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Fylnetra (pegfilgrastim-pbbk)1 injection is biosimilar to Neulasta® (pegfilgrastim). A recombinant granulocyte colony stimulating factor (rG-CSF).
Fylnetra is made entirely in the United States.
Decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Fylnetra is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.
Multiple in vitro analytical similarity studies using state-of-the-art orthogonal analytical methods demonstrated similarity between Fylnetra® and Neulasta® in key features such as: primary structure, molecular conformation, charge variants, protein content, purity, and biological activity.1,4
Comparative stability studies between Fylnetra® and Neulasta® under accelerated and forced degradation conditions have demonstrated similar behavior and degradation pathways for the two products.1,4
Fylnetra® clinical comparability included data from 120 healthy subjects evaluated in 1 PK/PD study and 230 healthy subjects in 1 immunogenicity/safety study:
1. Strong comparability PK package in healthy volunteer clinical study: The PK similarity of both products was established for serum filgrastim AUC0-t; AUC0-inf and Cmax.1,4
2. Strong Comparability PD package in healthy volunteer clinical study: As a surrogate for clinical efficacy, PD similarity of both products was established for baseline-corrected absolute neutrophil count (ANC) AUEC0-t and Emax for ANC:1,4
References:
1. Fylnetra® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761084Orig1s000TOC.cfm
2. Food and Drug Administration, FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry, 2015.
3. Food and Drug Administration, FDA. Draft Guidance: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations, 2019.
4. Fylnetra® Full Prescribing Information – https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eeadd641-573d-47fe-897a-61006e5f9e03
Fylnetra® is a biosimilar filgrastim which has been developed in comparison with Neulasta® as the Reference Product (RP).
Multiple state-of-the-art analytical methods were applied to evaluate all quality attributes required of the biosimilar and confirmed analytical similarity between Fylnetra® and Neulastra®1:
Representative Peptide Mapping Chromatograms* of Fylnetra® and Neulasta®
The post-translational modification analyses demonstrated a similar relative content of acidic and basic forms between both proteins.
Similar protein content and high purity was found in both Fylnetra® and Neulasta®.
Comparative accelerated and forced degradation studies have shown a similar behavior and degradation profile of Fylnetra® and Neulasta®.
Similarity between Fylnetra® and Neulasta® in terms of molecular conformation was demonstrated as seen by identical Far-UV Circular Dichroism Spectra, and Intrinsic Fluorescence spectra.
Representative Far-UV Circular Dichroism Spectra of Fylnetra® and Neulasta®
Overlay of Representative Intrinsic Fluorescence Spectra of Fylnetra® and Neulasta®
Multiple state-of-the-art orthogonal methods demonstrated the similarity of Fylnetra® to its reference product regarding biological activity. Highly similar potency of Fylnetra® and Neulasta® relative to filgrastim reference standard was seen in the M-NFS-60 Cell Proliferation Assay.
Representative Potency Dose Response Curve Showing Similar Potency of Fylnetra® and Neulasta® in M-NFS-60* Cell Proliferation Assay
Comparative Results of Receptor Binding by ELISA*:
Representative ELISA Dose Response Curve for Fylnetra® Versus Neulasta
Comparative Results of RP-HPLC* Chromatography of Fylnetra® and Neulasta®
References:
1. Fylnetra® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761084Orig1s000TOC.cfm
One PK/PD study was carried out in healthy volunteers’ to investigate and compare the PK profiles of Fylnetra® and Neulasta® and confirm bioequivalence between both products:
The mean serum PEG-rhG-CSF* concentration versus time profiles following a single SC injection of 2mg Fylnetra (TPI-120) and Neulasta are shown in a linear scale.
It was statistically confirmed that Fylnetra® was bioequivalent to Neulasta® for the primary parameters AUC (0-t), AUC (0-∞) and Cmax, as the 90% CI were fully contained within the pre-defined bioequivalence limits of 0.80 – 1.25.1
References:
1. Fylnetra® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761084Orig1s000TOC.cfm
Table 23 TPI-CL-109-A: Summary of TEAEs in ≥ 2 Subjects in the TPI-120 Treatment Arm (Safety Population)4
FMQ* |
Study TPI-CL-109-A |
|
|---|---|---|
TPI-120 |
US-Neulasta |
|
All subjects |
60 (50.4%) |
56 (50.5%) |
Back pain |
30 (25.2%) |
31 (27.9%) |
Headache |
18 (15.1%) |
17 (15.3%) |
Myalgia |
6 (5.0%) |
2 (1.8%) |
Pain in extremity |
4 (3.4%) |
6 (5.4%) |
Arthralgia |
3 (2.5%) |
2 (1.8%) |
Local administration reaction |
2 (1.7%) |
4 (3.6%) |
Abdominal pain |
2 (1.7%) |
0 |
Upper respiratory tract |
2 (1.7%) |
0 |
Pain |
2 (1.7%) |
1 (0.9%) |
FMQ* |
All subjects |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
60 (50.4%) |
56 (50.5%) |
|
FMQ* |
Back pain |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
30 (25.2%) |
31 (27.9%) |
|
FMQ* |
Headache |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
18 (15.1%) |
17 (15.3%) |
|
FMQ* |
Myalgia |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
6 (5.0%) |
2 (1.8%) |
|
FMQ* |
Pain in extremity |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
4 (3.4%) |
6 (5.4%) |
|
FMQ* |
Arthralgia |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
3 (2.5%) |
2 (1.8%) |
|
FMQ* |
Local administration reaction |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
2 (1.7%) |
4 (3.6%) |
|
FMQ* |
Abdominal pain |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
2 (1.7%) |
0 |
|
FMQ* |
Upper respiratory tract infection |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
2 (1.7%) |
0 |
|
FMQ* |
Pain |
|
|---|---|---|
Study TPI-CL-109-A |
TPI-120 |
US-Neulasta |
2 (1.7%) |
1 (0.9%) |
|
*Grouped Terms by FDA Medical Query (FMQ).
Incidences are based on the number of subjects, not the number of events. Although a subject may have had 2 or more clinical AEs, the subject is counted only once in a category. The same subject may appear in different categories.
[Source: ADAE.xpt and ADSL.xpt]
References:
1. Fylnetra® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761084Orig1s000TOC.cfm
2. Food and Drug Administration, FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry, 2015.
3. Food and Drug Administration, FDA. Draft Guidance: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations, 2019.
4. Fylnetra® Full Prescribing Information – https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eeadd641-573d-47fe-897a-61006e5f9e03
The PK/PD study provided the comparative PD characteristics that established PD similarity and hence comparative clinical efficacy for Fylnetra® versus Neulasta®.
PD concentration time curve shown below revealed the peak and overall baseline-corrected blood ANC (as measured by geometric mean Emax and AUEC0-t) were similar following a SC injection of either Fylnetra (TPI-120) or Neulasta, as shown by the less than 10% difference in Emax and AUEC0-t between treatments.
The 90% CIs around the GMR of blood ANC Emax and AUEC0-t for TPI-120 relative to Neulasta were within the limits of the 80.00% – 125.00% boundary, and hence PD bioequivalence was demonstrated.
References:
1. Fylnetra® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761084Orig1s000TOC.cfm
2. Food and Drug Administration, FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry, 2015.
3. Food and Drug Administration, FDA. Draft Guidance: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations, 2019.
4. Fylnetra® Full Prescribing Information – https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eeadd641-573d-47fe-897a-61006e5f9e03
Indication: FYLNETRA is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Limitations of Use: FYLNETRA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.
Indication: FYLNETRA is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Limitations of Use: FYLNETRA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.
Contraindications: Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products.
Before taking FYLNETRA, tell your healthcare provider if you are pregnant or plan to breast feed, and if you have sickle cell disorder, kidney problems or receiving radiation therapy.
Warnings and Precautions:
Adverse Reactions: Most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity.