Summary Basis of Decision for Pavblu

Pavblu 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 using Pavblu, Eylea authorized in the European Union, and Eylea authorized in the United States. Health Canada considers Eylea authorized in the European Union 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 assessment of analytical similarity between Pavblu and Eylea is based on data from an extensive array of qualified physicochemical and biological assays that evaluate biological activity, primary and higher order structure, glycosylation, product-related substances and impurities, general properties, and thermal stability and degradation profiles of the products using side-by-side testing, independent testing, and age-dependent testing.

The results of the biosimilarity assessment demonstrate that Pavblu is highly similar to Eylea. Compared to the reference biologic product, Pavblu has lower levels of high mannose, high molecular weight species, and fragments at release, and degradation studies support that Pavblu has improved stability for size-related variants. Minor differences in the glycosylation profiles were observed and larger differences were observed in the charge profiles. Enrichment and extended characterization studies support the expectation that the observed differences are not clinically meaningful and will not impact safety or efficacy. Attributes such as protein content and volume indicate that Pavblu and the reference biologic drug similarly meet the label claim. Overall, the results of the biosimilarity assessment support the conclusion that Pavblu is biosimilar to Eylea and the observed differences are not expected to be clinically meaningful.

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.

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

Drug Substance

The Pavblu drug substance is manufactured in Chinese hamster ovary cells. The manufacturing process begins with thawing a working cell bank vial followed by cell expansion. The harvested cell culture fluid is then purified through a series of chromatography steps, viral inactivation and filtration, ultrafiltration/diafiltration, polysorbate addition, and final filtration prior to filling into storage bags.

Acceptable ranges for process parameters and controls of critical steps of the drug substance manufacturing process were established during development, based on product quality attribute assessment, process risk assessment, and process characterization studies. The drug substance process was validated and demonstrates that the manufacturing process is capable of consistently manufacturing drug substance with the desired product quality.

Drug Product

The drug product is supplied in a glass vial or a prefilled syringe as a solution intended for intravitreal administration. The drug product manufacturing processes consist of drug substance thaw, optional drug substance hold, formulation, bioburden reduction filtration, filtered formulated drug product hold, sterile filtration, aseptic filling, inspection, and storage. The prefilled syringe manufacturing process includes additional assembly steps, sealing into blister packs, and sterilization of the external surface.

Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.

Controls of critical steps of the drug product manufacturing processes were established during manufacturing development, based on a risk assessment and the results of process characterization studies. In-process controls and lot release tests for the drug product were established and validated.

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 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 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

Each lot is tested for appearance, content, identity, potency, purity, impurities, and safety (endotoxins and microbial contamination or sterility). Established test specifications and validated analytical test methods are considered acceptable.

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).

Pavblu 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 36-month shelf life at 2 °C to 8 °C for both presentations of Pavblu is considered acceptable when protected from light, with a short-term room temperature storage (up to 30 °C) for a single period of up to 3 days when protected from light.

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

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

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.

Raw materials of animal and recombinant deoxyribonucleic acid (DNA) origin used in the manufacturing process are adequately tested to ensure absence of adventitious agents. 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.

The non-clinical database consisted of one comparative ocular distribution study in healthy rabbits and one comparative one-month repeat-dose toxicity study in healthy cynomolgus monkeys comparing the distribution, toxicology, and toxicokinetics of Pavblu to that of Eylea. In rabbits, exposures of Pavblu and Eylea in aqueous humor and vitreous humor were generally comparable following a single intravitreal dose of approximately 1 mg per eye. In cynomolgus monkeys, no Pavblu- or Eylea-related adverse effects were observed, including in ocular and related/relevant tissues, following two intravitreal doses of 1 mg per eye administered one month apart. There were also no clear differences between Pavblu and Eylea in the toxicity endpoints assessed. In addition, no unique toxicities were observed following the administration of Pavblu compared to Eylea, and systemic exposures and concentrations in vitreous fluid were generally comparable between Pavblu and Eylea.

The non-clinical database submitted for Pavblu was in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

In view of the intended use of Pavblu, 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 (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 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 which 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 New Drug Submission for Pavblu did not include a bioequivalence study in healthy subjects using the traditional pharmacokinetic endpoints of area under the concentration-time curve (AUC) and maximum concentration (C_max). This was considered acceptable given that aflibercept is administered directly in the eye by intravitreal injection, yielding very low and variable systemic exposures, and also due to feasibility and ethical reasons associated with the invasiveness of intravitreal injections. Thus, the pharmacokinetic data were collected in a subset of 49 patients with neovascular (wet) age-related macular degeneration (AMD; 8.5% of the total patients randomized) from the pivotal Phase III study (Study 20170542) to assess the systemic exposure of free aflibercept. Of these, 19 patients were treated with Pavblu and 30 were treated with Eylea. Serum concentrations of free aflibercept were measured before the first dose, 24 hours after first dose, and at Week 8. Overall, the serum level of aflibercept was low following intravitreal administration (2 mg intravitreal injection every 4 weeks for the first 12 weeks, followed by 2 mg intravitreal injection every 8 weeks until Week 48). No significant differences in systemic exposure of aflibercept were observed between those treated with Pavblu compared to those treated with Eylea.

Comparative Clinical Efficacy, Safety, and Immunogenicity

The clinical data to support the biosimilarity of Pavblu to Eylea were primarily derived from the results of Study 20170542, a Phase III, randomized, multicentre, double-masked, active-controlled study. In the full analysis set, a total of 576 patients 50 years of age and older with wet AMD were randomized 1:1 to receive Pavblu (288 patients) or Eylea (288 patients) as per the authorized dosing recommendations for aflibercept in this patient population (2 mg administered via intravitreal injection at weeks 0, 4, and 8, and every 8 weeks thereafter until the final dose at Week 48). Patients who received Eylea for the first 16 weeks of treatment were re-randomized 1:1 to Pavblu (Eylea/Pavblu) or continuation on Eylea (Eylea/Eylea) from Week 16 to Week 52, while patients who were initially randomized to Pavblu remained on that treatment (Pavblu/Pavblu). At Week 16, there were 273, 134 and 136 patients in the Pavblu/Pavblu, Eylea/Pavblu, and Eylea/Eylea treatment arms, respectively.

Approximately 92% of patients across treatment arms completed the study. Patients were 56% female with a mean age of 76 years (range: 51 to 95 years) and 91.5% were 65 years of age or older. The majority of patients were White (86.5%) or Asian (13.0%). The mean duration of disease at study entry was approximately 7 weeks.

The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) at Week 8. Biosimilarity between Pavblu and Eylea was demonstrated as the mean change in BCVA from baseline at Week 8, which was +6.4 letters for Pavblu and +6.5 letters for Eylea, for a treatment difference of +0.1 (90% Confidence Interval [CI]: -1.1, +1.3). This was well within the pre-specified similarity margin of ±3 letters. Sensitivity and subgroup analyses were consistent with the primary analysis.

Secondary endpoints were also supportive of similarity between Pavblu and Eylea. Baseline BCVA values were 59.0, 57.8, and 57.2 letters in the Pavblu/Pavblu, Eylea/Pavblu, and Eylea/Eylea treatment arms at baseline as compared to 66.6, 66.2, and 67.0 letters at Week 52, respectively. At Week 8, 29.4% of Pavblu-treated patients and 32.7% Eylea-treated patients gained 10 or more letters. At Week 52, 41.8%, 51.2%, and 49.6% of patients in the Pavblu/Pavblu, Eylea/Pavblu, and Eylea/Eylea treatment arms gained 10 or more letters and 95.6%, 95.9%, and 97.6% of patients maintained vision (a loss of less than 15 letters), respectively.

In terms of structural disease changes, change from baseline choroidal neovascularization (CNV) area size was smaller at Week 8 for Pavblu (-4.863 mm²) compared to Eylea (-5.371 mm²) but similar at Week 16 (-4.002 mm² for Pavblu and -4.398 mm² for Eylea). Change from baseline in central subfield thickness (CST) at Week 8 was -136.0 µm for Pavblu and -145.8 µm for Eylea and remained comparable across treatment arms through Week 52 (-157.1 µm Pavblu/Pavblu, -177.4 µm Eylea/Pavblu, and -159.1 µm Eylea/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). By Week 16, 0.3% of Pavblu-treated patients and 1.4% of Eylea-treated patients had treatment-emergent binding ADAs; however, there were too few patients to assess impact on safety or efficacy.

Some differences were observed in the safety profile between Pavblu- and Eylea-treated patients. Over the course of the entire study, there were more Pavblu-treated patients than Eylea-treated patients who experienced treatment-emergent adverse events (TEAEs) (66.3% Pavblu/Pavblu, 66.9% Eylea/Pavblu, and 59.6% Eylea/Eylea), ocular TEAEs (31.1% Pavblu/Pavblu, 32.3% Eylea/Pavblu, and 27.2% Eylea/Eylea), treatment interruption due to adverse events (10.6% Pavblu/Pavblu, 8.3% Eylea/Pavblu, and 5.1% Eylea/Eylea), and events of interest (5.1% Pavblu/Pavblu, 6.0% Eylea/Pavblu, and 1.5% Eylea/Eylea). Explanations for the imbalances were provided by the sponsor and deemed reasonable when considered in conjunction with the lack of imbalances for other safety endpoints (e.g., ocular serious adverse events and increases in intraocular pressure), the composition and existing risk factors of the primarily elderly patient population, and the similarity of rates compared to rates in the Eylea Product Monograph for key events of interest (e.g., cerebrovascular events).

In the first 16 weeks of study, there were 16.0% of Pavblu- and 17.0% of Eylea-treated patients that experienced ocular TEAEs. The most common ocular TEAEs in the study eye through Week 16 were conjunctival hemorrhage (4.2% Pavblu, 3.8% Eylea) and injection site pain (1.4% Pavblu, 0.3% Eylea). There were no serious ocular TEAEs during the first 16 weeks of study.

From Weeks 16 to 52, there were 22.3% of Pavblu/Pavblu, 24.1% of Eylea/Pavblu, and 18.4% of Eylea/Eylea patients that experienced ocular TEAEs. The most common ocular adverse events in the study eye from Weeks 16 to 52 were reduced visual acuity (2.9% Pavblu/Pavblu, 3.8% Eylea/Pavblu, 0.7% Eylea/Eylea), cataract (2.2% Pavblu/Pavblu, 0.8% Eyela/Pavblu, 2.2% Eylea/Eylea), retinal hemorrhage (1.8% Pavblu/Pavblu, 3.0% Eylea/Pavblu, 0.7% Eylea/Eylea), and conjunctival hemorrhage (1.1% Pavblu/Pavblu, 6.0% Eylea/Pavblu, 3.7% Eylea/Eylea). From weeks 16 to 52, there were 0% Pavblu/Pavblu-, 0% Eylea/Pavblu-, and 1.5% Eylea/Eylea-treated patients that experienced serious ocular TEAEs.

Other than ocular TEAEs, the most common events during the first 16 weeks were hypertension (1.7% Pavblu, 2.1% Eylea) and coronavirus disease of 2019 (COVID-19) (0.7% Pavblu, 2.4% Eylea). After re-randomization at Week 16, the most common non-ocular TEAE was COVID-19 (5.1% Pavblu/Pavblu, 3.8% Eylea/Pavblu, 3.7% Eylea/Eylea).

The results demonstrated that no clinically meaningful differences in efficacy, safety, and immunogenicity were observed between Pavblu and Eylea in patients with wet AMD. Extrapolation to other sought indications (i.e., 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, and myopic choroidal neovascularization) is based on scientific justifications, that is, the same mechanism of action of aflibercept and the findings of consistent safety profiles across the indications currently authorized for Eylea.

Appropriate warnings and precautions are in place in the approved Product Monograph for Pavblu to address the identified safety concerns, as are found in the Product Monograph for Eylea.

Indications

Pavblu 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 drug submission, the sponsor requested the authorization of Pavblu for all of the indications that were authorized for Eylea at the time the NDS was filed.

Similarity between Pavblu 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 sponsor provided data from a comparative clinical study conducted in adult patients with wet AMD, demonstrating biosimilarity between Pavblu 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 Pavblu. 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, Pavblu was authorized for all of the indications currently held by Eylea, as follows:

Pavblu 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).