Summary Basis of Decision for Nypozi
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Nypozi is located below.
Recent Activity for Nypozi
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 Nypozi, a product which contains the medicinal ingredient filgrastim. 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: 2024-06-19
Drug Identification Number (DIN):
- DIN 02520990 – 300mcg /0.5ml filgrastim, solution, intravenous, subcutaneous administration.
- DIN 02521008 – 480mcg /0.8mL filgrastim, solution, intravenous, subcutaneous administration.
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
Drug product (DIN 02520990, 02521008) market notification |
Not applicable |
Date of first sale: 2024-01-24 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 220512 |
2019-01-17 |
Issued NOC 2021-10-08 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Nypozi
Date SBD issued: 2022-01-18
The following information relates to the New Drug Submission for Nypozi.
Filgrastim
Drug Identification Number (DIN):
- DIN 02520990 - 300 mcg/0.5 mL (600 mcg/mL) filgrastim, solution, intravenous or subcutaneous administration
- DIN 02521008 - 480 mcg/0.8 mL (600 mcg/mL) filgrastim, solution, intravenous or subcutaneous administration
Tanvex BioPharma USA, Inc.
New Drug Submission Control Number: 220512
On October 8, 2021, Health Canada issued a Notice of Compliance (NOC) to Tanvex BioPharma USA, Inc. for Nypozi, a biosimilar to Neupogen (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. Nypozi contains the medicinal ingredient filgrastim, which has been demonstrated to be highly similar to filgrastim contained in the reference product, Neupogen.
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. In order 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, Neupogen is the reference biologic drug. Similarity between Nypozi and Neupogen 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 Nypozi for all of the indications that are currently authorized for Neupogen.
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 Nypozi is considered to be similar to the benefit-risk profile of the reference product, and is therefore considered favourable for the following indications:
- Cancer patients receiving myelosuppressive chemotherapy
Nypozi (filgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.
Nypozi 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 Nypozi 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 cells/L after expected chemotherapy-induced nadir.
- Patients with acute myeloid leukemia
Nypozi 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
Nypozi 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 three times per week following marrow infusion to monitor marrow reconstitution.
- Cancer patients undergoing peripheral blood progenitor cell (PBPC) collection and therapy
Nypozi is indicated for the mobilization of autologous peripheral blood progenitor cells in order to accelerate hematopoietic recovery by infusion of such cells, supported by Nypozi, after myelosuppressive or myeloablative chemotherapy.
- Patients with severe chronic neutropenia (SCN)
Nypozi 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 immunodeficiency virus (HIV) infection
Nypozi is indicated in patients with HIV infection for the prevention and treatment of neutropenia, to maintain a normal ANC (e.g., between 2 × 109 cells/L and 10 × 109 cells/L). Nypozi 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 two weeks, once weekly for an additional two weeks, then once monthly thereafter, or as clinically indicated) during Nypozi therapy.
1 What was approved?
Nypozi, a granulocyte colony-stimulating factor, was authorized for use in cancer patients receiving myelosuppressive chemotherapy, patients with acute myeloid leukemia, cancer patients receiving myeloablative chemotherapy followed by bone marrow transplantation, cancer patients undergoing peripheral blood progenitor cell (PBPC) collection and therapy, patients with severe chronic neutropenia (SCN), and patients with human immunodeficiency virus (HIV) infection.
Nypozi is a biosimilar to Neupogen. Both drugs contain the medicinal ingredient filgrastim, which is produced in Escherichia coli cells using recombinant deoxyribonucleic acid (DNA) technology.
Similarity between Nypozi and the reference biologic drug, Neupogen, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, a comparative immunogenicity study in healthy subjects, and comparative pharmacokinetic and pharmacodynamic studies in healthy subjects, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Nypozi (600 mcg/mL filgrastim) is presented as a solution, supplied in single-use prefilled syringes containing 480 mcg filgrastim in 0.8 mL or 300 mcg filgrastim in 0.5 mL. In addition to the medicinal ingredient, the solution contains acetate, polysorbate 80, sodium, sorbitol, and water for injection.
The use of Nypozi is contraindicated in patients who are hypersensitive to E. coli-derived products, filgrastim, pegfilgrastim, or any non-medicinal ingredient or component of the container.
The drug product Nypozi was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Nypozi Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical and Basis for Decision sections.
2 Why was Nypozi approved?
Based on Health Canada's review, the benefit-risk profile of Nypozi is considered to be similar to that of the reference product, and is therefore considered favourable for use in cancer patients receiving myelosuppressive chemotherapy, patients with acute myeloid leukemia, cancer patients receiving myeloablative chemotherapy followed by bone marrow transplantation, cancer patients undergoing peripheral blood progenitor cell collection and therapy, patients with severe chronic neutropenia, and patients with human immunodeficiency virus (HIV) infection.
Similarity between Nypozi and Neupogen was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Nypozi is considered to be biosimilar to Neupogen. Neupogen is authorized and marketed in Canada for several indications related to neutropenia. Neutropenia is a low number of neutrophils in the blood. Neutrophils are a type of white blood cells 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.
The New Drug Submission (NDS) filed for Nypozi requested authorization for all of the indications and clinical uses that are currently authorized for Neupogen. The indications have been authorized on the basis of demonstrated similarity between Nypozi and the reference biologic drug.
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. The results of one comparative pharmacokinetic/pharmacodynamic study (TX01-02) and one comparative pharmacodynamics study (TX01-03), both conducted in healthy volunteers, provided the main clinical basis to support the biosimilarity assessment. Additionally, one comparative immunogenicity study (TX01-04) conducted in healthy volunteers supported the similarity of Nypozi and the reference drug in terms of immunogenicity. The reference product, Neupogen authorized in the United States (US-Neupogen), was used as a suitable proxy for the Canadian reference product in the 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 and therefore clinical trials are not required to support each indication.
Nypozi has demonstrated a comparable safety profile with its reference biologic drug, Neupogen. Therefore, the Adverse Reactions section of the Nypozi Product Monograph is based on the clinical experience with the reference biologic drug. As with Neupogen, 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 Nypozi Product Monograph, as can be found in the Neupogen Product Monograph.
A Risk Management Plan (RMP) for Nypozi was submitted by Tanvex BioPharma USA, 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.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Nypozi Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
The initially proposed brand name, Tanvex-Filgrastim, was not accepted as the Policy Statement on the Naming of Biologic Drugs recommends that biologic drugs have unique brand names. The sponsor submitted an assessment for the brand name Nypozi, including testing for look-alike sound-alike attributes. Upon review, the new brand name Nypozi was accepted.
Overall, Nypozi is considered to have a benefit-risk profile comparable to that established for the authorized indication of its reference biologic drug, Neupogen. The benefits of Nypozi are considered to outweigh the potential risks in the target patient populations. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Nypozi Product Monograph to address the identified safety concerns and are aligned with the information presented in the labeling for the reference product, Neupogen.
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. For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical and Basis for Decision sections.
3 What steps led to the approval of Nypozi?
A Notice of Deficiency (NOD) was issued primarily due to concerns with the comparative analytical assessment which were identified during the review of the quality (chemistry and manufacturing) data. In the response to the NOD, the sponsor submitted the requested third-party audit to support the accuracy, reliability, and correctness of the data used in the biosimilarity assessment. Although not requested, the sponsor also submitted comprehensive data regarding drug product manufacturing, as this activity had been transferred to a different site. Health Canada decided to review this additional information as part of the response to the NOD. A comment included in the NOD regarding the clinical data was also adequately addressed by the sponsor. Upon review of the response to the NOD, the outstanding concerns were considered to be resolved and a Notice of Compliance (NOC) was issued for Nypozi.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Nypozi
| Submission Milestone | Date |
|---|---|
| New Drug Submission filed | 2019-01-15 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2019-03-08 |
| Review 1 | |
| Review of Risk Management Plan completed | 2019-11-04 |
| Labelling review completed | 2019-11-20 |
| Non-clinical evaluation completed | 2019-11-29 |
| Clinical/medical evaluation completed | 2019-12-04 |
| Quality evaluation completed | 2019-12-18 |
| Notice of Deficiency issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate (quality issues) | 2019-12-27 |
| Response to Notice of Deficiency filed | 2020-11-16 |
| Screening 2 | |
| Screening Acceptance Letter issued | 2020-12-14 |
| Review 2 | |
| Quality evaluation completed | 2021-09-22 |
| Clinical/medical evaluation completed | 2021-10-04 |
| Labelling review completed | 2021-10-04 |
| Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate | 2021-10-08 |
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 Nypozi sponsor to monitor the post-market safety profile of this biosimilar 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 Nypozi 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.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Quality Basis for Decision
Nypozi was developed as a biosimilar to the reference biologic drug, Neupogen. 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 Nypozi is considered to be representative of the mechanism of action and pharmacological effect of Neupogen.
Comparative Structural and Functional Studies
A Notice of Deficiency (NOD) was issued primarily due to concerns with the biosimilarity assessment which were identified during the review of the quality (chemistry and manufacturing) data. In the response to the NOD, the sponsor submitted the requested third-party audit to support the accuracy, reliability, and correctness of the data used in the biosimilarity assessment. The outstanding concerns were considered to be resolved, and a Notice of Compliance (NOC) was issued for Nypozi.
Health Canada considers Neupogen authorized in the United States (US-Neupogen; the designated reference biologic product) as a suitable proxy for Neupogen authorized in Canada, as it meets all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. A two-way biosimilarity assessment was performed for Nypozi and US-Neupogen to compare the physicochemical and biological properties of the two products. The assessment was conducted over two time periods during the course of development of Nypozi and employed a three-part approach to thoroughly evaluate the similarity between the two products.
The results of the biosimilarity assessment indicate that Nypozi is identical to US-Neupogen with respect to primary structure, and highly similar with regards to higher-order structure, product-related substances and impurities, protein content, potency, and other physical properties. Minor differences were detected with respect to oxidized and deamidated species as well as norleucine misincorporation. However, the observed differences had no effects on biological activity and are not expected to be clinically meaningful.
Similar degradation profiles were observed for Nypozi and US-Neupogen, as the two products share the same degradation pathways and exhibit similar degradation kinetics when exposed to different stress conditions. Some minor differences were identified in response to shear and light stress, where the degradation kinetics was slower for Nypozi than for US-Neupogen. However, this represents an improvement over US-Neupogen and is not likely to be clinically meaningful. Collectively, the results of the biosimilarity assessment demonstrate that Nypozi is highly similar to US-Neupogen, and support the quality requirements for Nypozi to be considered a biosimilar to the reference biologic drug.
Characterization of the Drug Substance
The medicinal ingredient in Nypozi is filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF). Filgrastim is a protein consisting of 175 amino acids with a molecular weight of 18,800 Da. Its amino acid sequence is identical to the natural sequence predicted by a human deoxyribonucleic acid (DNA) sequence analysis, except for the addition of an N-terminal methionine, which is needed for expression in Escherichia coli.
Detailed characterization studies were performed during the biosimilarity assessment, which demonstrated that filgrastim, the medicinal ingredient in Nypozi, 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
The drug substance, filgrastim, is produced in E. coli cells which have been engineered to express this protein through recombinant deoxyribonucleic acid (DNA) technology. A culture of these E. coli cells is initiated, and filgrastim is expressed as the cell culture expands. When the culture reaches commercial scale, the cells are harvested and lysed to release inclusion bodies, and filgrastim is solubilized and refolded. Filgrastim is isolated through two chromatography steps, and then filtered and filled into bottles.
Manufacturing of Nypozi, the drug product, involves drug substance thaw, dilution and formulation, primary filtration for bioburden reduction, sterile filtration, aseptic filling and closing, and visual inspection.
The control strategies for both the drug substance and drug product manufacturing processes were based on risk assessments and process knowledge. Process validation was carried out using several process performance qualification (PPQ) lots of the drug substance and the drug product manufactured at commercial scale. All results met the acceptance criteria for batch release testing. Overall, the results of the PPQ studies reflect the ability of the manufacturing processes to consistently produce drug substance or drug product with the desired qualities.
None of the non-medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of filgrastim with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
Nypozi 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 and shown to be fit for purpose.
All in-house analytical methods were appropriately validated, and compendial methods complied with the appropriate pharmacopeia. The proposed release and stability specifications are based on manufacturing process history, batch release data, and stability data at commercial scale and relevant development studies.
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 24 months at 2 °C to 8 °C for Nypozi is considered acceptable. Nypozi may be stored at room temperature (not above 25 °C) for one single period of up to 15 days. Additional storage and special handling instructions are included in the Nypozi Product Monograph.
Facilities and Equipment
Based on risk assessment scores determined by Health Canada during the review of Nypozi, an on-site evaluation (OSE) of the drug product manufacturing site was not recommended. However, an OSE was recommended for the drug substance manufacturing site. It was not feasible to conduct an OSE due to the production schedule, as well as travel restrictions imposed during the coronavirus disease 2019 (COVID-19) pandemic. Reports from a recent pre-approval inspection (PAI) of the facility conducted by the United States Food and Drug Administration (FDA) were reviewed, along with the sponsor’s efforts to address the observations. This successfully mitigated the concerns identified in the risk assessment, and an OSE is recommended for the drug substance manufacturing site at the next opportunity.
Adventitious Agents Safety Evaluation
The master and working cell banks were characterized and confirmed to be free of viral contaminants and other adventitious agents.
The raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens. The filgrastim drug substance is manufactured through bacterial fermentation in E. coli cells, which do not support the growth of mammalian viruses.
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 Nypozi complied with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Four in vivo non-clinical studies were submitted, which demonstrated the comparability of Nypozi to US-Neupogen with respect to pharmacodynamics, pharmacokinetics/toxicokinetics, toxicology, and local tolerance. No new toxicological findings were observed for Nypozi.
The results of the comparative non-clinical studies as well as the potential risks to humans have been included in the Nypozi Product Monograph. Considering the intended use of Nypozi, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Nypozi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Clinical basis for decision
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.
Comparative Pharmacokinetic and Pharmacodynamic Studies
Filgrastim is a human 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 results from treatment with myelosuppressive antineoplastic drugs, thereby decreasing the overall incidence of infection.
For filgrastim 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 results of one comparative PK/PD study (TX01-02) and one comparative PD study (TX01-03) provided the main clinical support for the biosimilarity assessment.
Study TX01-02 (single-dose PK/PD study in healthy subjects)
Study TX01-02 was conducted in 49 healthy subjects to compare the pharmacokinetics, pharmacodynamics, safety, and tolerability of Nypozi and the reference biologic drug (Neupogen authorized in the United States; US-Neupogen). Both Nypozi and US-Neupogen were administered as single subcutaneous doses of 5 mcg/kg each. The subjects were randomized into two treatment sequences: 25 subjects were randomized to Nypozi followed by US-Neupogen (Nypozi/US-Neupogen) and 24 subjects were randomized to US-Neupogen followed by Nypozi (US-Neupogen/Nypozi). The two treatment periods were separated by a washout period of at least 21 days. Three subjects in each treatment sequence did not complete the study, and therefore the statistical comparisons were based on 43 subjects who completed the crossover design.
Pharmacokinetic comparability between Nypozi and the reference biologic drug, US-Neupogen, was demonstrated. The 90% confidence interval (CI) of the ratio of geometric means for exposure, as measured by the relative mean of the area under the serum concentration-time curve (AUCT), was contained within the predefined equivalence margins of 80.0% to 125.0%. The ratio of geometric means (GMR) for the maximum serum concentration (Cmax) was also contained within the equivalence margins of 80.0% to 125.0%.
Pharmacodynamic comparability was evaluated based on the 95% CIs of the relative mean values for the area under the effect (absolute neutrophil count [ANC])-time curve from zero to the last measurable time point (AUECANC) and the maximum effect (ANCmax). The ANC is recognized as a relevant pharmacodynamic marker for granulocyte colony-stimulating factor activity. The 95% CIs were 87.0% to 105.6% for the AUECANC and 93.6% to 105.5% for the ANCmax; both of which are contained within the predefined equivalence margins of 80.0% to 125.0%, thereby demonstrating pharmacodynamic comparability.
Study TX01-03 (multiple-dose PD study in healthy subjects)
Study TX01-03 was conducted in 50 healthy subjects to compare the pharmacodynamic effects of multiple doses of Nypozi and US-Neupogen. Subjects were randomized to one of two treatment sequences: 25 subjects were randomized to Nypozi followed by US-Neupogen (Nypozi/US-Neupogen) and 25 subjects were randomized to US-Neupogen followed by Nypozi (US-Neupogen/Nypozi). A subcutaneous 5 mcg/kg dose of either Nypozi or US-Neupogen once daily was administered for 5 days. Following a washout period of at least 28 days and no more than 42 days after the last dose, subjects received a subcutaneous 5 mcg/kg dose of the alternate product once daily for 5 days. Three subjects did not complete the study, and therefore the statistical comparisons were based on the remaining 47 subjects.
Pharmacodynamic comparability was evaluated based on the 95% CIs of the relative mean values for the area under the effect CD34+-time curve (AUECCD34+) and the maximum effect (CD34+max). The CD34+ cell count is recognized as a relevant pharmacodynamic marker to support the indication for the mobilization of autologous peripheral blood progenitor cells. The 95% CIs were 93.2% to 113.7% for the AUECCD34+ and 95.8% to 116.4% for the CD34+max; both of which are contained within the predefined equivalence margins of 80.0% to 125.0%, thereby demonstrating pharmacodynamic comparability.
For further details, please refer to the Nypozi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Clinical Safety
The clinical safety of Nypozi was evaluated in the studies TX01-02, TX01-03 (both described in the Comparative Pharmacokinetic and Pharmacodynamic Studies section) and TX01-04 (described in the Comparative Immunogenicity section).
The safety profile of Nypozi is generally consistent with the known safety profile of US-Neupogen. In particular, data from the multiple-dose PK/PD study, TX01-03, and the immunogenicity study, TX01-04, did not indicate a different safety profile for Nypozi.
The treatment-emergent adverse events and drug-related adverse events observed were mild to moderate in severity. The most commonly reported events were headache, back pain, and musculoskeletal pain. All reported adverse events were evenly balanced between both treatment arms, and were consistent with those described in the Product Monograph of Neupogen.
The major identified safety concerns for filgrastim include the risk of splenic rupture, and the risk of severe sickle cell crises in patients with sickle cell trait or sickle cell disease. Splenic rupture and severe sickle cell crises have been highlighted in a Serious Warnings and Precautions box in the Neupogen and Nypozi Product Monographs.
Overall, the safety profile of Nypozi is considered to be comparable to that which has been established for the reference biologic drug Neupogen. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warnings and Precautions section of the Nypozi Product Monograph, as they are in the Product Monograph for Neupogen.
For more information, refer to the Nypozi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Immunogenicity
Study TX01-04 was conducted in 221 healthy subjects to compare the immunogenicity of Nypozi and US-Neupogen. Subjects were randomized to one of two treatment groups to receive a subcutaneous 5 mcg/kg dose of either Nypozi (110 subjects) or US-Neupogen (111 subjects) once daily for 5 days (Cycle 1). Following a washout period of 28 to 30 days, subjects received a single subcutaneous dose of the same filgrastim product (Cycle 2). None of the subjects were confirmed to have anti-drug antibodies (ADAs) at baseline. To test for the development of ADAs, samples were collected from subjects prior to the first dose in each cycle, at two weeks after the last dose in each cycle (Day 19 in Cycle 1 and Day 15 in Cycle 2), and at the end of study (Day 30 after the dose in Cycle 2). Samples from Day 1 of each cycle were collected before the administration of the first dose. Five subjects withdrew from the study, and therefore the statistical comparisons were based on data from 106 subjects who received Nypozi and 110 subjects who received US-Neupogen.
The results demonstrated that Nypozi is non-inferior to US-Neupogen in terms of immunogenicity. The upper bound of the 95% CI for the difference (test-reference) in the ADA rates was below the non-inferiority margin of 10%. The observed ADA rate was consistent with previously reported rates for Neupogen. The observed ADAs were transient, and there was no evidence of neutralizing antibodies for any of the subjects.
Indications
Similarity between Nypozi and Neupogen 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 sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication.
The indications have been authorized on the basis of demonstrated similarity between Nypozi 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, Nypozi was authorized for the same indications currently held by the reference biologic drug, Neupogen, as follows:
- Cancer patients receiving myelosuppressive chemotherapy
Nypozi (filgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.
Nypozi 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 Nypozi 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 cells/L after expected chemotherapy-induced nadir.
- Patients with acute myeloid leukemia
Nypozi 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
Nypozi 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 three times per week following marrow infusion to monitor marrow reconstitution.
- Cancer patients undergoing peripheral blood progenitor cell (PBPC) collection and therapy
Nypozi is indicated for the mobilization of autologous peripheral blood progenitor cells in order to accelerate hematopoietic recovery by infusion of such cells, supported by Nypozi, after myelosuppressive or myeloablative chemotherapy.
- Patients with severe chronic neutropenia (SCN)
Nypozi 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 immunodeficiency virus (HIV) infection
Nypozi is indicated in patients with HIV infection for the prevention and treatment of neutropenia, to maintain a normal ANC (e.g., between 2 × 109 cells/L and 10 × 109 cells/L). Nypozi 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 two weeks, once weekly for an additional two weeks, then once monthly thereafter, or as clinically indicated) during Nypozi therapy.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| NYPOZI | 02521008 | TANVEX BIOPHARMA USA, INC. | FILGRASTIM 480 MCG / 0.8 ML |
| NYPOZI | 02520990 | TANVEX BIOPHARMA USA, INC. | FILGRASTIM 300 MCG / 0.5 ML |