Summary Basis of Decision for Yesafili

Yesafili 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 Yesafili and Eylea authorized in the United States (US-Eylea). Health Canada considers US-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.

Biosimilarity was assessed by a range of orthogonal analytical methods to compare the protein content, sequence, higher-order structure, glycans, charge and size variants, post-translational modifications, potency, and target binding. A side-by-side testing approach was used for each of the tests performed. Biological attributes were tested by assessing the binding to vascular endothelial growth factor A165 (VEGF-A165) and the inhibition of VEGF-A165 binding to VEGF receptor 1 and 2 (VEGFR-1 and VEGFR-2), which is the major mechanism of action for aflibercept. In addition, two forced degradation studies were performed and showed similar degradation profiles for Yesafili and US-Eylea under various stress conditions.

Overall, the data from these studies demonstrated similar physiochemical attributes between Yesafili and US-Eylea. Both products had identical primary structure, highly similar secondary and tertiary structures, and similar purity/impurity profiles with minor differences in charge variants and glycan profiles that did not impact functionality. Additionally, highly similar results were observed for functional assays, potency and binding affinity. Forced degradation profiles were comparable following exposure to stressed conditions. Collectively, the results demonstrated that Yesafili is highly similar to US-Eylea and support the quality requirements for Yesafili to be considered a biosimilar of 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 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 risk of the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes is considered negligible or low; therefore, no confirmatory testing is required.

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

The drug substance is manufactured using recombinant deoxyribonucleic acid (rDNA) 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 working cell banks 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 consists of the thawing of a single WCB vial, followed by cell expansion, cell culture, and harvest. After the culture fluid is harvested and clarified, it is subjected to downstream process steps including chromatography, viral inactivation and neutralization, filtration, viral filtration, ultrafiltration, and diafiltration. The final formulation is frozen and stored as bulk drug substance.

The drug product manufacturing is a standard aseptic filling process for a sterile injectable product. It consists of thawing, pooling and mixing of the drug substance, bioburden reduction and sterile filtration, aseptic filling and stoppering of vials, followed by visual inspection. There are no formulation or dilution steps, and no additional excipients are added to the drug substance during the drug product manufacturing process.

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Comparability studies were performed to assess the potential impact of the changes made throughout process development. Overall, the comparability data demonstrated that the changes to the drug product manufacturing process had no negative impact on the quality of the resulting drug product.

The materials used in the manufacture of the drug substance and drug product (including biological materials) are considered suitable and/or meet standards appropriate for their intended use. 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.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

An integrated control strategy was developed to ensure that the manufacturing processes consistently deliver drug substance and drug product of required quality. The control strategy reflected the knowledge of the product quality attributes (PQAs) and their impact on patient safety and product efficacy, as well as an understanding of how these attributes are controlled during manufacturing. The PQAs were defined using the results from process development and characterization studies. Risk-based approaches, which included identification of the critical quality attributes, and assessment of the criticality of the performance attributes and the process parameters, were also employed during the establishment of the control strategy. In addition, the control strategy included the testing of raw and starting materials to ensure their suitability for use in the manufacture of the drug substance and drug product. The successful control of the manufacturing process was also evaluated through in-process tests, release and stability testing of the drug substance and drug product batches (including clinical lots and process performance qualification lots), and continuous process verification.

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with ICH guidelines.

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.

Yesafili 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 shelf-life of 24 months is considered acceptable when Yesafili is protected from light and stored at 2 °C to 8 °C at ambient relative humidity. Prior to usage, unopened vial of Yesafili may be stored at room temperature (25°C) for up to 4 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 facility involved in the manufacture and testing of the drug substance was not warranted since the facility recently underwent a virtual on-site evaluation (OSE) and received a compliant rating. Virtual OSEs are conducted to provide additional regulatory oversight and to mitigate any residual risks identified during review. Information obtained through this virtual OSE supported the issuance of a Notice of Compliance. In addition, the facility also recently underwent a pre-approval inspection by the United States Food and Drug Administration, which had a positive outcome.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.

Both 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.

Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately tested to ensure absence of adventitious agents. The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens and were found to be 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). 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 Yesafili 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 the 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.

The review of this submission focused mainly on the comparison of efficacy and safety, as both Yesafili and Eylea are administered via intravitreal injection, which results in limited systemic exposure to the drug. Data from the pivotal Study MYL-1701P-3001, a Phase III, randomized, double-masked, active-controlled, parallel-group, multicentre study, provided evidence of similarity comparing the efficacy, safety, immunogenicity, and pharmacokinetics of Yesafili and Eylea authorized in the United States (US-Eylea) in adult patients (over the age of 18 years) with diabetic macular edema. Health Canada considered US-Eylea a suitable proxy for Eylea authorized in Canada, as it met all of the requirements for a non-Canadian reference biologic drug stipulated in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Justification was provided for the extrapolation of data to the other indications that have been authorized for Eylea, which was deemed acceptable.

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 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.

No clinical bioequivalence study was conducted, as aflibercept is administered by intravitreal injection directly into the eye; therefore, systemic exposure is low (i.e., negligible) and variable. Instead, a pharmacokinetic (PK) substudy was conducted within the pivotal comparative clinical Study MYL-1701P-3001. The objective of the PK substudy was to descriptively compare the peak plasma concentrations of the study drugs. Data were collected in a subset of subjects (about 23% of those randomized) to assess systemic exposure (i.e., plasma concentrations of free aflibercept). Peak plasma concentrations were observed 2 days post dose. The mean plasma concentrations at Day 2 after the first dose were 25.2 ng/mL in the Yesafili arm (total number of subjects [n] = 42) and 27.6 ng/mL in the US-Eylea arm (n = 47). The mean plasma concentrations at Day 2 after the fifth dose (Week 16) were also comparable: 34.4 ng/mL in the Yesafili arm and 30.8 ng/mL in the US-Eylea arm. There was no accumulation of free aflibercept after repeated intravitreal dosing. As expected, the concentrations obtained at the pre-dose time point and at other time points up to Week 52 for both treatment groups were all below the lower limit of quantification (15 ng/mL).

Comparative Clinical Efficacy and Safety

The efficacy, safety, immunogenicity, and pharmacokinetics of Yesafili and US-Eylea were compared in the pivotal Study MYL-1701P-3001, a Phase III, randomized, double-masked, active-controlled, parallel-group, multicentre study conducted in adult patients (over the age of 18 years) with diabetic macular edema.

In total, 355 subjects were randomized in a 1:1 ratio to receive 2 mg (in 0.05 mL) of Yesafili (n = 179) or US-Eylea (n = 176) administered by intravitreal injection into the studied eye every 4 weeks for the first 5 injections, followed by once every 8 weeks for subsequent injections (with the option of administering additional four-weekly doses). The median number of doses received for each treatment arm was 9 injections (range: 1 to 13) during the 52‑week study period. The mean age of patients in the Yesafili group was 62.8 years (range: 30 to 80 years) as compared to 61.6 years (range: 27 to 83 years) for the US-Eylea group. In addition, 59.8% of patients were male and 40.2% were female in the Yesafili group as compared to the US-Eylea group which included 61.9% male and 38.1% female patients.

The primary endpoint of the study was the change from baseline in best-corrected visual acuity (BCVA) at 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. The BCVA changes from baseline to Week 24 and Week 52 were evaluated as secondary endpoints. There were 172 (96.1%) subjects in the Yesafili arm and 173 (98.3%) in the US-Eylea arm who completed the study up to Week 8, whereas 161 (89.9%) subjects in the Yesafili arm and 158 (89.8%) subjects in the US-Eylea arm completed the study until the Week 52 (end-of-study) visit.

The mean (adjusted) treatment difference in terms of change from baseline in BCVA between Yesafili and US-Eylea at Week 8 was -0.04 letters (95% confidence interval [CI]: -1.40, 1.47). The 95% CI met the predefined equivalence margins of [-3 letters, 3 letters]. The changes in BCVA from baseline at Week 24 and Week 52 (secondary endpoints) were also comparable between both treatment arms (mean difference at Week 24: 0.72 [95% CI: -0.90, 2.35] and at Week 52: 0.24 [95% CI: -1.40, 1.88]).

There were no clinically meaningful differences between the Yesafili and US-Eylea safety profiles in terms of the type of adverse events reported or their frequency and severity (for both ocular and non-ocular adverse events) over the course of the 52-week study. The safety findings from the study were consistent with the safety profile previously reported for Eylea. No new safety signals were detected. The majority of the reported treatment-emergent adverse events (TEAEs) were considered not related to the study drug. The incidence of study drug-related TEAEs was low: 5 (2.8%) subjects in the Yesafili arm and 12 (6.8%) subjects in the US-Eylea arm experienced TEAEs. All TEAEs considered definitely related to the study drug were ocular in nature and occurred in the study eye. In the Yesafili arm, TEAEs considered definitely related to the study drug included increased intraocular pressure, conjunctival hemorrhage, corneal abrasion, keratitis, and papilledema. In the US-Eylea arm, these TEAEs included increased intraocular pressure, conjunctival hemorrhage, eye pain, eye irritation, vitreous floaters, vitreous detachment, episcleritis, visual impairment, corneal edema, blurred vision, and eye inflammation.

The pivotal clinical study indicated that there were no clinically meaningful differences between the biosimilar and the reference biologic drug. Because 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 Yesafili 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 Yesafili, as they are in the Product Monograph for Eylea.

Comparative Immunogenicity

The immunogenicity results at baseline, and at Week 8, Week 24, and Week 52 were similar for both Yesafili and US-Eylea. 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 the pivotal Study MYL-1701P3001, the immunogenicity of Yesafili and US-Eylea was assessed by measuring the ADA levels in blood samples collected at baseline and post-baseline time points. The pre-treatment incidence of ADA ranged from 9.6% to 10.2% across the treatment groups. After dosing with Yesafili and US-Eylea at Week 8, Week 24, and Week 52, the rates of ADA-positive subjects were 6.3%, 9.3%, and 6.4% in the Yesafili treatment group and 9.3%, 9.6%, and 9.9% in the Eylea treatment group, respectively, indicating that the overall proportion of ADA-positive subjects remained similar after treatment with Yesafili or US-Eylea.

Indications

Similarity between Yesafili and Eylea was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. The sponsor requested the authorization of Yesafili 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 Yesafili. The rationale addressed the common mechanism of action of aflibercept across all indications and the comparable pharmacokinetic, efficacy, safety, and immunogenicity profiles of aflibercept across approved indications and patient populations.

Upon review of the evidence submitted, Yesafili 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).