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Biologicals : Journal of the... Jul 2017Recombinant human granulocyte-colony stimulating factor (G-CSF, filgrastim) is used primarily to reduce incidence and duration of severe neutropenia and its associated... (Comparative Study)
Comparative Study
BACKGROUND
Recombinant human granulocyte-colony stimulating factor (G-CSF, filgrastim) is used primarily to reduce incidence and duration of severe neutropenia and its associated complications in cancer patients that have received a chemotherapy regimen. The pegylated form of filgrastim, "pegfilgrastim", is a long-acting form that requires only a once-per-cycle administration for the management of chemotherapy-induced neutropenia. Apobiologix, a division of ApoPharma USA, Inc., and Intas Pharmaceuticals Limited have co-developed a proposed pegfilgrastim biosimilar to US-licensed pegfilgrastim.
METHODS
The analytical similarity of Apobiologix pegfilgrastim and US-licensed pegfilgrastim with respect to their physicochemical profile was established using a wide range of rigorous orthogonal analytical techniques. Biological function was compared using receptor binding analyses, in vitro proliferation assays, and in vivo hematopoietic progenitor mobilization.
RESULTS
Apobiologix pegfilgrastim and the US-licensed pegfilgrastim reference product were found to be highly similar analytically with respect to molecular mass, primary, secondary and tertiary protein structures, purity, charge, and hydrophobicity. No differences in receptor binding affinity were observed, and all samples demonstrated similar in vitro and in vivo bioactivity.
CONCLUSION
These studies provide robust evidence supporting the structural and functional similarity between Apobiologix pegfilgrastim and the US-licensed reference pegfilgrastim, and hence their biosimilarity.
Topics: Biosimilar Pharmaceuticals; Cell Line; Filgrastim; Humans; Neutropenia; Polyethylene Glycols
PubMed: 28619479
DOI: 10.1016/j.biologicals.2017.06.001 -
Scientific Reports Feb 2020PEGylated recombinant human granulocyte colony stimulating factor (pegfilgrastim) is used clinically to accelerate immune reconstitution following chemotherapy and is...
PEGylated recombinant human granulocyte colony stimulating factor (pegfilgrastim) is used clinically to accelerate immune reconstitution following chemotherapy and is being pursued for biosimilar development. One challenge to overcome in pegfilgrastim biosimilar development is establishing pharmacokinetic (PK) similarity, which is partly due to the degree of PK variability. We herein report that commercially available G-CSF and PEG ELISA detection kits have different capacities to detect pegfilgrastim aggregates that rapidly form in vitro in physiological conditions. These aggregates can be observed using SDS-PAGE, size-exclusion chromatography, dynamic light scattering, and real-time NMR analysis and are associated with decreased bioactivity as reflected by reduced drug-induced cellular proliferation and STAT3 phosphorylation. Furthermore, individual variability in the stability and detectability of pegfilgrastim in human sera is also observed. Pegfilgrastim levels display marked subject variability in sera from healthy donors incubated at 37 °C. The stability patterns of pegfilgrastim closely match the stability patterns of filgrastim, consistent with a key role for pegfilgrastim's G-CSF moiety in driving formation of inactive aggregates. Taken together, our results indicate that individual variability and ELISA specificity for inactive aggregates are key factors to consider when designing and interpreting studies involving the measurement of serum pegfilgrastim concentrations.
Topics: Animals; Biological Variation, Individual; Cell Line, Tumor; Cell Proliferation; Enzyme-Linked Immunosorbent Assay; Filgrastim; Humans; Mice; Polyethylene Glycols; STAT3 Transcription Factor
PubMed: 32051479
DOI: 10.1038/s41598-020-59346-z -
Advances in Therapy Jul 2020PF-06881894 is a proposed biosimilar to pegfilgrastim (Neulasta). This study evaluated the pharmacodynamic/pharmacokinetic (PD/PK) equivalence, immunogenicity, and... (Comparative Study)
Comparative Study
PF-06881894, a Proposed Biosimilar to Pegfilgrastim, Versus US-Licensed and EU-Approved Pegfilgrastim Reference Products (Neulasta): Pharmacodynamics, Pharmacokinetics, Immunogenicity, and Safety of Single or Multiple Subcutaneous Doses in Healthy Volunteers.
INTRODUCTION
PF-06881894 is a proposed biosimilar to pegfilgrastim (Neulasta). This study evaluated the pharmacodynamic/pharmacokinetic (PD/PK) equivalence, immunogenicity, and safety of PF-06881894 vs pegfilgrastim reference products (US- and EU-Neulasta) in healthy volunteers.
METHODS
A phase 1, open-label, randomized, crossover study was conducted to assess the pharmacologic equivalence and safety of a single 6-mg dose of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU. The primary PD endpoints were area under the effect-versus-time curve for absolute neutrophil count (ANC) from dose administration to 288 h postdose, and maximum observed ANC value among subjects confirmed negative for anti-pegfilgrastim antibodies. Primary PK variables included area under the serum pegfilgrastim-versus-time curve from the time of dose administration to time infinity and maximum observed serum pegfilgrastim concentration. A second phase 1, open-label, randomized (1:1), parallel-group, non-inferiority study was conducted to assess the immunogenicity and safety of multiple 6-mg doses of PF-06881894 versus pegfilgrastim-US. The primary endpoint for the immunogenicity study was the proportion of subjects with both negative baseline and confirmed positive postdose anti-pegfilgrastim antibodies at any time during the study.
RESULTS
Across the single- and multiple-dose studies (N = 153 and N = 420 treated subjects, respectively), demographics for age (18-65 years), male gender (n = 264/573), and white race (n = 423/573) were similar. Three-way PD/PK equivalence of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU was demonstrated with the primary PD endpoints and primary PK variables being completely contained within the predefined 90% confidence interval acceptance limits (80-125%). The non-inferiority of PF-06881894 versus pegfilgrastim-US in terms of immunogenicity was established according to the prespecified non-inferiority margin (≤10%). Overall, there were no clinically meaningful differences in safety profiles among or between study groups.
CONCLUSIONS
Single-dose PF-06881894 demonstrated PD/PK equivalence and comparable safety with US- and EU-pegfilgrastim reference products. Multiple-dose PF-06881894 demonstrated immunogenicity non-inferiority to pegfilgrastim-US with comparable safety. Both studies contributed to the totality of evidence supporting biosimilarity.
TRIAL REGISTRATION
ClinicalTrials.gov identifiers: NCT02629289; NCT03273842 (C1221005).
Topics: Adolescent; Adult; Asian People; Biosimilar Pharmaceuticals; Cross-Over Studies; Double-Blind Method; Female; Filgrastim; Healthy Volunteers; Humans; Male; Neutrophils; Polyethylene Glycols; Therapeutic Equivalency; Young Adult
PubMed: 32524499
DOI: 10.1007/s12325-020-01387-x -
BMC Cancer Aug 2019Febrile neutropenia (FN) is a serious complication of myelosuppressive chemotherapy. Clinical practice guidelines recommend routine prophylactic coverage with...
BACKGROUND
Febrile neutropenia (FN) is a serious complication of myelosuppressive chemotherapy. Clinical practice guidelines recommend routine prophylactic coverage with granulocyte colony-stimulating factor (G-CSF)-such as pegfilgrastim-for most patients receiving chemotherapy with an intermediate to high risk for FN. Patterns of pegfilgrastim prophylaxis during the chemotherapy course and associated FN risks in US clinical practice have not been well characterized.
METHODS
A retrospective cohort design and data from two commercial healthcare claims repositories (01/2010-03/2016) and Medicare Claims Research Identifiable Files (01/2007-09/2015) were employed. Study population included patients who had non-metastatic breast cancer or non-Hodgkin's lymphoma and received intermediate/high-risk regimens. Pegfilgrastim prophylaxis use and FN incidence were ascertained in each chemotherapy cycle, and all cycles were pooled for analyses. Adjusted odds ratios for FN were estimated for patients who did versus did not receive pegfilgrastim prophylaxis in that cycle.
RESULTS
Study population included 50,778 commercial patients who received 190,622 cycles of chemotherapy and 71,037 Medicare patients who received 271,944 cycles. In cycle 1, 33% of commercial patients and 28% of Medicare patients did not receive pegfilgrastim prophylaxis, and adjusted odds of FN were 2.6 (95% CI 2.3-2.8) and 1.6 (1.5-1.7), respectively, versus those who received pegfilgrastim prophylaxis. In cycle 2, 28% (commercial) and 26% (Medicare) did not receive pegfilgrastim prophylaxis; corresponding adjusted FN odds were comparably elevated (1.9 [1.6-2.2] and 1.6 [1.5-1.8]). Results in subsequent cycles were similar. Across all cycles, 15% of commercial patients and 23% of Medicare patients did not receive pegfilgrastim prophylaxis despite having FN in a prior cycle, and prior FN increased odds of subsequent FN by 2.1-2.4 times.
CONCLUSIONS
Notwithstanding clinical practice guidelines, a large minority of patients did not receive G-CSF prophylaxis, and FN incidence was substantially higher among this subset of the population. Appropriate use of pegfilgrastim prophylaxis may reduce patient exposure to this potentially fatal but largely preventable complication of myelosuppressive chemotherapy.
Topics: Aged; Chemoprevention; Chemotherapy-Induced Febrile Neutropenia; Disease Management; Female; Filgrastim; Hematologic Agents; Humans; Incidence; Male; Middle Aged; Polyethylene Glycols; Practice Patterns, Physicians'; Retrospective Studies; Risk; United States
PubMed: 31399079
DOI: 10.1186/s12885-019-6010-9 -
Journal of Managed Care & Specialty... Jul 2022It is unknown whether using pegfilgrastim biosimilars is cost saving in a real-world setting. To compare medical costs including pegfilgrastim drug costs and febrile...
Patient out-of-pocket and payer costs for pegfilgrastim originator vs biosimilars as primary prophylaxis of febrile neutropenia in the first cycle among a commercially insured population.
It is unknown whether using pegfilgrastim biosimilars is cost saving in a real-world setting. To compare medical costs including pegfilgrastim drug costs and febrile neutropenia (FN) treatment and management costs between pegfilgrastim biosimilars (pegfilgrastim-jmdb, pegfilgrastim-cbqv) and originator users for primary prophylaxis of febrile neutropenia. A retrospective cohort study using 2019 IBM MarketScan Commercial and Medicare Supplemental databases was conducted in adult patients with cancer initiating myelosuppressive chemotherapy courses. At least 2 diagnoses of the same cancer (at least 7 days apart) were required within 30 days of the chemotherapy initiation date. Pegfilgrastim (excluding on-body injector) costs included drug costs only (excluding administration fees). FN-related costs included all FN-related health care utilizations that were defined as having neutropenia, fever, or infection diagnosis. Per-patient per-cycle (PPPC) out-of-pocket (OOP) costs, health plan costs, and total costs were compared between originator (excluding on-body injector) and biosimilars users in the first cycle. A generalized linear model and a 2-part model were used. A total of 1,930 patients were included, of whom 884 (45.8%) used pegfilgrastim originator, 427 (22.1%) used pegfilgrastim-jmdb, and 619 (32.1%) used pegfilgrastim-cbqv. Adjusted PPPC OOP pegfilgrastim costs in the first cycle were significantly lower for the biosimilars vs the originator ($182 for pegfilgrastim-jmdb and $159 for pegfilgrastim-cbqv vs $299 for originator, < 0.0001 for both comparisons). However, there was no difference in health plan costs ($5,783 for pegfilgrastim-jmdb and $5,845 for pegfilgrastim-cbqv vs $5,618 for originator) and total costs. In addition, no difference was observed for adjusted PPPC FN treatment and management OOP costs, health plan costs, and total costs in the first cycle. FN treatment OOP costs were $192 for originator, $197 for pegfilgrastim-jmdb ( = 0.958), and $240 for pegfilgrastim-cbqv ( = 0.680). FN treatment health plan costs were $2,804 for originator, $2,970 for pegfilgrastim-jmdb ( = 0.692), and $2,745 for pegfilgrastim-cbqv ( = 0.879). In a commercially insured population, using pegfilgrastim biosimilars in the first cycle for primary prophylaxis of FN led to cost savings for patients but not payers. No difference in FN-related costs was observed.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biosimilar Pharmaceuticals; Febrile Neutropenia; Filgrastim; Humans; Medicare; Neoplasms; Polyethylene Glycols; Retrospective Studies; United States
PubMed: 35737859
DOI: 10.18553/jmcp.2022.28.7.795 -
In Vivo (Athens, Greece) 2018The effectiveness and safety of pegfilgrastim during bleomycin, etoposide and cisplatin (BEP) chemotherapy have not yet been investigated.
BACKGROUND
The effectiveness and safety of pegfilgrastim during bleomycin, etoposide and cisplatin (BEP) chemotherapy have not yet been investigated.
PATIENTS AND METHODS
Patients with germ cell tumors (GCTs) who received pegfilgrastim during BEP at the Kanazawa University Hospital between January 2014 and December 2016 were retrospectively analyzed. The frequency of adverse events and effectiveness in inhibiting neutropenia were compared between cycles using pegfilgrastim and those using filgrastim.
RESULTS
Pegfilgrastim and filgrastim were administered in 13 and 22 cycles, respectively. The absolute neutrophil count at the nadir was significantly lower in patients receiving pegfilgrastim than in those receiving filgrastim (p=0.003). The duration of grade 2-4 neutropenia in cycles using filgrastim was significantly longer than that in those pegfilgrastim (p=0.01). No significant differences in the incidence of febrile neutropenia and serious adverse events were observed.
CONCLUSION
Pegfilgrastim can be safely and effectively administrated during BEP for patients with GCT.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Drug-Related Side Effects and Adverse Reactions; Etoposide; Female; Filgrastim; Humans; Male; Middle Aged; Neoplasms, Germ Cell and Embryonal; Neutropenia; Polyethylene Glycols; Retrospective Studies
PubMed: 29936477
DOI: 10.21873/invivo.11326 -
Journal of Managed Care & Specialty... Sep 2021Pegfilgrastim is available as a prefilled syringe (PFS) and an on-body injector (OBI). Whether the administration method of pegfilgrastim affects the effectiveness and... (Observational Study)
Observational Study
Pegfilgrastim is available as a prefilled syringe (PFS) and an on-body injector (OBI). Whether the administration method of pegfilgrastim affects the effectiveness and health care resources has not been evaluated in the setting of routine care. To compare real-world clinical and economic outcomes between PFS and OBI methods of administration. This was a retrospective observational study in patients diagnosed with breast cancer or non-Hodgkin lymphoma who received myelosuppressive chemotherapy and prophylactic use of pegfilgrastim via PFS or OBI between January 1, 2017, and May 31, 2018, according to MarketScan research databases. A propensity score was used to match the PFS cohort 1:1 to the OBI cohort. Outcomes were compared among the matched cohorts using a generalized linear model and generalized estimating equations with log-link function. 3,152 patients were identified. After matching, the final sample included 2,170 patients, representing 1,085 in each cohort. The incidence of febrile neutropenia (FN) in the first chemotherapy cycle was 1.01% for OBI (95% CI = 0.56-1.82) vs 1.48% for PFS (95% CI = 0.91-2.39; = 0.336). In all chemotherapy cycles (total cycles = 7,467), the FN incidence was 0.91% for OBI (95% CI = 0.64-1.30) vs 1.22% for PFS (95% CI = 0.90-1.64; = 0.214). There was no statistically significant difference in adjusted per-member per-month all-cause total cost health care resource utilization (HCRU) for hospitalizations, emergency department visits, and pharmacy claims. In a matched cohort of patients representing real-world utilization, there was no statistically or clinically meaningful difference in FN incidence between OBI and PFS methods of pegfilgrastim administration. There was no difference in total HCRU or total costs. OBI and PFS methods of administration are both indicated for patients requiring prophylactic pegfilgrastim, which is important considering that biosimilar PFS options are now available. This study was funded by Sandoz, Inc. Wang, Li, and K. Campbell are employees of Sandoz, Inc. Schroader and D. Campbell are employees of Xcenda, which was contracted by Sandoz, Inc., to provide study and manuscript development. McBride reports receiving payment from Sandoz, Inc., as a consultant, unrelated to this study; Coherus for advisory board and speaker engagements; and Pfizer for advisory board participation during the time of this study.
Topics: Adult; Aged; Aged, 80 and over; Data Analysis; Female; Filgrastim; Humans; Injections; Male; Middle Aged; Outcome Assessment, Health Care; Polyethylene Glycols; Retrospective Studies; Syringes; Young Adult
PubMed: 33929269
DOI: 10.18553/jmcp.2021.21010 -
Journal of Medical Economics Aug 2020For this economic analysis, we aimed to model: (1) the cost-efficiency of prophylaxis with biosimilar pegfilgrastim-bmez for chemotherapy-induced (febrile) neutropenia...
For this economic analysis, we aimed to model: (1) the cost-efficiency of prophylaxis with biosimilar pegfilgrastim-bmez for chemotherapy-induced (febrile) neutropenia (CIN/FN) compared to reference pegfilgrastim, and (2) the expanded access to CIN/FN prophylaxis and anti-neoplastic treatment that could be achieved with biosimilar cost-savings on a budget-neutral basis. In a hypothetical panel of 20,000 cancer patients receiving CIN/FN prophylaxis and using the average sales price (ASP) for the second quarter of 2019 for reference pegfilgrastim, we: conducted an simulation from the payer perspective of the cost-savings of 10-100% conversion from reference to biosimilar pegfilgrastim-bmez using drug price discounting ranging from 10-35%; estimated the budget-neutral expanded access to biosimilar pegfilgrastim-bmez enabled by these cost-savings; and estimated the budget-neutral expanded access to anti-neoplastic treatment with pembrolizumab. The simulations were replicated using fourth quarter 2019 wholesale acquisition cost (WAC) for reference pegfilgrastim and biosimilar pegfilgrastim-bmez in a analysis. In ASP simulations, cost-savings of using pegfilgrastim-bmez over reference pegfilgrastim in a 20,000 patient panel range from $1.3 M (at 15% price discount) to $3 M (35%) at 10% conversion rate and from $6.4 M to $14.9 M, respectively, at 50% conversion. These savings could provide prophylaxis with pegfilgrastim-bmez to an additional 352 (15% discount) to 1,076 patients (35%) at 10% conversion or 1,764-5,384, respectively, at 50% conversion. Alternatively, savings could be reallocated for anti-neoplastic treatment with pembrolizumab to 3 (15% discount) to 9 (35%) patients at 10% conversion or 19-45, respectively, at 50% conversion. When utilizing WAC, cost-savings range from $4.6 M (10% conversion) to $23.1 M (50%) which could provide pegfilgrastim-bmez to an additional 1,174 (10% conversion) to 5,873 patients (50%). Prophylaxis with biosimilar pegfilgrastim-bmez increases the value of cancer care by generating significant cost-savings that could be reallocated to provide expanded access to CIN/FN prevention and anti-neoplastic therapy on a budget-neutral basis.
Topics: Biosimilar Pharmaceuticals; Chemotherapy-Induced Febrile Neutropenia; Cost-Benefit Analysis; Filgrastim; Hematologic Agents; Humans; Models, Economic; Neoplasms; Polyethylene Glycols; United States
PubMed: 32323582
DOI: 10.1080/13696998.2020.1760284 -
British Journal of Clinical Pharmacology Jun 2020Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of... (Randomized Controlled Trial)
Randomized Controlled Trial
A large multicentre, randomized, double-blind, cross-over study in healthy volunteers to compare pharmacokinetics, pharmacodynamics and safety of a pegfilgrastim biosimilar with its US- and EU-reference biologics.
AIMS
Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of febrile neutropenia. Biosimilar pegfilgrastim is expected to reduce the financial burden of this complication of chemotherapy. The aim of this study was to demonstrate biosimilarity between Sandoz biosimilar pegfilgrastim and its US- and EU-approved reference biologics.
METHODS
Phase I, randomized, double-blind, single-dose, 3-period, 6-sequence cross-over, multicentre study to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of Sandoz biosimilar pegfilgrastim with US- and EU-references in healthy adults.
RESULTS
Pharmacokinetic and pharmacodynamic similarity was demonstrated between the 3 biologics, as the 90% confidence interval for all primary pharmacokinetic and pharmacodynamic endpoint comparisons were contained within the predefined similarity margins of 0.80-1.25. Safety, immunogenicity and tolerability were also similar.
CONCLUSIONS
Sandoz biosimilar pegfilgrastim demonstrated pharmacokinetic and pharmacodynamic similarity to both US- and EU-reference biologics. No meaningful differences in safety, local tolerability and immunogenicity were identified.
Topics: Adult; Biosimilar Pharmaceuticals; Cross-Over Studies; Double-Blind Method; Filgrastim; Healthy Volunteers; Humans; Polyethylene Glycols
PubMed: 32022282
DOI: 10.1111/bcp.14226