assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score. This instrument measures the ability of the eye to distinguish the details and shapes of objects (the clarity or sharpness of vision) at a given distance.

In all, 348 randomized patients were treated with study drug (173 with Eydenzelt and 175 with Eylea) and 335 patients (96.3%) completed treatment up to Week 24 (168 [97.1%] in the Eydenzelt arm and 167 [95.4%] in the Eylea arm). Thirteen patients discontinued the study. The most common reasons were withdrawal by patient (2 patients in the Eydenzelt arm and 3 patients in the Eylea arm) and adverse events (2 patients in each arm).

Therapeutic equivalence for the primary endpoint of change from baseline at Week 8 in BCVA 8 was achieved. The change from baseline at Week 8 was a least squares (LS) mean of +9.43 letters for Eydenzelt (total number [n] = 169) and +8.85 letters for Eylea (n = 172), for an estimated treatment difference of +0.58 and a 90% confidence interval (CI) of -0.52 to +1.67. Therefore, the criterion for therapeutic equivalence of the 90% CI being within the equivalence margin of ±3 letters was achieved. Sensitivity analyses for the primary endpoint and secondary ocular endpoints (e.g., gain/loss of thresholds, BCVA, and central subfield thickness at Week 24) showed a consistent similarity between Eydenzelt and Eylea.

After 24 weeks of treatment, the safety profiles associated with Eydenzelt and Eylea treatment were similar, with no clinically meaningful differences in systemic/non-ocular or ocular safety endpoints patients in either group. Patients had received a mean of 5.8 (of 6 possible) injections, and 93% of patients remained in the study after the Week 24 data cut-off for this submission. There were no observed imbalances between treatment arms in ocular treatment-emergent adverse effects in the study eye or fellow eye, or in non-ocular safety profile. There were no safety signals associated with Eydenzelt alone. An assessment of safety endpoints known to be associated with the use of aflibercept (i.e., intraocular pressure, arterial thromboembolic events, and adverse events associated with intravitreal injection) demonstrated a similar or slightly better profile with Eydenzelt compared to Eylea. There were no notable differences in slit lamp exam or indirect ophthalmoscopy between treatment arms.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). An immunogenicity assessment of Eydenzelt was conducted as part of Study 3.1 using validated assays for ADAs and neutralizing antibodies (NAbs). Blood samples were collected prior to administration of the study drug at Week 0 (Day 1), 8, 16, 24, and 52 (end-of-study), or when immune-related adverse events occurred. Immunogenicity was evaluated based on the safety set for the main study period, defined as all randomly assigned patients who received at least one dose (full or partial) of study drug (Eydenzelt or Eylea) in the main study period.

The proportion of patients who had at least one ADA-positive result after the first administration of study drug was the same (3 [1.7%] patients) in each treatment group. For both groups, the majority of the detected ADAs were generally of low titer over the study period. The proportion of patients who had at least one NAb-positive result after drug exposure was similar (2 [1.2%] Eydenzelt patients and 1 [0.6%] Eylea patient). There were too few ADA-positive patients in either arm to assess the impact of immunogenicity on safety or efficacy.

The pivotal clinical study indicated that there were no clinically meaningful differences between the biosimilar and the reference biologic drug. Given that aflibercept has the same mechanism of action and safety profile across all the different target diseases, the extrapolation of these data to the other indications authorized for Eylea is acceptable. Overall, the safety profile of Eydenzelt is considered to be comparable to that which has been established for the reference biologic drug Eylea. The identified safety concerns are appropriately addressed in the Product Monograph for Eydenzelt, as they are in the Product Monograph for Eylea.

Indications

Similarity between Eydenzelt and Eylea was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. The sponsor requested the authorization of Eydenzelt for all of the indications that were authorized for Eylea at the time the New Drug Submission was filed. The demonstration of similarity between a proposed biosimilar and its reference biologic drug enables the sponsor's submission for the proposed biosimilar to rely on the safety and efficacy information already generated for the reference biologic drug, and therefore, clinical trials are not required to support each of the sought indications. An acceptable scientific rationale was provided by the sponsor for requesting the authorization of indications that were not directly studied in the clinical development program for Eydenzelt. The rationale noted that the submission package provided adequate evidence of comparability of Eylea and Eydenzelt as far as quality, non-clinical, pharmacokinetics, immunogenicity, efficacy, and safety profiles in one of the indicated conditions. They further provided a summary of previously-established similarities for pharmacokinetics, safety, and immunogenicity profiles for aflibercept across the authorized indications.

Upon review of the evidence submitted, Eydenzelt was authorized for all of the indications held by Eylea at the time of authorization, namely, for the treatment of:

• neovascular (wet) age-related macular degeneration (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 (myopic CNV).