Summary Basis of Decision for Filra

Filra was developed as a biosimilar of the reference biologic drug, Neupogen. 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 physicochemical and biological properties of Filra and Neupogen authorized in the United States (US-sourced Neupogen) were examined in comparative structural and functional studies. Neupogen authorized in the United States is considered a suitable proxy for Neupogen authorized in Canada, as it meets all of the requirements for a non-Canadian reference biologic drug set out in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. 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 Filra and US-sourced Neupogen are highly similar in terms of primary structure, higher-order structure, and potency. Minor differences were observed in product-related substances and impurities, such as charged variants and sequence variants (e.g., single amino acid misincorporations). These differences had no impact on the biological activity of filgrastim. Moreover, these differences are not expected to have a clinical impact given their small magnitude. They therefore do not preclude a determination of similarity between Filra and US-sourced Neupogen. Nonetheless, the control strategy for Filra 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 Filra and US-sourced Neupogen, thereby further supporting the similarity of the products.

Characterization of the Drug Substance

The medicinal ingredient in Filra is filgrastim, a recombinant methionyl human granulocyte colony stimulating factor (r-metHuG-CSF) produced by recombinant deoxyribonucleic acid (DNA) technology. Filgrastim is a 175 amino acid protein produced by Escherichia coli (E. coli) bacteria, into which has been inserted the human granulocyte colony stimulating factor gene. Filgrastim has a molecular weight of approximately 19 kDa. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E. coli.

Detailed characterization studies were performed to provide assurance that filgrastim 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 initial steps of the manufacturing process for Filra (filgrastim) drug substance are the same as those for the pegfilgrastim product Pexegra, both produced by the same manufacturer. The related data were found to be acceptable when reviewed as part of the New Drug Submission (NDS) for Pexegra, and were not re-evaluated in the NDS for Filra. Data specific to the manufacturing of the Filra drug substance and drug product were reviewed in this NDS and found to be acceptable.

The drug substance manufacturing process involves the manufacturing of a drug substance intermediate, from which the drug substance is prepared. It begins with a fermentation process to generate inclusion bodies from E. coli cells which have been genetically engineered to express filgrastim. Cells from a working cell bank are thawed, cultured, and expanded to the desired cell density, then used to inoculate and ferment in a production bioreactor. Cells are harvested by centrifugation and homogenized to isolate the inclusion bodies containing the filgrastim protein. The inclusion bodies are solubilized to release the filgrastim protein, which is then refolded into its active conformation. This is followed by multiple chromatography and filtration steps, filling into bottles, and storage of the resulting drug substance intermediate at -70 °C ± 10 °C. The preparation of the drug substance involves thawing of the intermediate, dilution, formulation, filtration, filling into bottles, and storage at -70 °C.

The drug product manufacturing process involves the preparation of the formulation buffer, thawing of the drug substance, drug product formulation, sterile filtration, filling into syringes, visual inspection, assembly, and packaging. The syringes are stored at 2 °C to 8 °C for long-term storage.

Process validation studies were conducted on consecutively manufactured lots of both the Filra drug substance and drug product. Overall, the process validation data demonstrate that the established manufacturing processes are capable of consistently manufacturing Filra drug substance and drug product that meet the pre-defined specifications and quality attributes.

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 filgrastim with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The control strategy for Filra includes multiple control elements, including control of materials, process parameters, in-process controls, release specifications, and facility and equipment controls.

The analytical procedures used in the release and stability testing of the drug substance and drug product were adequately validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Compendial methods were verified under conditions of use and found to be satisfactory. The corresponding specifications were set using compendial guidelines, product and process knowledge, and statistical analyses of release and stability data. The established Filra release and stability specifications are considered appropriate and in line with ICH guidelines.

A two-tiered reference standard system is in place, with reference standards that have been well-characterized, and an appropriate program established to qualify future primary and working reference material.

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. No risks were identified for the presence of N-nitrosamine impurities in Filra. Accordingly, no confirmatory testing or mitigation plans are required.

Filra 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. Filra should be stored refrigerated at 2 °C to 8 °C in the outer carton to protect it from light. It must not be shaken or frozen.

Filra may be taken out of the refrigerator 30 minutes prior to injection to reach room temperature. Filra that has been left at room temperature for longer than 24 hours must be discarded. Additional storage and special handling instructions are included in the product monograph for Filra.

Facilities and Equipment

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

Adventitious Agents Safety Evaluation

The raw and starting materials of animal origin were assessed for transmissible spongiform encephalopathy (TSE) and adventitious viral agents. It was determined that the risk for transmission of adventitious agents by Filra is negligible. The filgrastim drug substance intermediate is expressed in a bacterial cell host which does not support replication of viral agents that may infect humans.

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.

Data from two non-clinical studies were submitted for Filra, a 28-day subcutaneous repeat-dose study in rats and an in vitro immunogenicity study using dendritic cell-T (DC-T) cells. Safety pharmacology, pharmacodynamic, genotoxicity, carcinogenicity, and reproductive toxicology studies were not conducted as they are not generally required for biosimilars based on Health Canada’s Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

In the in vitro immunogenicity study, the proposed and reference products performed similarly with respect to the frequency and strength of the immune response. The repeat-dose study in rats included a battery of examinations and assessments to evaluate the toxicity of both products, and determined that the no-observed-adverse-effect level (NOAEL) was greater than the highest dose administered (1,150 mcg/kg) for both Filra and Neupogen. Toxicokinetic analyses found similar dose-related increases in serum filgrastim levels for both products. Similar incidences were observed for the generation of anti-drug antibodies between Filra and Neupogen in an assessment of in vivo immunogenicity.

The results of the comparative non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Filra. Considering the intended use of Filra, 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.

One pivotal comparative pharmacokinetic and pharmacodynamic study (Study TPI-CL-106) and one comparative immunogenicity study (TPI-CL-110) were conducted to evaluate the biosimilarity of Filra to United States (US)-sourced Neupogen (hereafter referred to as Neupogen). Data from a separate clinical pharmacokinetic and pharmacodynamic study (TPI-CL-101) was also provided to further support the safety of Filra.

Comparative Pharmacokinetics and Pharmacodynamics

Filgrastim is a granulocyte colony‑stimulating factor (G-CSF) that binds to cell surface receptors on hematopoietic cells. This stimulates proliferation, differentiation, commitment, and end cell functional activation, which elevates the number of granulocytes in the blood. This increase in granulocytes counteracts the effects of febrile neutropenia that result from treatment with myelosuppressive antineoplastic drugs, thereby decreasing the overall incidence of infection.

For filgrastim products, pharmacokinetic and pharmacodynamic studies in healthy subjects can be considered as pivotal clinical studies to support the overall assessment of biosimilarity. The main clinical support for the biosimilarity assessment came from the pivotal comparative pharmacokinetic and pharmacodynamic study, TPI-CL-106. This study was conducted to evaluate the pharmacokinetic and pharmacodynamic profiles of Filra and Neupogen following a single 5 mcg/kg dose subcutaneous injection. Fifty-four participants completed the study and received both Filra and Neupogen.

The pharmacokinetic results showed that the ratio of geometric means for the maximum concentration (C_max) between Filra and Neupogen was 89.6%. The 90% confidence interval (CI) of the ratio of geometric means for the area under the concentration-time curve to the time of the last quantifiable concentration (AUC_0-t) was 85.7% to 97.4%. These results were within the equivalence margins of 80.0% to 125.0% and demonstrated comparable pharmacokinetic profiles between the two products.

The pharmacodynamic evaluation of absolute neutrophil count (ANC) indicated that the 95% CI of the ratio of geometric means for the maximum effect (E_max) was 101.2% to 112.2% and the area under the effect-time curve from time zero to the last measurable effect (AUEC) was 100.4% to 116.4%. These results were within the equivalence margins of 80.0% to 125.0% and demonstrated comparable ANC profiles between Filra and Neupogen. No new safety concerns were identified following treatment with Filra. No clinically meaningful difference in safety and immunogenicity profiles were observed between Filra and Neupogen.

Comparative Safety and Immunogenicity

The comparative safety and immunogenicity of Filra and Neupogen were primarily evaluated in Study TPI-CL-110, in healthy adult subjects following multiple 5 mcg/kg doses injected subcutaneously. In total, 134 subjects who received at least one dose of the assigned treatment were included in the analyses of immunogenicity and safety, of which 67 were randomized in each treatment group. No subject had treatment-emergent antibodies against recombinant human G-CSF from either Filra treatment or Neupogen treatment. No clinically meaningful differences in safety were identified. The supportive study, TPI-CL-101, further supported the safety of Filra, and results showed that the safety profiles of Filra and Neupogen were similar.

The risk of splenic rupture, including fatal cases, has been reported following the administration of filgrastim. Additionally, severe sickle cell crises, which have resulted in death in some cases, have been associated with the use of filgrastim in patients with sickle cell trait or sickle cell disease. Both are highlighted in a Serious Warnings and Precautions box in the Product Monograph for Filra.

Indications

Filra is a biosimilar biologic drug to the reference drug Neupogen. Neupogen is authorized and marketed in Canada for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with non‑myeloid malignancies receiving myelosuppressive drugs.

Within this drug submission, the sponsor requested the authorization of Filra for the indications that are currently authorized for Neupogen in Canada.

Similarity between Filra and Neupogen 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. Therefore, clinical trials are not required to support each of the submitted indications.

The indications have been authorized on the basis of demonstrated similarity between Filra and the reference biologic drug, in structural and functional studies, mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug.

Upon Health Canada's review, Filra was authorized for the same indications currently held by the reference biologic drug, Neupogen, as follows:

• Cancer Patients Receiving Myelosuppressive Chemotherapy

Filra (filgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-neoplastic drugs.

Filra is indicated in adult and pediatric patients with cancer receiving myelosuppressive chemotherapy. A complete blood count (CBC) and platelet count should be obtained prior to chemotherapy, and twice per week during Filra therapy to avoid leukocytosis and to monitor the neutrophil count. In Phase III clinical studies, filgrastim therapy was discontinued when the absolute neutrophil count (ANC) was > 10 × 10⁹/L after expected chemotherapy-induced nadir.

• Patients with Acute Myeloid Leukemia

Filra is indicated for the reduction in the duration of neutropenia, fever, antibiotic use and hospitalization, following induction and consolidation treatment for acute myeloid leukemia.

• Cancer Patients Receiving Myeloablative Chemotherapy Followed by Bone Marrow Transplantation

Filra is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients undergoing myeloablative therapy followed by bone marrow transplantation.

A CBC and platelet count should be obtained at a minimum of 3 times per week following marrow infusion to monitor marrow reconstitution.

• Cancer Patients Undergoing Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy

Filra is indicated for the mobilization of autologous peripheral blood progenitor cells in order to accelerate haematopoietic recovery by infusion of such cells, supported by Filra, after myelosuppressive or myeloablative chemotherapy.

• Patients with Severe Chronic Neutropenia (SCN)

Filra is indicated for chronic administration to increase neutrophil counts and to reduce the incidence and duration of infection in patients with a diagnosis of congenital, cyclic or idiopathic neutropenia.

• Patients with Human Immunodefeiciency Virus (HIV) Infection

Filra is indicated in patients with HIV infection for the prevention and treatment of neutropenia, to maintain a normal ANC (e.g., between 2 × 10⁹ and 10 × 10⁹/L). Filra therapy reduces the clinical sequelae associated with neutropenia (e.g., bacterial infections) and increases the ability to deliver myelosuppressive medications used for the treatment of HIV and its associated complications. It is recommended that complete blood counts and platelet counts be monitored at regular intervals (e.g., initially twice weekly for 2 weeks, once weekly for an additional 2 weeks, then once monthly thereafter, or as clinically indicated) during Filra therapy.