Summary Basis of Decision for Nyvepria

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Nyvepria is located below.

Recent Activity for Nyvepria

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

 

The following table describes post-authorization activity for Nyvepria, a product which contains the medicinal ingredient pegfilgrastim. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2024-07-31

 

Drug Identification Number (DIN):

DIN 02506238 – 10 mg/mL pegfilgrastim, solution, subcutaneous administration

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 256790

2021-09-17

Issued NOC 2022-02-14

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information to align with that of the reference biologic drug, Neulasta, and to migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 259237

2021-12-07

Issued NOL 2022-01-10

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug substance manufacturing facility. The submission was considered acceptable, and an NOL was issued.

SNDS # 250936

2021-03-22

Issued NOC 2021-11-08

Submission filed as a Level I – Supplement to add an alternate drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 247675

2020-12-18

Issued NOC 2021-06-03

Submission filed as a Level I – Supplement to propose labelling updates for a demonstration toolkit. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02506238) market notification

Not applicable

Date of first sale: 2021-01-18

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 233373

2019-11-12

Issued NOC 2020-10-28

NOC issued for New Drug Submission.

Summary Basis of Decision (SBD) for Nyvepria

Date SBD issued: 2021-03-22

The following information relates to the New Drug Submission for Nyvepria.

Pegfilgrastim

Drug Identification Number (DIN):

  • DIN 02506238 - 10 mg/mL pegfilgrastim, solution, subcutaneous administration

Pfizer Canada ULC

New Drug Submission Control Number: 233373

 

On October 28, 2020, Health Canada issued a Notice of Compliance (NOC) to Pfizer Canada ULC for Nyvepria, a biosimilar to Neulasta (the reference biologic drug). The terms "biosimilar biologic drug" and "biosimilar" are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as subsequent entry biologics in Canada. Nyvepria contains the medicinal ingredient pegfilgrastim, which has been demonstrated to be highly similar to pegfilgrastim contained in the reference product, Neulasta.

Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. To be considered a biosimilar, the weight of evidence is provided by the structural and functional studies; the non‑clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non‑clinical, pharmacokinetic and pharmacodynamic, and clinical studies.

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought.

For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

In this drug submission, Neulasta is the reference biologic drug. Similarity between Nyvepria and Neulasta was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within this drug submission, the sponsor requested the authorization of Nyvepria for the same indication that is currently authorized for Neulasta.

The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada's review, the benefit‑risk profile of Nyvepria is considered to be similar to the benefit‑risk profile of the reference product. Nyvepria is therefore considered favourable for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with non‑myeloid malignancies receiving myelosuppressive anti-neoplastic drugs.

 

1 What was approved?

 

Nyvepria, a granulocyte colony‑stimulating factor (G‑CSF), was authorized for the same indication as the reference biologic drug Neulasta to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non‑myeloid malignancies receiving myelosuppressive anti-neoplastic drugs.

The safety and effectiveness of Nyvepria in pediatric patients (<18 years of age) have not been established.

In clinical studies, 15% of the total number of patients with cancer who received pegfilgrastim were 65 years or older. No overall differences in safety or effectiveness were observed in these patients versus younger patients. However, due to the small number of elderly patients, small but clinically relevant differences cannot be excluded.

Nyvepria is a biosimilar to Neulasta. Both drugs contain the medicinal ingredient pegfilgrastim, which is produced in Escherichia coli cells using recombinant deoxyribonucleic acid (DNA) technology. Pegfilgrastim is a longer‑acting, PEGylated version of the recombinant methionyl human G‑CSF, filgrastim.

Similarity between Nyvepria and the reference biologic drug, Neulasta, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, comparative pharmacokinetic and pharmacodynamic studies, and comparative safety and immunogenicity studies, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Nyvepria is contraindicated in patients with known hypersensitivity to E. coli‑derived proteins‚ pegfilgrastim‚ filgrastim, or any other component of the product.

Nyvepria was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Nyvepria (10 mg/mL pegfilgrastim, supplied as a solution [0.6 mL] containing 6 mg pegfilgrastim) is presented as a sterile solution for injection. In addition to the medicinal ingredient, the solution contains sodium, acetate, sorbitol, polysorbate 20 and water for injection.

For more information, refer to the Quality (Chemistry and Manufacturing), Non‑clinical, and Clinical Basis for Decision sections.

Additional information may be found in the Nyvepria Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Nyvepria approved?

 

Health Canada considers that the benefit‑risk profile of Nyvepria is highly similar to that of the reference biologic drug Neulasta. The requested and authorized indication is the same as for Neulasta, which is to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non‑myeloid malignancies receiving myelosuppressive antineoplastic drugs.

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

Neutropenia is an abnormally low number of neutrophils in the blood. Neutrophils are a type of white blood cell with a critical role in fighting infection. Since neutropenia weakens the immune system, affected patients are at an increased risk of developing an infection. Neutropenia may have various causes, but it is often a consequence of myelosuppressive chemotherapy. Its occurrence represents a dose‑limiting factor in chemotherapy regimens. The development of severe neutropenia during chemotherapy often leads to dose reduction or dose interruption for the patient, which can interfere with the success of treatment.

Pegfilgrastim, the medicinal ingredient in Nyvepria, is the PEGylated, longer‑acting form of the recombinant methionyl human granulocyte colony‑stimulating factor (G‑CSF), filgrastim. PEGylation refers to the addition of a polyethylene glycol (PEG) moiety to a molecule, most typically to peptides and proteins, including antibody fragments. Filgrastim binds to surface receptors on hematopoietic cells, which stimulates proliferation, differentiation, commitment, and end‑cell functional activation, including the proliferation of neutrophils. Pegfilgrastim has the same mechanism of action as filgrastim, but its larger size results in a greater residence time in circulation and a prolonged pharmacodynamic effect, thereby requiring less frequent dosing than filgrastim. While filgrastim requires daily administration, pegfilgrastim may be administered once per cycle of chemotherapy.

The quality attributes of the biosimilar and the reference biologic drug were determined to be highly similar based on evidence from comparative structural and functional studies. A comparative pharmacokinetic and pharmacodynamic study in healthy subjects provided the main clinical basis to support the biosimilarity (quality) assessment. Additionally, one comparative immunogenicity study conducted in healthy volunteers and one supportive clinical study conducted in breast cancer patients further support the immunogenicity and/or safety of Nyvepria. The demonstration of similarity enables the biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug for the authorized indication.

Nyvepria has demonstrated a comparable safety profile with the reference product, Neulasta. Therefore, the Adverse Reactions section of the Nyvepria Product Monograph is based on the clinical experience with the reference biologic drug. As with Neulasta, the major identified safety concerns include splenic rupture and severe sickle cell crises. These risks have been listed in the Serious Warnings and Precautions box in the Nyvepria Product Monograph, as can be found in the Neulasta Product Monograph.

A Risk Management Plan (RMP) for Nyvepria was submitted by Pfizer Canada ULC to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Nyvepria was accepted.

Overall, Nyvepria is considered to have a benefit‑risk profile comparable to that established for the authorized indication of its reference biologic drug Neulasta. The benefits of Nyvepria are considered to outweigh the potential risks in the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Nyvepria Product Monograph to address the identified safety concerns and are aligned with the information presented in the labeling for the reference product Neulasta.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. For more information, refer to the Quality (Chemistry and Manufacturing), Non‑clinical, and Clinical Basis for Decision sections.

 

3 What steps led to the approval of Nyvepria?

 

Submission Milestones: Nyvepria

Submission Milestone Date
Pre-submission meeting 2019-08-13
Submission filed 2019-11-11
Screening  
Screening Acceptance Letter issued 2020-01-02
Review  
Review of Risk Management Plan complete 2020-08-21
Clinical/Medical Evaluation complete 2020-09-14
Labelling Review complete 2020-09-23
Quality Evaluation complete 2020-10-07
Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate 2020-10-28

 

The Canadian regulatory decision on the review of Nyvepria was based on a critical assessment of the data package submitted to Health Canada. Review documents from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were consulted for relevant supplementary information.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

The onus is on the Nyvepria sponsor to monitor the post-market safety profile of this biosimilar product as well as the Product Monograph of the reference biologic drug for safety signals that could impact the biosimilar, and make safety updates to the Nyvepria Product Monograph as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.

 

5 What post-authorization activity has taken place for Nyvepria?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Nyvepria is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Quality Basis for Decision

 

Nyvepria was developed as a biosimilar to the reference biologic drug, Neulasta. For biosimilars, the weight of evidence 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.

The biological activity of Nyvepria is considered to be representative of the mechanism of action and pharmacological effect of Neulasta.

Comparative Structural and Functional Studies

The biosimilarity assessment for Nyvepria was based on pairwise comparisons between Nyvepria and Neulasta authorized in the European Union (EU‑Neulasta), Nyvepria and Neulasta licensed in the United States (US‑Neulasta), and EU‑Neulasta and US‑Neulasta. The demonstration of similarity between EU‑Neulasta and US‑Neulasta was included to provide support for the use of either one as the comparator to Nyvepria in the comparative clinical studies.

The reference biologic drug for Nyvepria is specifically EU‑Neulasta, as it was used to derive the quality ranges for the similarity assessment. Additionally, EU‑Neulasta meets the requirements for the use of non‑Canadian reference biologic drugs outlined in Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The results of the biosimilarity assessment indicate that Nyvepria is identical to Neulasta with respect to primary structure, and highly similar with regards to higher order structures and potency. Lower levels of total related proteins, total charge and size variants, dimers, oxidation, deamidation, and des‑PEGylated species were detected in lots of Nyvepria. However, the observed differences in product‑related substances and impurities have no impact on biological activity.

Similar degradation profiles were observed for Nyvepria, EU‑Neulasta, and US‑Neulasta based on comparative stability and forced degradation studies conducted under different stress conditions. Collectively, the results of the biosimilarity assessment demonstrate that Nyvepria is highly similar to EU‑Neulasta, and support the quality requirements for Nyvepria to be considered a biosimilar to the reference biologic drug.

Characterization of the Drug Substance

Detailed characterization studies were performed, which demonstrated that pegfilgrastim, the medicinal ingredient in Nyvepria, consistently exhibits the desired characteristic structure and biological activity. Product‑ and process‑related impurities were evaluated and found to be adequately controlled.

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

Manufacturing of pegfilgrastim, the medicinal ingredient in Nyvepria, occurs in two stages: the manufacturing of the filgrastim intermediate (the parent compound), and the addition of a polyethylene glycol (PEG) moiety to filgrastim to produce pegfilgrastim.

Filgrastim is expressed from Escherichia coli cells, which have been engineered to express this protein through recombinant deoxyribonucleic acid (DNA) technology. A seed culture of E. coli cells is used to inoculate a production fermenter in which the cell culture expands to commercial scale. The production fermentate is harvested, homogenized, and centrifuged to release the filgrastim inclusion bodies. Filgrastim is released from inclusion bodies, and refolded to restore it to its biologically active configuration. It is purified through a series of chromatography steps, and then undergoes concentration, buffer exchange, formulation and filtration.

Pegfilgrastim is produced through the addition of a PEG moiety to the filgrastim intermediate; a process known as PEGylation. The newly created pegfilgrastim undergoes chromatography and buffer exchange and is adjusted to the target concentration. The formulated bulk solution is sterile filtered to produce the drug substance.

Manufacturing of Nyvepria, the drug product, involves preparation of formulation buffer, preparation of drug product solution, bioburden reduction filtration, sterile filtration, aseptic filling, visual inspection, secondary packaging, and storage at 5°C.

Process validation was conducted using batches of the filgrastim intermediate, drug substance (pegfilgrastim), and drug product (Nyvepria) manufactured at the intended commercial scale at the proposed manufacturing sites. The process performance qualification data reviewed reflect consistency in the manufacturing processes.

All non‑medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drugs Regulations. The compatibility of pegfilgrastim with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Nyvepria is a Schedule D (biologic) drug and is therefore subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. Consistency lot testing for Nyvepria was not feasible due to the shutdown of laboratories in the early stages of the coronavirus disease 2019 (COVID‑19) pandemic. A paper‑based assessment was conducted in its place, which involved a review of the standard operating procedures and an in‑house analysis of raw data from multiple lots of the drug product. The results of the review support the consistency of the manufacturing process.

A comprehensive, multi‑level control strategy has been implemented for the manufacturing of the filgrastim intermediate, drug substance, and drug product. The control strategy was found to be suitable for controlling the critical process parameters and ensuring that production of Nyvepria meets pre‑defined criteria and specifications.

All in‑house analytical methods were appropriately validated, and reference standards have been well characterized. All release and stability acceptance criteria were met for the filgrastim intermediate, drug substance, and drug product.

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 satisfactory. The proposed shelf life of 36 months at 2‑8°C for Nyvepria is considered acceptable. Nyvepria may be stored at room temperature for up to 15 days. Additional storage and special handling instructions are included in the Nyvepria Product Monograph.

Facilities and Equipment

An on‑site evaluation (OSE) was recommended for the facility at which the filgrastim intermediate is manufactured. However, the OSE was waived because production is expected to be transferred to a different site. An OSE was not recommended for the drug substance and drug product site at the time of review, as an OSE had recently been conducted and the site received a compliant rating.

Adventitious Agents Safety Evaluation

The master and working cell banks were extensively characterized and confirmed to be free of fungal contaminants, bacteriophages, and other adventitious agents. Microbial testing is performed throughout the manufacturing process as part of the in‑process and release tests.

The raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.

 

7.2 Non-Clinical Basis for Decision

 

For biosimilars, the degree of similarity 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 data submitted for Nyvepria complied with the requirements for non‑clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. One comparative 4‑week repeat dose study conducted in rats demonstrated no notable differences between Nyvepria and Neulasta for any toxicological endpoints.

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

 

 

7.3 Clinical basis for decision

 

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in support of the indications being sought, and therefore clinical trials are not required to support each indication.

For biosimilars, the purpose of the clinical program 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 Pharmacokinetic and Pharmacodynamic Studies

Pegfilgrastim and its parent compound, filgrastim, are granulocyte colony‑stimulating factors that bind 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.

Studies on cellular proliferation, receptor binding, and neutrophil function demonstrate that filgrastim and pegfilgrastim have the same mechanism of action. Pegfilgrastim is the PEGylated form of filgrastim. Due to its larger size, it has a longer residence time in circulation, allowing for a more sustainable pharmacodynamic effect and less frequent dosing.

For filgrastim and pegfilgrastim 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 was provided by Study ZIN‑130‑1505, a pivotal Phase I study to compare the pharmacokinetics and pharmacodynamics of Nyvepria to Neulasta authorized in the European Union (EU‑Neulasta) and Neulasta licensed in the United States (US‑Neulasta).

Study ZIN‑130‑1505 was an open‑label, three‑way crossover study conducted in 153 healthy subjects. Subjects were randomized to one of six sequence groups, to receive each of the three study drugs over three treatment periods (one drug per treatment period). The study drugs were administered as a single 6 mg subcutaneous injection in the deltoid region, with a washout period of at least 56 days between treatment periods to minimize carryover effects. While both US‑Neulasta and EU‑Neulasta were included in the study, EU‑Neulasta was identified as the official Canadian reference product. As such, the results focused on the comparison of Nyvepria to EU‑Neulasta.

Pharmacokinetic and pharmacodynamic comparability between Nyvepria and EU‑Neulasta were demonstrated through the outcomes of this study. The two primary pharmacokinetic endpoints were the area under the serum pegfilgrastim concentration curve from time zero to the last measurable time point (AUCT), and the maximum observed pegfilgrastim concentration (Cmax). The ratio of the geometric means of Nyvepria to EU‑Neulasta for the AUCT was 0.97 (90% confidence interval [CI]: 0.91, 1.05), and the point estimate of the Cmax was 0.95 (90% CI: 0.88, 1.02). The two primary pharmacodynamic endpoints were the area under the effect absolute neutrophil count (ANC)‑time curve from zero to the last measurable time point (AUECANC), and the maximum effect (ANCCmax). Absolute neutrophil count is considered as a valid and sensitive pharmacodynamic marker in response to treatment with pegfilgrastim. The ratio of geometric means was 0.98 (95% CI: 0.96, 1.00) for the AUECANC and 0.99 (95% CI: 0.96, 1.01) for the Cmax. The ratios of geometric means for pharmacokinetic and pharmacodynamic endpoints were all contained within the pre‑specified acceptability margins, which met Health Canada's criteria for pharmacokinetic and pharmacodynamic comparability between Nyvepria and EU‑Neulasta.

For further details, please refer to the Nyvepria Product Monograph, approved by Health Canada and available through the Drug Product Database.

Comparative Clinical Safety

The clinical safety of Nyvepria was evaluated in Study ZIN‑130‑1505 (the pivotal study, described in detail in the Comparative Pharmacokinetic and Pharmacodynamic Studies section), Study C1221005 (a Phase I non‑inferiority study, described further in the Comparative Immunogenicity section), and Study ZIN‑130‑1504 (a supportive Phase I/II ascending dose study).

Data from Study ZIN‑130‑1505 indicated that the overall safety of Nyvepria is comparable to that of Neulasta. At least one treatment‑emergent adverse event (TEAE) was observed in 147 subjects (99.3%) in the Nyvepria treatment arm, 141 subjects (95.3%) in the EU‑Neulasta treatment arm, and 139 subjects (95.2%) in the US‑Neulasta treatment arm. Vessel puncture site bruises, lacerations, and dizziness were reported more frequently in subjects in the Nyvepria treatment arm than in subjects in the reference treatment arms (EU‑Neulasta and US‑Neulasta). Injection site reactions were reported more frequently in subjects in the Nyvepria treatment arm than the EU‑Neulasta treatment arm, but less frequently in subjects in the US‑Neulasta treatment arm. None of the differences in injection site reactions, vessel puncture site bruises, lacerations, or dizziness were considered to be clinically relevant.

In Study C1221005, the most common TEAEs (in ≥20% of subjects) reported in either treatment arm were back pain, headache, and musculoskeletal pain. Some TEAEs were reported at a higher incidence in the Nyvepria arm than in the US‑Neulasta arm (i.e., dizziness, injection site pain, non‑cardiac chest pain, infections, oropharyngeal pain, and potential allergic reactions). The observed differences in the incidences of TEAEs were attributed to chance findings, and are not considered to be clinically meaningful or due to product‑related differences.

Study ZIN‑130‑1504 was conducted in patients with non‑metastatic breast cancer. The initial objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and safety of Nyvepria. Due to the study design and the patient population in which it was conducted, the pharmacokinetic and pharmacodynamic comparability could not be assessed in the context of a biosimilar submission. However, the safety data reviewed were consistent with the known safety profile of pegfilgrastim drugs.

As with Neulasta, the major identified safety concerns for Nyvepria include the risk of splenic rupture, and the risk of severe sickle cell crises in patients with sickle cell trait or sickle cell disease. These concerns have been associated with pegfilgrastim and its parent compound, filgrastim, and were detected post‑market in patients who received Neulasta. Splenic rupture and severe sickle cell crises have been highlighted in a Serious Warnings and Precautions box in the Nyvepria and Neulasta Product Monographs.

Overall, the safety profile of Nyvepria is considered to be comparable to that established for the reference biologic drug Neulasta. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warnings and Precautions section of the Nyvepria Product Monograph, as they are in the Product Monograph for Neulasta.

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

Comparative Immunogenicity

The comparative immunogenicity of Nyvepria and US‑Neulasta was evaluated in Study C1221005, a Phase I open‑label non‑inferiority study conducted in 420 randomized healthy subjects. Immunogenicity data were also collected in Study ZIN‑130‑1505 (the pivotal study, described in the Comparative Pharmacokinetic and Pharmacodynamic Studies section).

In Study C1221005, subjects were randomized to one of two treatment arms: Nyvepria or US‑Neulasta. Each subject received a total of two doses of 6 mg of Nyvepria or US‑Neulasta via subcutaneous (SC) injection. There was an interval of approximately one month between the first and second injection. The duration of treatment period 1 was 30 days (± 2 days) and the duration of treatment period 2 was 60 days (± 5 days). Blood samples were collected to test for the presence of anti‑drug antibodies (ADAs; including anti‑pegfilgrastim and anti‑polyethylene glycol [PEG] antibodies). Samples were collected on Day 1 (pre‑treatment baseline), Day 13, and Day 30 (± 2 days) in treatment period 1, and on Day 13, Day 30 (± 2 days) (or early withdrawal), and Day 60 (± 5 days) in treatment period 2.

The primary immunogenicity endpoint was the proportion of subjects with a negative baseline anti‑pegfilgrastim antibody test result and confirmed post‑dose positive anti‑pegfilgrastim antibody test result at any time during the study. Of the 420 subjects who received at least one dose of study drug, anti‑pegfilgrastim antibodies were confirmed in 32 subjects at least once during the study. Fourteen (6.7%) of these subjects were in the Nyvepria treatment arm and 18 subjects (8.6%) were in the US‑Neulasta treatment arm. The risk difference of the primary endpoint was ‑1.91%, with a 95% confidence interval (CI) of ‑7.36% to 3.36%. This result establishes non‑inferiority between the two drugs, as the upper limit of the 95% CI for the risk difference was less than or equal to the pre‑specified non‑inferiority margin of 10%. The incidence of anti‑PEG antibody was comparable between the two treatment arms.

There was no evidence of neutralizing antibodies (NAb) among subjects in either treatment arm who tested negative for anti‑pegfilgrastim antibodies at baseline. One subject in the Nyvepria treatment arm who tested positive for anti‑pegfilgrastim antibodies at baseline also tested positive for NAb during the study. This case was not determined to be clinically relevant.

In Study ZIN‑130‑1505, ADAs were reported in 4.1% of subjects in the Nyvepria treatment arm, compared with 1.4% of subjects each in the EU‑Neulasta and US‑Neulasta treatment arms. Two ADA‑positive subjects in the Nyvepria treatment arm had a single sample positive for neutralizing antibodies (NAbs), but they were not considered to be clinically meaningful. The incidence of anti‑PEG antibodies was comparable in all treatment arms.

Indications

Nyvepria is a biosimilar biologic drug to the reference drug Neulasta. Neulasta 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 anti‑neoplastic drugs.

Within this drug submission, the sponsor requested the authorization of Nyvepria for the same indication currently authorized for Neulasta.

Similarity between Nyvepria and Neulasta was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug. These data support the authorization of the same indication for the biosimilar drug.

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

 

 

 

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