Summary Basis of Decision for Pexegra

Pexegra (pegfilgrastim) was developed as a biosimilar of the reference biologic drug Neulasta. The weight of evidence of similarity between a proposed 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 with the reference biologic drug.

Comparative Structural and Functional Studies

Comparative structural and functional studies were conducted to compare the physicochemical and biological properties of Pexegra and Neulasta authorized in the United States (US-Neulasta). For the purpose of this drug submission, Health Canada considered US-Neulasta a suitable proxy for Neulasta authorized in Canada, as it met all of the requirements for a non-Canadian reference biologic drug set out in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Overall, the comparative analytical assessment evaluated a comprehensive array of quality attributes relevant to both products using appropriate methods, an appropriate data analysis plan, and appropriate lots for the assessment.

The results of the biosimilarity studies demonstrate that Pexegra is highly similar to US-sourced Neulasta in terms of the primary structure, higher-order structure, and potency. While there were differences in product-related substances and impurities, Pexegra generally exhibited higher purity than US-sourced Neulasta. Sequence variants (i.e., single amino acid misincorporations) were detected at very low levels in both products. Except for one sequence variant, which was detected in Pexegra at very low levels, all other sequence variants identified were present in both products at similar levels. These analytical differences observed in product-related substances and impurities had no impact on the biological activity of pegfilgrastim. Moreover, these differences are not expected to have a clinical impact given their small magnitude. Nonetheless, the control strategy for Pexegra includes adequate release and stability specifications to control for sequence variants and other product-related impurities. Comparative stability and forced degradation studies using different stress conditions generated similar degradation profiles for Pexegra and US-sourced Neulasta, thereby further supporting similarity of the products.

Overall, the results demonstrate that Pexegra is highly similar to US-Neulasta and confirm that Pexegra meets the necessary quality standards to be recognized as a biosimilar of Neulasta.

Characterization of the Drug Substance

Pegfilgrastim, the medicinal ingredient in Pexegra, is a covalent conjugate of recombinant methionyl human granulocyte colony-stimulating factor (referred to as filgrastim) with a single 20 kDa polyethylene glycol (PEG) molecule.

Detailed characterization studies were performed to provide assurance that pegfilgrastim 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 presence of nitrosamine impurities was conducted according to requirements outlined in the 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 manufacturing process of the Pexegra drug substance, pegfilgrastim, starts with the manufacture of the drug substance intermediate, filgrastim. Filgrastim is produced in a genetically engineered strain of Escherichia coli. The manufacturing process of filgrastim involves bacterial fermentation that generates inclusion bodies containing the filgrastim protein. This is followed by cell harvest and homogenization to isolate the inclusion bodies, and solubilization of the inclusion bodies to release the filgrastim protein, which is then refolded into its active conformation. The protein is purified by chromatography steps, concentrated by ultrafiltration/diafiltration, formulated, filtered, and stored frozen (at -70 °C ± 10 °C).

Subsequently, the filgrastim drug substance intermediate is thawed and subjected to a pegylation reaction, i.e., conjugation with a 20 kDa PEG molecule. The resulting pegfilgrastim is purified by chromatography, concentrated by ultrafiltration/diafiltration, formulated with polysorbate 20, filtered, and stored frozen (at -70 °C ± 10 °C).

The manufacturing process of the drug product consists of the preparation of the formulation buffer, thawing of the drug substance, drug product formulation, sterile filtration, filling into syringes, 100% visual inspection, prefilled syringe assembly with a needle safety device, labelling, and packaging. Pexegra is supplied in a single-use prefilled syringe with UltraSafe Plus Passive Needle Guard. None of the non-medicinal ingredients (excipients) found in Pexegra are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of pegfilgrastim with the excipients is supported by the stability data provided.

Process validation studies were conducted by manufacturing consecutive lots of the drug substance intermediate, drug substance, and drug product at the proposed commercial scales and manufacturing sites. All critical process parameters, in-process controls, and release testing results met pre-established acceptance criteria and specification limits for all validation lots. All ancillary validation studies were deemed successful and supportive of in-process hold times, impurity clearance, resin and membrane reuse, extractables and leachables testing, filters, media fills, and shipping. Overall, the process validation data demonstrate that the established Pexegra manufacturing processes are capable of consistently manufacturing Pexegra drug substance and drug product that meet the predefined specifications and quality attributes. A continuous process verification program has been implemented to ensure all Pexegra commercial manufacturing processes remain within their validated states.

Control of the Drug Substance and Drug Product

The release and stability specifications for the filgrastim intermediate, Pexegra drug substance, and Pexegra drug product were appropriately set and justified.

Analytical procedures used in the release and stability testing of the filgrastim intermediate, Pexegra drug substance, and Pexegra drug product were adequately validated according to relevant guidelines. Compendial methods were satisfactorily verified under conditions of use.

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.

Pexegra 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 filgrastim intermediate, Pexegra drug substance, and Pexegra drug product were adequately supported and are considered to be satisfactory. The shelf life of 24 months at 2 °C to 8 °C for the Pexegra drug product, when protected from light, is considered acceptable.

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

Facilities and Equipment

Based on a risk assessment performed by Health Canada, on-site evaluations of the drug substance and drug product manufacturing sites were not deemed necessary.

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

Adventitious Agents Safety Evaluation

Adequate control measures are incorporated in the manufacturing process of Pexegra to prevent contamination and maintain microbial control.

The bacterial protein expression system used (Escherichia coli) does not support the growth of viral adventitious agents. Bacteriophage, bioburden, and endotoxin testing procedures are integrated in the control strategy and meet relevant guidelines and requirements.

Raw materials of biologic origin are appropriately sourced and tested. The risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered negligible.

There are no excipients of human or animal origin in the drug product formulation.

For biosimilars, the degree of similarity to the reference product 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 sponsor submitted non-clinical data for Pexegra (pegfilgrastim, also referred to as TPI-120) in accordance with the requirements outlined in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

In a repeat-dose toxicity study in rats, subcutaneous administration of either TPI-120 or US-Neulasta once weekly for 13 weeks at a dose of 1,000 µg/kg was well tolerated. Toxicokinetic evaluations did not show any apparent differences between TPI-120 and US-Neulasta. Overall, TPI-120 and US-Neulasta demonstrated similar toxicologic, toxicokinetic, and immunogenic profiles.

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.

Two clinical studies were conducted in healthy adult subjects to demonstrate similarity between Pexegra and Neulasta authorized in the United States (US-Neulasta): one comparative pharmacokinetic and pharmacodynamic study (TPI-CL-109) and one comparative immunogenicity study (ADL-CL-112). Health Canada considered US-Neulasta a suitable proxy for Neulasta 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.

Comparative Pharmacokinetics and Pharmacodynamics

A comparative Phase I, randomized, double-blind, single-dose, two-period, crossover study (TPI-CL-109) in healthy subjects compared the pharmacokinetic and pharmacodynamic profiles of Pexegra and US-Neulasta after a single subcutaneous dose of 2 mg. The study enrolled 120 subjects, 109 of whom completed the study and received both Pexegra and US-Neulasta. The pharmacokinetic results showed that the ratio of geometric means for the maximum concentration observed (C_max) of Pexegra to US-Neulasta was 107.38%, and the 90% confidence interval (CI) of the ratio of geometric means for the area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUC_0-t) of Pexegra to US-Neulasta was 97.3% to 119.4%. These results fell within the comparative pharmacokinetic bioavailability margins of 80.0% to 125.0% set out in Health Canada’s Guidance Document: Comparative Bioavailability Standards: Formulations Used for Systemic Effects (2018). Accordingly, the study demonstrated comparable pharmacokinetic profiles of Pexegra and the reference drug.

Pharmacodynamic comparability of Pexegra to US-Neulasta was also demonstrated in the study, based on the assessment of the absolute neutrophil count (ANC) as a relevant pharmacodynamic marker for the activity of products containing recombinant granulocyte colony-stimulating factor. The ratio of geometric means for the maximum observed effect for ANC (E_max) of Pexegra to US-Neulasta was 102.12%. In addition, the 95% CI of the ratio of geometric means for the area under the effect-time curve from time zero to the time of the last measurable effect for ANC (AUEC_0-tlast) of Pexegra to US-Neulasta was 94.41% to 106.18%. The results were within the predefined equivalence margins of 80.00% to 125.00%.

Comparative Immunogenicity and Safety

The immunogenicity profiles of Pexegra and US-Neulasta were compared in a randomized, single-blind, repeat-dose, two-cycle, parallel-arm, comparative immunogenicity study (ADL-CL-112) in healthy subjects. Subjects were administered one subcutaneous dose of 6 mg of Pexegra or US-Neulasta on Day 1 of Cycle 1 followed by one subcutaneous dose on Day 1 of Cycle 2, with a gap of 21 days between the two cycles.

The primary endpoint of the study was the relative anti-drug antibodies (ADAs) incidence between the Pexegra and US-Neulasta groups. Immunogenicity was evaluated in 222 of the 230 subjects enrolled (114 Pexegra-treated subjects and 108 US-Neulasta-treated subjects). Eight subjects were excluded from the analysis for having a positive pre-dose immune response (seven subjects) or not providing any post-dose samples (one subject).

By the end of study, 7% of Pexegra-treated subjects and 14.8% of US-Neulasta-treated subjects had tested positive for ADAs. Neutralizing ADAs were detected only in one subject in the US-Neulasta group. The ADAs were mostly transient in nature (only one subject in the US-Neulasta group continued to test positive for ADAs until the end of the study).

The number of subjects with confirmed ADAs was higher in the US-Neulasta group than in the Pexegra group (16 versus 8). Anti-drug antibodies with confirmed specificity towards the polyethylene glycol (PEG) molecule were reported in 9 of the 16 ADA-positive subjects in the US-Neulasta group versus none of the 8 ADA-positive subjects in the Pexegra group. The observed difference is not expected to significantly impact the biosimilarity between Pexegra and Neulasta.

The secondary objective of the study was to compare the safety profiles of Pexegra and Neulasta. The incidences of treatment-emergent adverse events were similar in the Pexegra and US-Neulasta groups (94% in the Pexegra group vs 95% in the US-Neulasta group). The most commonly reported treatment-emergent adverse events (Pexegra group vs US-Neulasta group) were headache (65% vs 65%), back pain (52% vs 53%), myalgia (37% vs 37%), local administration reactions such as injection site pain (10% vs 11%) and injection site erythema (9% vs 11%), arthralgia (17% vs 12%), nausea (17% vs 14%), erythema (3% vs 2%), and abdominal pain (4% vs 4%). All treatment-emergent adverse events were mild or moderate in severity. There were no severe treatment-emergent adverse events or deaths reported in the study. The safety profile of Pexegra is considered to be comparable to that of the reference biologic drug Neulasta.

Indication

Within this drug submission, the sponsor requested the authorization of Pexegra for the indication granted for Neulasta, the reference biologic drug.

Similarity between Pexegra and Neulasta was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. Importantly, 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.

Considering the totality of evidence submitted, including results of structural, functional, non-clinical, and clinical pharmacokinetic, pharmacodynamic, immunogenicity, and safety comparisons between Pexegra and Neulasta, Health Canada authorized Pexegra for the same indication held by Neulasta, as follows:

Pexegra is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.