Summary Basis of Decision for Ahzantive

Ahzantive 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 assessment for Ahzantive was based on comparison with Eylea authorized in the European Union (herein referred to as EU-Eylea). For the purpose of this drug submission, Health Canada considers EU-Eylea a suitable proxy for the Canadian reference product, as it meets the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. Supportive data from product lots of Eylea authorized in the United States were also reviewed in the similarity studies.

Aflibercept in Ahzantive and in EU-Eylea were found to have identical amino acid sequences, and were highly similar with respect to mass, secondary and tertiary structures, purity, and biological activities. Differences observed with respect to other characteristics were appropriately justified and are not expected to impact clinically relevant attributes. Additionally, comparable degradation pathways and degradation rates were observed between Ahzantive and EU-Eylea in stability studies. Collectively, the results of the biosimilarity assessment demonstrate that Ahzantive is highly similar to EU‑Eylea, and support the quality requirements for Ahzantive to be considered a biosimilar to the reference biologic drug.

Characterization of the Drug Substance

Aflibercept, the drug substance, is a recombinant fusion glycoprotein that consists of two identical polypeptide chains. Each chain consists of the extracellular domains of the human vascular endothelial growth factor (VEGF) receptor fused to the fragment crystallizable (Fc) domain of human immunoglobulin G1. It is a soluble decoy receptor that binds VEGF-A, VEGF-B, and placental growth factor with high affinity.

Detailed characterization studies were performed to provide assurance that aflibercept consistently exhibits the desired characteristic structure and biological activity. Primary sequence, secondary and tertiary structures, charge and size variants, post-translational modifications, and biological and physico-chemical properties were all examined.

Product‑ and process‑related impurities were evaluated and found to be adequately controlled. 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

Aflibercept (the drug substance) is manufactured from Chinese hamster ovary (CHO) cells which were genetically modified to express this protein. A cell culture is initiated and allowed to expand to commercial scale through a fed-batch process. The cell culture is harvested when it reaches the target culture time and is within the targeted cell viability and cell density. The drug substance is purified from this culture through a series of filtration, chromatography, and viral inactivation steps, followed by formulation, sterile filtration into bottles, and storage at ‑60 °C or lower.

Manufacturing of Ahzantive, the drug product, involves drug substance thawing, pooling and mixing, bioburden reduction filtration, sterile filtration, filling, visual inspection, packaging, and storage at 2 °C to 8 °C.

Process validation was conducted using drug substance batches and drug product lots manufactured at the intended commercial scale. The process performance qualification data reflect consistency in the manufacturing processes for both the drug substance and the drug product. All process parameters, in-process controls, release testing results, and stability results met pre-defined criteria, acceptance limits, and specifications for all validation lots. Any deviations were discussed and appropriately justified as not impeding process validation. Ancillary process validation studies were deemed successful and supportive of hold times, impurity clearance, resin/membrane lifetimes, filters, extractables and leachables, sterility, aseptic 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 aflibercept with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Process parameters and in-process controls have been established to ensure process performance and product consistency. The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. The in-house analytical methods were validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and compendial methods complied with pharmacopeial standards. All release and stability acceptance criteria were met for both the drug substance and the drug product.

Ahzantive 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 °C to 8 °C is considered acceptable when Ahzantive is stored in its original vial and protected from light. The drug product shelf life includes a period of up to 24 hours at 25 °C. Additional storage and special handling instructions are included in the Product Monograph for Ahzantive.

Facilities and Equipment

The risk assessment score determined by Health Canada indicated that an on-site evaluation (OSE) was recommended for the drug substance manufacturing site. However, factors including the Good Manufacturing Practices (GMP)-compliant status of the site, its location within the United States, and a recent approval of the site by the United States Food and Drug Administration mitigated the risk and therefore negated the OSE recommendation.

An OSE was not recommended for the drug product manufacturing site based on its risk assessment score.

Adventitious Agents Safety Evaluation

The cell banks were extensively characterized and confirmed to be free of mycoplasma and endogenous and adventitious viruses.

The drug substance purification process is capable of consistently reducing retrovirus-like particles to levels below the acceptable threshold. In-process adventitious agents testing has been established to monitor potential adventitious agents contamination.

The raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.

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 (described in the Comparative Structural and Functional Studies section) demonstrated a high degree of similarity between Ahzantive 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 non-clinical studies reviewed in this submission were deemed non-pivotal. Following the intravitreal administration of Ahzantive or EU-Eylea in rabbits, similar exposures were observed in ocular matrices (vitreous humor, aqueous humor, retina/choroid tissue). No unique ocular or systemic toxicities were observed with Ahzantive compared with EU-Eylea.

For more information, refer to the Product Monograph for Ahzantive, approved by Health Canada and available through the Drug Product Database.

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 that 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 (VEGFR)-1 and VEGFR-2, 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, which is believed to contribute to vision loss in a variety of ocular diseases.

Aflibercept, the medicinal ingredient in Ahzantive, acts as a soluble decoy receptor. It binds VEGF-A and PlGF with higher affinity than their natural receptors, and thereby can inhibit the binding and activation of these cognate VEGF receptors.

Due to the invasive nature of an intravitreal injection, a Phase I pharmacokinetic study was not conducted. To support the evaluation of the pharmacokinetics of aflibercept, the comparative bioavailability of Ahzantive and EU-Eylea was assessed in a subset of 57 patients with neovascular (wet) age-related macular degeneration (AMD) from the Phase III study, FYB203-03-01 (described in the Comparative Clinical Efficacy, Safety, and Immunogenicity section). Thirty-one (31) participants were in the Ahzantive group and 26 participants were in the EU-Eylea group. Total and free aflibercept concentrations were assessed at Week 0 prior to the first dose, 48 hours after the first dose, and 48 hours after the third dose. The analysis of pharmacokinetic data was descriptive due to the limited number of patients. In both groups, systemic aflibercept exposures were low and highly variable, but were consistent between Ahzantive and EU-Eylea. Collectively, the limited clinical pharmacology data support pharmacokinetic similarity between Ahzantive and EU-Eylea.

Comparative Clinical Efficacy, Safety, and Immunogenicity

The comparative efficacy of Ahzantive and EU-Eylea was evaluated in the Phase III study FYB203-03-01 in adult patients with wet AMD. In total, 434 patients were randomized 1:1 to receive Ahzantive or EU-Eylea by intravitreal injection. Patients received a 2 mg/0.05 mL dose of the assigned drug once every four weeks for the first three months, followed by once every eight weeks until the last dose at Week 48.

The primary efficacy endpoint of this study was the change from baseline in best-corrected visual acuity (BCVA), as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score, at Week 8 of treatment with Ahzantive or EU-Eylea. Based on the data reviewed, the 95.2% confidence interval (CI) of the difference in BCVA from baseline at Week 8 between EU-Eylea and Ahzantive was ‑0.6 to 2.5 letters, which is entirely contained within the equivalence margin of ± 3.5 letters. This finding supports similarity between the two products. Therefore, therapeutic equivalence in terms of change from baseline in BCVA score was demonstrated. Overall, results of the efficacy analysis support the clinical comparability between Ahzantive and EU-Eylea.

The safety profile of Ahzantive, based on observations from Study FYB203-03-01, is consistent with the safety profile of EU-Eylea. The overall incidence of adverse events was consistent between Ahzantive and EU-Eylea throughout the study. No clinically meaningful imbalances were observed with respect to the overall incidence and severity of adverse events, serious adverse events, or adverse events of special interest, nor in the incidence and reasons for discontinuation due to adverse events. Seven deaths occurred during the study - four patients in the Ahzantive group, one patient in the EU-Eylea group, and two patients who did not receive any treatment (screening period). The deaths were not considered related to the study treatment or study procedure, and were attributed to the patients’ medical conditions.

No consistent imbalances in immunogenicity were observed between Ahzantive and EU-Eylea. The incidence of anti-drug antibodies (ADAs), which have the potential to neutralize the biological activity of the drug, was low in all treatment groups throughout the study. However, given the limited data, no conclusions can be drawn regarding whether ADAs have a clinically meaningful impact on the efficacy and safety of either Ahzantive or EU-Eylea.

Overall, the results of Study FYB203-03-01 did not identify any clinically meaningful differences in efficacy, safety, or immunogenicity between Ahzantive and EU-Eylea.

For more information, refer to the Product Monograph for Ahzantive, approved by Health Canada and available through the Drug Product Database.

Indications

Ahzantive is considered to be biosimilar to Eylea, the reference biologic drug. Eylea is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Eylea is authorized in adult patients are 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). Eylea is additionally indicated in preterm infants for the treatment of retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 2+ or 3+) or aggressive posterior ROP (AP-ROP) disease.

Within this drug submission, the sponsor requested the authorization of Ahzantive for all of the adult indications that are currently authorized for Eylea. The sponsor did not request authorization for the pediatric indication for Eylea, i.e., for the treatment of ROP in preterm infants.

Similarity between Ahzantive 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 trials are not required to support each of the submitted indications.

The indications have been authorized on the basis of demonstrated similarity between Ahzantive and the reference biologic drug, in structural and functional studies, mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, dosage regimen, clinical experience with the reference biologic drug.