Summary Basis of Decision for Ziextenzo

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 Ziextenzo is located below.

Recent Activity for Ziextenzo

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 Ziextenzo, 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: 2024-03-07

Drug Identification Number (DIN):

DIN 02497395 – 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

NC # 278571

2023-08-25

Issued NOL 2023-11-21

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the modification of a primary container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 276788

2023-06-29

Issued NOL 2023-08-29

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

NC # 270644

2022-12-14

Issued NOL 2023-03-22

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in specification for the materials. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 270623

2022-12-13

Issued NOL 2023-02-16

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

NC # 269559

2022-11-09

Issued NOL 2022-12-13

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug substance (release and stability). The submission was considered acceptable, and an NOL was issued.

SNDS # 249908

2021-02-25

Issued NOC 2021-08-13

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Action and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 243258

2020-08-26

Issued NOC 2021-03-22

Submission filed as a Level I – Supplement for changes to the drug substance manufacturing process, including the fermentation process, control strategy, and purification process. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 243893

2020-09-11

Issued NOL 2020-12-18

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an extension of the reference standard shelf-life or retest period and a change to reference standard qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 244087

2020-09-17

Issued NOL 2020-10-19

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the labelled storage conditions for the drug product or the diluted or reconstituted product. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 240748

2020-06-17

Issued NOL 2020-09-24

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls (in‐process tests and/or acceptance criteria) applied during the drug substance manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02497395) market notification

Not applicable

Date of first sale: 2020-05-15

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

NDS # 220445

2019-04-09

Issued NOC 2020-04-21

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Ziextenzo

Date SBD issued: 2020-07-31

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

Pegfilgrastim

Drug Identification Number (DIN):

  • DIN 02497395 - 10 mg/mL, solution, subcutaneous administration

Sandoz Canada Inc.

New Drug Submission Control Number: 220445

 

On April 21, 2020, Health Canada issued a Notice of Compliance (NOC) to Sandoz Canada Inc. for Ziextenzo, 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. Both Ziextenzo and Neulasta contain highly similar versions of the medicinal ingredient, pegfilgrastim.

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 Ziextenzo 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 Ziextenzo for the 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 Ziextenzo is considered to be highly similar to the reference biologic drug, Neulasta, which is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non myeloid malignancies receiving myelosuppressive antineoplastic drugs.

 

1 What was approved?

 

Ziextenzo, a granulocyte colony‑stimulating factor, 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 antineoplastic drugs.

Ziextenzo 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 granulocyte colony‑stimulating factor (G‑CSF), filgrastim.

Similarity between Ziextenzo and 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.

Ziextenzo is not authorized for use in pediatric patients (<18 years of age), as its safety and effectiveness have not been established in this population.

Ziextenzo is contraindicated in patients with known hypersensitivity to E. coli‑derived products, pegfilgrastim, filgrastim, or any other component of the product, including any non-medicinal ingredient, or component of the container.

Ziextenzo 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.

Ziextenzo (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 acetic acid, polysorbate 20, sorbitol, sodium hydroxide, and water for injection.

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.

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

 

2 Why was Ziextenzo approved?

 

Health Canada considers that the benefit‑risk profile of Ziextenzo is highly similar to 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 Ziextenzo 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, and 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 Ziextenzo, 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, comparative clinical trials ruled out clinically meaningful differences in safety and immunogenicity between the biosimilar and the reference biologic drug in female patients with breast cancer receiving established myelosuppressive chemotherapy. The demonstration of similarity enables the biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug in the indication authorized.

Ziextenzo has demonstrated a comparable safety profile with the reference product, Neulasta. Therefore, the Adverse Reactions section of the Ziextenzo 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 Ziextenzo Product Monograph, as can be found in the Neulasta Product Monograph.

A Risk Management Plan (RMP) for Ziextenzo was submitted by Sandoz Canada Inc. 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 Ziextenzo was accepted.

Overall, Ziextenzo 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 Ziextenzo 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 Ziextenzo Product Monograph to address the identified safety concerns and are aligned with the information presented in the labelling 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 Ziextenzo?

 

Submission Milestones: Ziextenzo

Submission Milestone Date
Submission filed: 2019-04-09
Screening  
Screening Acceptance Letter issued: 2019-05-27
Review  
Review of Risk Management Plan complete: 2020-01-21
Quality Evaluation complete: 2020-03-22
Clinical Evaluation complete: 2020-03-22
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2020-03-22
Patent Hold  
Submission placed on Patent Hold: 2020-03-19
Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate: 2020-04-21

 

The Canadian regulatory decision on the review of Ziextenzo was based on a critical assessment of the data package submitted to Health Canada. Review reports 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 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 Ziextenzo 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 Ziextenzo 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 Ziextenzo?

 

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's life cycle.

The PAAT for Ziextenzo 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

 

Ziextenzo 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 Ziextenzo is considered to be representative of the mechanism of action and pharmacological effect of Neulasta.

Comparative Structural and Functional Studies

The biosimilarity assessment for Ziextenzo was based on comparisons involving Neulasta authorized in Canada (Neulasta‑CA, the Canadian reference product), in the European Union (Neulasta‑EU), and in the United States (Neulasta‑US). Tests were performed to demonstrate comparability between Neulasta‑EU and Neulasta‑US, which were used in the comparative studies with Ziextenzo. Ziextenzo and Neulasta‑CA were each compared to both Neulasta‑EU and Neulasta‑US through head‑to‑head analyses and release testing results, establishing a link between Ziextenzo and Neulasta‑CA.

The physicochemical and biological properties of the drugs were characterized, and comparative stability assessments were conducted through various methods, using a well‑justified risk‑based tiered approach. The results of characterization tests met suitable, pre‑defined acceptance criteria.

Comparative stability studies were performed under intended, accelerated, and stressed conditions, as well as under mechanical stress conditions. Similar degradation profiles were observed between Ziextenzo and the reference drug. No new impurities were identified in Ziextenzo. Collectively, the data reviewed for the biosimilarity assessment indicate that Ziextenzo is highly similar to the reference product, Neulasta.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that pegfilgrastim, the medicinal ingredient in Ziextenzo, consistently exhibits the desired characteristic structure and biological activity. Product‑related substances and impurities in the drug substance were characterized, and levels were highly comparable to those found in Neulasta (EU and US). No new impurities were detected in Ziextenzo. Collectively, the data reviewed demonstrate that Ziextenzo is highly comparable to the reference biologic drug, Neulasta.

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

Manufacturing of pegfilgrastim, the medicinal ingredient in Ziextenzo, occurs in two stages: the manufacturing of the filgrastim intermediate (the parent compound), and the PEGylation of filgrastim to produce pegfilgrastim.

The process begins with the expression and purification of filgrastim from Escherichia coli cells, which were engineered to express this protein through recombinant deoxyribonucleic acid (DNA) technology. The E. coli culture is initiated from a single working cell bank vial and allowed to expand to commercial scale.

At the end of the fermentation process, the cell culture is harvested and the cells are lysed to release filgrastim inclusion bodies, which are isolated and solubilised. The purification of filgrastim and its restoration to a biologically active configuration are accomplished through refolding of the protein, followed by a series of chromatography steps. The intermediate bulk substance is stored frozen in pre‑sterilized bottles.

Pegfilgrastim is produced through the addition of a polyethylene glycol (PEG) moiety to the filgrastim intermediate, a process known as PEGylation. The newly created pegfilgrastim is purified and stored frozen.

To produce the drug product, the bulk drug substance is thawed and combined with the excipient solution, which is then adjusted to the proper pH and volume. The solution is sterile filtered, filled into pre‑sterilized syringes, sealed with stoppers, and the product is visually inspected.

During product development, changes were made to the manufacturing processes for the filgrastim intermediate, drug substance, and drug product due to scaling up and in order to optimize the processes. Comparability studies were conducted to evaluate pre‑ and post‑change batches, which demonstrated that product quality was not affected by the changes. The manufacturing process is considered to be adequately controlled within justified limits.

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

Control of the Drug Substance and Drug Product

The control strategies for the filgrastim intermediate, drug substance, and drug product were examined and found to be appropriate. The results of process validation studies showed that pre‑defined acceptance criteria for parameters related to quality, efficacy, and safety are consistently met.

Ziextenzo is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. As part of this program, final product lots were tested using a subset of release methods and shown to be fit for purpose.

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 Ziextenzo is considered acceptable. Additional storage and special handling instructions are included in the Ziextenzo Product Monograph.

Facilities and Equipment

Risk‑based assessments conducted by Health Canada during the review of Ziextenzo indicated that there were no factors which would require an on‑site evaluation (OSE) at the facilities responsible for manufacturing of the filgrastim intermediate, drug substance, and drug product. Therefore, OSEs were not conducted in connection with this submission.

Adventitious Agents Safety Evaluation

The manufacturing process of Ziextenzo incorporates adequate control measures to prevent contamination and maintain microbial control.

The cell banks used in the manufacture of Ziextenzo met suitable acceptance criteria with respect to identity, purity, plasmid retention, and sequence integrity. They were confirmed to be free of viral contaminants and other adventitious agents.

None of the raw materials used in the production of Ziextenzo are of animal or human origin.

 

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 Ziextenzo was in compliance with the requirements for non‑clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

A comprehensive non‑clinical pharmacology package was submitted for Ziextenzo, including pharmacokinetic/pharmacodynamic (PK/PD) studies, toxicity studies, dose range‑finding studies, and exploratory studies in various appropriate animal models. The PK/PD studies compared the effects of single and multiple doses of Ziextenzo and Neulasta in naïve and neutropenic settings.

Enlarged spleen (splenomegaly) was the principal gross pathological finding in non‑clinical studies with the reference biologic drug, Neulasta.

Adverse effects were observed when pegfilgrastim was administered to pregnant rabbits, and non‑clinical data from pregnant rats indicate that very low levels of pegfilgrastim can cross the placenta. Therefore, pegfilgrastim should only be used during pregnancy if the potential benefit outweighs the risk to the fetus. Additionally, it is unknown whether pegfilgrastim is excreted in human milk. Ziextenzo is not recommended for nursing women, and should only be administered if the potential benefit outweighs the risk.

The results of the comparative non‑clinical studies as well as the potential risks to humans have been included in the Ziextenzo Product Monograph. Considering the intended use of Ziextenzo, there are no pharmacological or toxicological issues within this submission that preclude authorization of the product.

For more information, refer to the Ziextenzo 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 determines the scope and 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, a PEGylated granulocyte colony‑stimulating factor, binds to specific receptors on hematopoietic cells to promote their proliferation and differentiation into various types of granulocytes (a type of white blood cell). This elevates the level of granulocytes in the blood, counteracting the effects of febrile neutropenia resulting from treatment with myelosuppressive antineoplastic drugs, and thereby decreasing the overall incidence of infection.

Studies on cellular proliferation, receptor binding, and neutrophil function demonstrate that pegfilgrastim and its parent compound, filgrastim, have the same mechanism of action. Pegfilgrastim is the PEGylated, longer‑acting form of filgrastim. PEGylation refers to the addition of a polyethylene glycol (PEG) moiety to a molecule. Due to its larger size, pegfilgrastim has a longer residence time in circulation, allowing for a more sustained pharmacodynamic effect and less frequent dosing.

For filgrastim and pegfilgrastim products, pharmacokinetic and pharmacodynamic (PK/PD) studies in healthy subjects can be considered the pivotal clinical studies to support the overall assessment of biosimilarity. The main clinical support for the biosimilarity assessment was provided by Study LA‑EP06‑104, a single‑dose three‑way crossover study evaluating the pharmacokinetics and pharmacodynamics of Ziextenzo relative to Neulasta licensed in the United States (US‑Neulasta) and Neulasta authorized in the European Union (EU‑Neulasta). The study included three periods, and 577 healthy subjects were randomized to receive a single subcutaneous dose of each of the three drugs: Ziextenzo (A), US‑Neulasta (B), and EU‑Neulasta (C). Subjects were randomized into six groups, which differed by the order in which the three drugs were administered (ABC, ACB, BAC, BCA, CAB, and CBA). Although US‑Neulasta and EU‑Neulasta were both included in this study, US‑Neulasta was the designated reference biologic drug. The results therefore focused on the comparison of Ziextenzo to US‑Neulasta.

Three primary pharmacokinetic parameters were examined: the maximum observed serum concentration (Cmax), the area under the serum concentration‑time curve (a measure of exposure over time) measured from the time of dosing and extrapolated to infinity (AUC0‑inf), and the area under the serum concentration‑time curve measured from the time of dosing to the last measurable concentration (AUC0‑last). Pharmacokinetic similarity was evaluated based on the 90% confidence interval (CI) of the ratio of geometric means between Ziextenzo and the designated reference drug, US‑Neulasta. The ratios (Ziextenzo [Test]/US‑Neulasta [Reference]) for Cmax, AUC0‑inf, and AUC0‑last were all contained within pre‑defined margins, which met Health Canada's criteria, for pharmacokinetic similarity between Ziextenzo and US‑Neulasta.

Pharmacodynamic similarity between Ziextenzo and US‑Neulasta was evaluated based on absolute neutrophil count (ANC) over time, an established surrogate marker of efficacy for filgrastim and pegfilgrastim products. Specifically, this was achieved by measuring the area under the effective ANC concentration curve from the time of dosing to the last measurable concentration (AUEC0‑last), as well as determining the maximum effective ANC concentration attributable to the study drug (Emax). The results from Ziextenzo and US‑Neulasta were compared and the 95% CI of the geometric mean ratios (Ziextenzo/US‑Neulasta) of the AUEC0‑last and the Emax were entirely contained within the pre‑specified margins, which met Health Canada's criteria, for pharmacodynamic similarity between the two drugs. Immunogenicity and safety comparisons showed similar results between Ziextenzo and US‑Neulasta following a single injection in healthy subjects.

Pharmacokinetic and pharmacodynamic similarities were also demonstrated between Ziextenzo and EU‑Neulasta and between EU‑Neulasta and US‑Neulasta. This evidence of similarity across all three products provides support for the comparative safety analyses between Ziextenzo and EU‑Neulasta, which are described in the Comparative Clinical Safety and Immunogenicity section.

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

Comparative Clinical Safety and Immunogenicity

The clinical safety profile of Ziextenzo was shown to be comparable to that of Neulasta through two independent, double‑blind Phase III studies of similar design: LA‑EP06‑301 and LA‑EP06‑302. Both studies were conducted in female patients with breast cancer receiving established myelosuppressive chemotherapy.

Patients were randomized in a 1:1 ratio to receive either Ziextenzo or EU‑Neulasta, administered on Day 2 of each cycle of chemotherapy (docetaxel 75 mg/m2) in combination with doxorubicin (50 mg/m2) and cyclophosphamide (500 mg/m2), administered for up to six cycles. In both studies, Ziextenzo or EU‑Neulasta was administered subcutaneously as a 6 mg dose once in every chemotherapy cycle. The treatment duration was up to 18 weeks.

No differences in safety were observed between Ziextenzo and EU‑Neulasta in patients with breast cancer.

Treatment with any therapeutic protein is naturally 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 of Ziextenzo and Neulasta was compared in healthy subjects and in patients with breast cancer, and the incidence of ADAs was similar in all treatment groups examined. In the comparative pharmacokinetic and pharmacodynamic study (LA‑EP06‑104) in healthy subjects, neutralizing ADAs were reported: two in subjects who received EU‑Neulasta, and in one subject who received Ziextenzo.

Anti‑drug antibodies appeared to have minimal effects on the systemic clearance of pegfilgrastim or on the production and release of neutrophils. No unusual observations were noted in individual pharmacokinetic data or absolute neutrophil counts. Additionally, the low detection rate in the two Phase III safety studies indicates a low immunogenicity potential of Ziextenzo, similar to that reported for the reference biologic drug, Neulasta.

As with Neulasta, the major identified safety concerns for Ziextenzo 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 Ziextenzo and Neulasta Product Monographs.

Overall, the safety profile of Ziextenzo is comparable to that which has been established for the reference biologic drug, Neulasta. The identified safety concerns are appropriately addressed in the Ziextenzo Product Monograph, as they are in the Product Monograph for Neulasta.

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

Indication

Ziextenzo 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 antineoplastic drugs.

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

Similarity between Ziextenzo 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 the 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 indication has been authorized on the basis of demonstrated similarity between Ziextenzo 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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