Summary Basis of Decision for Opuviz

Opuviz 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 three-way pairwise analytical assessment of Opuviz, Eylea sourced from the European Union (hereafter referred to as EU Eylea), and Eylea sourced from the United States (hereafter referred to as US Eylea). EU Eylea and US Eylea were demonstrated to be comparable, and both of them were deemed suitable proxies for Eylea authorized in Canada as they met all of the requirements for a non-Canadian reference biologic drug outlined in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The results of the biosimilarity assessment demonstrate that Opuviz and the reference products, EU Eylea and US Eylea, have identical primary structures and highly similar higher-order structures, purity profiles, and biological activity.

Differences observed in post-translational modifications and product-related variants did not have an impact on the biological activity of the proteins.

In comparative forced degradation studies conducted under various stress conditions, Opuviz and the reference products exhibited similar degradation profiles. Minor differences were observed in relative oxidative contents between EU Eylea and US Eylea, and between Opuviz and the reference products. However, there was no statistically significant difference in the vascular endothelial growth factor (VEGF)-A 165 binding activity between Opuviz and the reference products, and studies enriching oxidative contents (induced by forced degradation) did not have an impact on other quality attributes.

Overall, the results of the biosimilarity assessment demonstrate that Opuviz is highly similar to EU Eylea and US Eylea and support the quality requirements for Opuviz to be considered a biosimilar of Eylea.

Characterization of the Drug Substance

Aflibercept is a recombinant fusion protein composed of portions of human VEGF receptors 1 and 2 extracellular domains fused to the fragment crystallizable (Fc) portion of human immunoglobulin G1 (IgG1).

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 a Chinese hamster ovary cell line genetically engineered to express the protein. After thawing of one vial of the working cell bank, the cell culture is serially expanded to allow for the inoculation of a production bioreactor. The protein in the harvested cell culture fluid is subsequently captured and purified through a series of chromatography, virus inactivation, and virus filtration steps. This is followed by an ultrafiltration/diafiltration step, formulation, filtration, and storage of the drug substance at -80 °C to -60 °C.

The drug product manufacturing process involves thawing and pooling of the drug substance, sterile filtration, aseptic filling, visual inspection, packaging, and storage at 2 °C to 8 °C. Opuviz is supplied as a sterile 40 mg/mL solution in a 2 mL glass vial or a 0.5 mL prefilled syringe. None of the non-medicinal ingredients (excipients) in Opuviz 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.

Process validation was conducted with drug substance and drug product batches manufactured consecutively at the intended commercial scale. Process performance qualification data demonstrate that the manufacturing process is capable of consistently manufacturing drug substance and drug product batches that meet the predefined specifications. All process parameters, process attributes, release testing results, and stability results met predefined criteria, acceptance limits, and specifications for all validation lots. All process validation studies were deemed successful and supportive of 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.

The control strategy implements controls at appropriate manufacturing unit operations to ensure consistency of the process and product quality across all stages of manufacturing. Overall, the drug substance and drug product manufacturing processes are controlled by multiple process parameters, in-process controls, and in-process tests with defined operating ranges, action limits, and acceptance criteria. The criticality of each parameter is appropriately defined.

Control of the Drug Substance and Drug Product

The release and stability specifications for the drug substance and drug product are appropriately set and justified. 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.

In-house analytical methods have been appropriately validated. The reference standards are well characterized and an appropriate program is in place to qualify new primary reference material.

Opuviz 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 shelf life is 36 months for the vial presentation and 23 months for the prefilled syringe presentation, when they are stored at 2 °C to 8 °C.

The compatibility of the drug product with the container closure system was demonstrated through stability studies and studies of extractables and leachables.

Facilities and Equipment

Based on the information reviewed, on-site evaluations of the drug substance and drug product manufacturing sites were not deemed necessary.

The design, operations, and controls of all facilities and equipment involved in the production are considered suitable. The sites are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The manufacturing process of the drug substance incorporates adequate control measures to prevent contamination and maintain microbial control.

Master cell banks, working cell banks, end-of-production cell banks, and unprocessed bulk undergo thorough testing for detectable adventitious agents (bacteria, fungi, mycoplasma, and viruses). The cell culture process includes in-process tests to monitor for bioburden, endotoxins, mycoplasma, and viruses. Scaled-down viral clearance studies demonstrate that the downstream purification process is capable of inactivating or removing model viruses with diverse physicochemical characteristics.

No raw materials of animal or human origin were used during cell bank preparation, or during drug substance and drug product manufacturing.

The drug product formulation does not contain excipients 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.

Nevertheless, in order to satisfy requirements from other drug regulators, the sponsor conducted one 4-week repeat-dose toxicity study (SBL327-008) in female cynomolgus monkeys to compare the potential toxicities of Opuviz and United States-sourced Eylea (hereafter referred to as US Eylea).

In SBL327-008, 12 female cynomolgus monkeys were randomized in a ratio of 1:1:1 to receive by intravitreal injection Opuviz 2 mg/0.05 mL per eye, US Eylea 2 mg/0.05 mL per eye, or a vehicle (i.e., the clinical formulation of Opuviz without the drug substance) 0.05 mL per eye. The intravitreal injections were given in both eyes once every 2 weeks, for 4 weeks (3 times in total: Day 1, Day 15, and Day 29). No significant toxicological findings were observed in any group and there were no significant differences in the toxicity profiles between Opuviz and US Eylea.

Overall, the non-clinical findings are supportive of similarity between Opuviz and US Eylea.

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

Due to the minimal systemic exposure of aflibercept expected after intravitreal injection and the invasiveness of intravitreal injections, a Phase I comparative pharmacokinetic study in healthy volunteers was not conducted.

The pharmacokinetic profiles of Opuviz and Eylea were compared in a subset of patients with neovascular (wet) age-related macular degeneration from a Phase III study (SB15-3001, described in the Comparative Efficacy, Safety, and Immunogenicity section). For the purpose of this drug submission, Health Canada considered the United States-sourced Eylea (hereafter referred to as 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.

The pharmacokinetic analysis set of Study SB15-3001 included 40 patients: 21 in the Opuviz group and 19 in the Eylea group. Serum concentrations of free aflibercept were measured before and after the intravitreal injections. Given the limited number of patients, the analysis of the obtained pharmacokinetic data was descriptive. In both groups, most pre-dose serum measurements were below the limit of quantitation, whereas post-dose serum measurements were generally low and highly variable. The results were consistent with the expectation of low systemic exposures to aflibercept following intravitreal injections.

Comparative Efficacy, Safety, and Immunogenicity

The comparative efficacy, safety, and immunogenicity of Opuviz and US Eylea were evaluated in a Phase III, randomized, double-masked, parallel-group, multicentre study (SB15-3001) in adult patients with neovascular (wet) age-related macular degeneration.

In total, 449 patients were randomized in a ratio of 1:1 to receive a 2 mg/0.05 mL dose of Opuviz or US Eylea by intravitreal injection. Patients received treatment once every 4 weeks for the first 3 months, followed by treatment once every 8 weeks until the last dose was administered at Week 48. At Week 32, patients in the US Eylea arm were rerandomized in a ratio of 1:1 to either continue receiving US Eylea or transition to receiving Opuviz.

The primary efficacy endpoint was the mean change from baseline in best-corrected visual acuity (BCVA) at Week 8. In the Opuviz group, the least-squares mean change from baseline in BCVA at Week 8 was 6.7 letters versus 6.6 letters in the US Eylea group. Hence, the difference in least-squares means of the change from baseline in BCVA at Week 8 between Opuviz and US Eylea was 0.1 letters with a 90% confidence interval (CI) of -1.1 to 1.2 letters and a 95% CI of -1.3 to 1.4 letters, both of which were entirely contained within the predefined equivalence margin of -3 to 3 letters.

The safety profile of Opuviz observed in Study SB15-3001 is consistent with the known safety profile of Eylea. The overall incidence of adverse events was consistent between Opuviz and Eylea throughout the study. No clinically meaningful imbalances were observed in the severity of adverse events and the rates of serious adverse events, adverse events of special interest, or discontinuations due to adverse events. Three patients died during the study: one Opuviz-treated patient and two Eylea-treated patients. None of the deaths was considered related to the study drug.

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). The incidence of ADAs was low in both treatment groups throughout the study, which precluded assessing the impact of the ADAs on the efficacy and safety of the drugs.

Overall, the submitted results of the comparative Phase III study indicate that there are no clinically meaningful differences between Opuviz and the reference biologic drug in terms of efficacy, safety, and immunogenicity.

Appropriate warnings and precautions are in place in the approved Product Monograph for Opuviz to address the identified safety concerns, as is found in the Product Monograph for Eylea. The Adverse Reactions section of the Product Monograph for Opuviz is based on the clinical experience with Eylea.

Indications

The sponsor sought the authorization of Opuviz for all of the indications that were authorized for Eylea at the time the New Drug Submission for Opuviz was filed.

Similarity between Opuviz 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 sought indications. The sponsor provided data from a comparative clinical trial conducted in adult patients with neovascular (wet) age-related macular degeneration. 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 Opuviz. The rationale addressed the consistent mechanism of action of aflibercept across all approved indications and the comparable pharmacokinetics, efficacy, safety, and immunogenicity of aflibercept across different approved indications and patient populations.

Upon review of the evidence submitted, Opuviz was authorized for the treatment of the following conditions:

• neovascular (wet) age-related macular degeneration

• visual impairment due to macular edema secondary to central retinal vein occlusion

• visual impairment due to macular edema secondary to branch retinal vein occlusion

• diabetic macular edema

• myopic choroidal neovascularization