Summary Basis of Decision for Armlupeg

Armlupeg (pegfilgrastim) was developed as a biosimilar of Neulasta (pegfilgrastim), the reference biologic drug. 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 Armlupeg 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 stipulated in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The results of the biosimilarity studies demonstrate that Armlupeg and US-Neulasta are identical with respect to the primary structure and highly similar with respect to the higher-order structure, biological activity, and drug product-related attributes. Differences were observed in the product-related substances and impurities. The lots of Armlupeg had lower levels of high-molecular-weight species, dipegylated variants, and deamidated variants. These analytical differences in product-related substances and impurities have no impact on the biological activity of pegfilgrastim and are unlikely to be clinically meaningful. Comparative forced degradation studies conducted under different stress conditions generated highly similar degradation profiles for Armlupeg and US-Neulasta, thereby further supporting the similarity of the products. Taken together, these results suggest that Armlupeg is highly similar to US-Neulasta and support the quality requirements for Armlupeg to be considered a biosimilar of Neulasta.

Characterization of the Drug Substance

Pegfilgrastim, the medicinal ingredient in Armlupeg, 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.

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

The manufacturing process of the Armlupeg drug substance, pegfilgrastim, starts with the manufacture of the critical intermediate, filgrastim. Filgrastim is produced in a genetically engineered strain of Escherichia coli. The manufacturing process of filgrastim involves fed-batch bacterial fermentation, cell separation, cell lysis, isolation and washing of inclusion bodies, refolding, ultrafiltration and diafiltration, purification, formulation, filtration, and storage at 2 °C to 8 °C. Subsequently, the filgrastim intermediate is subjected to a pegylation reaction, i.e., conjugation with a 20 kDa methoxy polyethylene glycol propionaldehyde (mPEG-PAL) to produce pegylated filgrastim (pegfilgrastim). The pegylated filgrastim then undergoes purification by cation-exchange chromatography, which is followed by ultrafiltration and diafiltration steps, the addition of polysorbate 20, filtration, and storage at 2 °C to 8 °C.

The manufacturing process of the drug product consists of pooling and mixing of the drug substance, sterile filtration, filling, visual inspection, packaging, and storage at 2 °C to 8 °C. Armlupeg is supplied in a prefilled syringe with a BD UltraSafe Plus^TM Passive Needle Guard. None of the non-medicinal ingredients (excipients) found in Armlupeg 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.

The control strategy of the manufacturing process implements controls at the most appropriate unit operation to ensure consistency of the process and product quality across all stages of manufacturing. Overall, the filgrastim intermediate, 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.

Process validation was conducted with consecutive batches of the filgrastim intermediate, drug substance, and drug product manufactured at the intended commercial scale. Process performance qualification data demonstrate that the manufacturing process is capable of consistently manufacturing filgrastim intermediate, drug substance, and drug product of acceptable quality. 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 hold times, impurity clearance, resin/membrane lifetimes, filters, extractables and leachables testing, sterility assurance, filling, shipping, and other supporting activities and equipment.

Control of the Drug Substance and Drug Product

The release and stability specifications for the drug substance and drug product were appropriately set and justified. All release and stability acceptance criteria were met for the filgrastim intermediate, drug substance, and drug product.

All in-house analytical methods were appropriately validated. 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.

A risk assessment for the 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.

Armlupeg 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, drug substance, and drug product were adequately supported and are considered to be satisfactory. The shelf life of 36 months at 2 °C to 8 °C for the 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

An on-site evaluation of the critical intermediate, drug substance, and drug product manufacturing facility was recommended based on the calculated risk assessment scores. However, such an evaluation was not conducted during the review period. Health Canada considered the results and observations of a recent virtual site evaluation of the same manufacturing facility conducted with respect to the manufacturing process of another biologic product. Additionally, Health Canada considered the United States Food and Drug Administration (FDA)’s inspection observations (cited in the FDA Form 483) and the corresponding corrective and preventive actions.

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

Adventitious Agents Safety Evaluation

Adequate control measures are incorporated in the manufacturing process of Armlupeg 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.

No raw materials of animal or human origin are used in the manufacturing process of the drug substance. Other materials used are in compliance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMA/410/01 rev. 3). The risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered negligible.

The excipients in the drug product formulation are not of animal or human origin.

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. 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 Armlupeg and Neulasta. 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 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 to demonstrate similarity between Armlupeg and Neulasta authorized in the United States (US-Neulasta): one comparative pharmacokinetic and pharmacodynamic study in healthy subjects (Study ARL/18/360/LBC-19-146) and one comparative immunogenicity study in patients with breast cancer (Study LRP/PegGCSF/2016/004). 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 stipulated in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document

Comparative Pharmacokinetics and Pharmacodynamics

The pharmacokinetic and pharmacodynamic profiles of Armlupeg and US-Neulasta were evaluated in a comparative Phase I, randomized, double-blind, single-dose, two-period, crossover study in healthy subjects (Study ARL/18/360/LBC-19-146).

In Period 1 of the study, healthy adult subjects were randomized to receive Armlupeg (131 subjects) or US-Neulasta (133 subjects) as a single subcutaneous dose of 6 mg. In Period 2, the subjects who received Armlupeg in Period 1 were administered US-Neulasta, and vice versa. There were 110 subjects who received Armlupeg and 113 subjects who received US-Neulasta in Period 2. Each period lasted 14 days. A washout period of at least 42 days separated the two periods. In total, 218 subjects completed the study and received both Armlupeg and US-Neulasta.

The comparison of pharmacokinetic parameters showed that the ratio of geometric means for the maximum concentration observed (C_max) of Armlupeg to US-Neulasta was 94.4%, and the 95% 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 Armlupeg to US-Neulasta was 89.9% to 100.0%. 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). Hence, the study demonstrated comparable pharmacokinetic profiles of Armlupeg and the reference drug.

Pharmacodynamic comparability of Armlupeg 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 value for ANC from baseline (ANC-C_max) of Armlupeg to US-Neulasta was 100.3%. 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 (AUEC_0-tlast) for ANC of Armlupeg to US-Neulasta was 98.7% to 101.8%. The results were within the predefined equivalence margins of 90.00% to 111.11%.

Comparative Immunogenicity

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 immunogenicity profiles of Armlupeg and US-Neulasta were compared in a randomized, open-label, parallel-group, comparative immunogenicity study in patients with breast cancer treated with myelosuppressive chemotherapy (Study LRP/PegGCSF/2016/004). Patients were randomized to receive Armlupeg (70 patients) or US-Neulasta (68 patients) at a dose of 6 mg administered subcutaneously on Day 2 or Day 3 of each 21-day chemotherapy cycle for four cycles. The proportions of patients with treatment-emergent anti-pegfilgrastim antibodies were low and balanced between groups (Armlupeg group: 1.7%, US-Neulasta group: 5.4%). The study showed that there were no clinically meaningful differences between Armlupeg and US-Neulasta in terms of immunogenicity.

Similarly, no clinically meaningful differences were observed in the frequencies of anti-pegfilgrastim binding antibodies and anti-pegfilgrastim neutralizing antibodies between healthy subjects who received Armlupeg and those who received US-Neulasta in the comparative pharmacokinetic and pharmacodynamic study (ARL/18/360/LBC-19-146).

Comparative Safety

Safety data were provided from the comparative pharmacokinetic and pharmacodynamic study (ARL/18/360/LBC-19-146) in healthy subjects and the comparative immunogenicity study (LRP/PegGCSF/2016/004) in patients with breast cancer.

There were no new safety concerns identified in healthy subjects following administration of a single subcutaneous dose of Armlupeg and in patients with breast cancer who received one dose of Armlupeg per chemotherapy cycle for four cycles. Based on the provided data, the safety profile of Armlupeg is considered to be comparable to that of the reference biologic drug Neulasta. As with Neulasta, appropriate warnings and precautions are in place in the Armlupeg Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box has been included in the Product Monograph for Armlupeg, as is found in the Product Monograph for Neulasta. It highlights the reported occurrence of splenic rupture, including fatal cases, following the administration of pegfilgrastim and its parent compound, filgrastim, as well as the reported occurrence of severe sickle cell crises, including fatal cases, associated with the use of pegfilgrastim (and filgrastim) in patients with sickle cell trait or sickle cell disease. The Adverse Reactions section of the Armlupeg Product Monograph is based on the clinical experience with Neulasta.

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

Indication

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

Similarity between Armlupeg 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, and clinical pharmacokinetic, pharmacodynamic, immunogenicity, and safety comparisons between Armlupeg and Neulasta, Health Canada authorized Armlupeg for the same indication held by Neulasta, as follows:

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