Summary Basis of Decision for Aflivu

Aflivu 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.

Comparative Structural and Functional Studies

The biosimilarity evaluation was conducted as a pairwise analytical assessment using Aflivu 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 results of the biosimilarity assessment demonstrate that Aflivu is identical to EU-Eylea with regards to primary structure. Aflivu is considered highly similar to EU-Eylea concerning higher order structure, purity, and biological activity. Differences were noted for some product-related variants, such as oxidation and deamidation, and for specific glycan populations at individual N-glycosylation sites. None of these differences impacted biological activity, as both products were highly similar regarding the main mechanisms of action of aflibercept. Comparative forced degradation studies using different stress conditions demonstrated similar degradation profiles for Aflivu and EU-Eylea, except for oxidative conditions. Oxidative forced degradation studies demonstrated different oxidative degradation rates for the two products. However, these differences do not affect biological activity, and oxidation is appropriately controlled as a product quality attribute. Together, the data support the assertion that Aflivu is similar to EU-Eylea and support the quality requirements for Aflivu to be considered a biosimilar to Eylea.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that aflibercept consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The identified and characterized impurities were found to be at levels that are either considered to have no impact on patient safety or are appropriately controlled.

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

The drug substance is manufactured using recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary cells. The drug substance manufacturing process consists of cell culture, expansion, harvest, virus inactivation, three-column purification, virus filtration, ultrafiltration/diafiltration, formulation, filtration, and storage.

Aflivu is supplied as a sterile, ready-to-use aqueous solution (40 mg/mL aflibercept) for intravitreal injection in a 3 mL glass vial or a 1 mL prefilled syringe. The drug product manufacturing process consists of drug substance thaw and dilution, sterile filtration, filling, visual inspection, packaging, and storage.

Process validation was conducted with consecutive drug substance and drug product batches manufactured at the intended commercial scale. Process performance qualification data demonstrates that the manufacturing process is capable of consistently manufacturing the drug substance and drug product. All process parameters, process attributes, release testing results, and stability results met pre-defined criteria, acceptance limits, and specifications for all validation lots. All process validation studies were deemed successful and supportive of hold times, impurity clearance, resin/membrane lifetimes, filters, extractables and leachables, sterility assurance, filling, shipping, and other supporting activities and equipment.

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

The control strategy implements controls at the most appropriate manufacturing unit operation to ensure consistency of the process and product quality across all stages of manufacturing. Overall, the drug substance and drug product manufacturing process is controlled by process parameters, in-process controls, and in-process tests with defined operating ranges, action limits, and acceptance criteria. The criticality of each parameter was appropriately defined. If the results are outside of the predefined criteria, an evaluation is performed, and the disposition decision is determined based on the outcome of the investigation. The quality of raw materials is compendial or according to in-house specifications to ensure identity, quality, and purity. Compendial raw materials comply with the quality requirements of the applicable compendial monographs.

All in-house analytical methods were appropriately validated. The reference standards have been well characterized, and an appropriate program is in place to qualify new primary and working reference material in the future. Each specification considers product characterization, criticality, historical release and stability batch data, manufacturing experience, process performance and validation data, and compendial requirements for protein-based products, where appropriate. All release and stability acceptance criteria were met for the drug substance and drug product.

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).

Aflivu 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

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 24-month shelf life at 2 ^oC to 8 ^oC for Aflivu is considered acceptable for both the vial and prefilled syringe presentation. Both presentations may be stored at room temperature for up to 24 hours.

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 and drug product has been successfully conducted by the Biologics and Radiopharmaceutical Drugs Directorate, Health Canada.

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 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.

No materials of human or animal origin are used in the drug substance or drug product manufacturing processes, except for a white colourant and polypropylene film of animal origin that is used in the drug substance container closure system. These two components have been confirmed to be in compliance 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), indicating that they are considered to be safe for human use.

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 Aflivu 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.

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 (VEGF)-A and placental growth factor (PlGF) are members of the VEGF family of pro-angiogenic factors. These factors can 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 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.

The pharmacokinetics of Aflivu was assessed in a subset of 44 patients (23 patients in the Aflivu group and 21 patients in the Eylea group) with neovascular (wet) age-related macular degeneration (AMD) from Study SCD411-CP101 (see Comparative Clinical Efficacy and Safety section for a description) following the first (Day 1) and the third (Week 8) intravitreal injection of 2 mg/0.05 mL. Of these 44 patients, 25 patients (13 in the Aflivu group and 12 in the Eylea group) had concentrations below the limit of detection (i.e., 20 ng/mL) at most time points. The mean maximum concentration (C_max) of free aflibercept in the plasma following the first and third dose ranged from 56 ng/mL to 82 ng/mL for Aflivu and from 45 ng/mL to 59 ng/mL for Eylea. Overall, the pharmacokinetic subset analysis demonstrated low systemic exposure of free aflibercept for both Aflivu and Eylea, consistent with the known systemic pharmacokinetic profile of aflibercept following intravitreal administration.

Comparative Clinical Efficacy and Safety

The clinical data to support the biosimilarity of Aflivu to Eylea were primarily derived from the results of Study SCD411-CP101, a Phase III, randomized, double-masked, parallel-group, multicentre study that compared the efficacy, safety, pharmacokinetics, and immunogenicity between Aflivu and Eylea. A total of 576 patients 50 years of age and older with wet AMD were randomized 1:1 to receive Aflivu (288 patients) or Eylea (288 patients) via intravitreal injection every 4 weeks for the first 3 injections and every 8 weeks thereafter until Week 48.

The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) at Week 8, a sensitive timepoint to allow for the detection of potential clinically relevant differences in BCVA between Aflivu and Eylea. The pre-defined equivalence margin for the primary endpoint selected for the review of this submission was ±3 BCVA letters at Week 8. Secondary endpoints included the change from baseline in BCVA at Week 52. The study design as well as the primary and secondary endpoints are acceptable for providing evidence of biosimilarity between Aflivu and Eylea.

The estimated mean change from baseline in BCVA at Week 8 was 5.5 letters for Aflivu and 5.8 letters for Eylea. The least squares mean difference between Aflivu and Eylea (Aflivu-Eylea) was ‑0.4 letters with a 95% confidence interval (CI) of ‑1.8 letters to 1.1 letters, which falls within the pre-defined equivalence margin of ±3.0 letters.

The estimated mean change from baseline in BCVA at Week 52 was 9.0 letters for Aflivu and 7.7 letters for Eylea.

Overall, Study SCD411-CP101 demonstrated similarity in efficacy between Aflivu and the reference biologic drug Eylea in patients with wet AMD.

The frequency of ocular treatment-emergent adverse events (TEAEs) in the study eye over 52 weeks was 24% in the Aflivu group vs. 25% in the Eylea group. The most common (occurring in 2% or more of patients) ocular TEAEs included reduced visual acuity (4.5% vs. 4.5%) and conjunctival hemorrhage (2.8% vs. 2.1%). Ocular serious TEAEs were reported in 1.7% of patients in the Aflivu group and 1.0% of patients in the Eylea group. The most common (occurring in 2 [0.7%] or more patients) ocular serious TEAEs were reduced visual acuity (0.7% vs. 0.3%) and retinal pigment epithelial tear (0.7% vs. 0%). The frequencies and types of non-ocular TEAEs over 52 weeks were similar between groups, occurring in 45% of patients in the Aflivu group and 46% of patients in the Eylea group. Non-ocular serious TEAEs occurred in 9.4% of patients in both groups.

Overall, the frequencies and types of ocular and non-ocular TEAEs observed in Study SCD411-CP101 were similar between Aflivu and Eylea. The safety findings were generally consistent with the known safety profile of Eylea. No new safety signals have been identified. Appropriate warnings and precautions are in place in the approved Product Monograph for Aflivu to address the identified safety concerns, as is found in the Product Monograph for Eylea.

Comparative Immunogenicity

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). In Study SCD411-CP101, the overall incidence of ADAs in the Aflivu group (20% to 40%) was similar to the Eylea group (19% to 52%) through 52 weeks of the study. Overall, Study SCD411-CP101 demonstrated biosimilarity in terms of immunogenicity between Aflivu and Eylea in patients with wet AMD.

Indications

Aflivu is considered to be biosimilar to Eylea, the reference biologic drug. Eylea is authorized and marketed in Canada for several indications and clinical uses. At the time this New Drug Submission (NDS) was filed, the specific diseases for which Eylea was authorized included 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).

Within this NDS, the sponsor requested authorization of Aflivu for all of the indications that were authorized for Eylea at the time the NDS was filed.

Similarity between Aflivu and Eylea was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. 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 studies are not required to support each of the submitted indications.

The sponsor provided data from a comparative clinical study conducted in adult patients with wet AMD, demonstrating biosimilarity between Aflivu and Eylea in terms of pharmacokinetics, safety, efficacy, and immunogenicity. In addition, the sponsor provided an acceptable scientific rationale for requesting the authorization of indications that were not directly studied in the clinical development program for Aflivu. The rationale addressed the critical points for extrapolation of data including the mechanism of action and general safety profile of aflibercept across all indications.

Upon review of the evidence submitted, Aflivu was authorized for all of the indications held by Eylea at the time the NDS was filed, as follows:

Aflivu (aflibercept injection) is indicated 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).