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Lickliter, Jason D., Paul Griffin, Emmanuelle Vincent, et al. "Pharmacokinetic/pharmacodynamic assessment of a proposed biosimilar MSB11455 versus the currently licensed pegfilgrastim: A randomized, double-blind trial." Journal of Clinical Oncology 37, no. 15_suppl (2019): e14514-e14514. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14514.
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e14514 Background: MSB11455 is a proposed biosimilar to the currently licensed pegfilgrastim (Neulasta). This phase I study (NCT03251248) assessed the pharmacokinetic (PK)/pharmacodynamic (PD) bioequivalence of MSB11455 to Neulasta. Methods: Healthy volunteers were randomized to one of two crossover sequences, MSB11455/Neulasta or Neulasta/MSB11455. Subjects received a single subcutaneous dose of either MSB11455 or Neulasta (both 6 mg/0.6 mL) on Day 1 of each study period. Samples for PK/PD analysis were taken predose and up to Day 16 postdose. Immunogenicity samples were taken predose and up to Day 84 postdose. Safety was assessed throughout the study. Results: 244 subjects were randomized and received both treatments. For all primary PK/PD parameters 90% repeated confidence intervals of the geometric mean ratio of MSB11455 versus Neulasta were within the pre-defined equivalence range (80.00%–125.00%): AUC0–∞ (96.59, 112.82), AUC0–last (97.29, 113.96), Cmax (97.13, 114.99), Emax (98.74, 102.39) and AUE0–t (97.30, 100.23). Safety and tolerability as well as immunogenicity were comparable between treatment sequences. No filgrastim-specific neutralizing antibodies were detected in either treatment sequence. Conclusions: PK/PD equivalence of MSB11455 and pegfilgrastim was demonstrated with comparable immunogenicity, safety, and tolerability. This study supports the biosimilarity of MSB11455 to Neulasta. Clinical trial information: NCT03251248.
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Glaspy, John, William Daley, Igor Bondarenko, Dean Rutty, and Jianmin Chen. "A Phase III, Randomized, Multi-Center, Open-Label, Fixed Dose, Neulasta Active-Controlled Clinical Trial of F-627, a Novel G-CSF, in Women with Breast Cancer Receiving Myelotoxic Chemotherapy." Blood 138, Supplement 1 (2021): 4290. http://dx.doi.org/10.1182/blood-2021-145760.
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Abstract Background - Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity in patients receiving myelotoxic chemotherapy which is associated with increased morbidity and early mortality. Ryzneuta TM (F-627), a recombinant fusion protein containing human granulocyte-colony stimulating factor (G-CSF) and IgG2-Fc fragment, is intended to reduce CIN by utilizing the neutrophilic proliferating and activating properties of G-CSF. F-627 was designed as a novel, non-pegylated molecule with dimeric G-CSF, which may possess stronger G-CSF receptor activating properties and improved efficacy compared to filgrastim and pegfilgrastim. The primary objective of this study was to evaluate the safety and efficacy of F-627 given as a single fixed dose (20 mg) pre-filled syringe (PFS) as compared to Neulasta® (6 mg) in the first chemotherapy cycle. Methods - This was a phase III, multi-center, randomized, open-label, two-arm, active-controlled study that randomized female patients with Stage I to III invasive breast cancer who received 4 cycles of myelotoxic taxane + cyclophosphamide chemotherapy treatment. Forty-one (41) sites across 5 countries participated in the trial, including Bulgaria, Hungary, Russia, Ukraine, and US. Patients were randomized to F-627 or Neulasta® in a 1:1 ratio on the day of chemotherapy and administered study drug 24 hours after chemotherapy administration in each cycle. A total of 393 patients were randomized and analyzed for efficacy and safety. Clinical assessments were cycle-specific and included physical examination, serum samples for immunogenicity before each chemotherapy cycle, laboratory assessments, hematology and CBC with differentials, urinalysis, body weight, vital signs, adverse event (AE) collection, and concomitant medications. The pharmacokinetics (PK) and the pharmacodynamics (PD) of F-627 were also assessed. The primary efficacy endpoint was the duration in days of Grade 4 (severe) neutropenia (ANC <0.5 × 10 9/L) during cycle 1 of chemotherapy. Results - The mean duration of Grade 4 neutropenia in chemotherapy cycle 1 was 0.2 days for both F-627 and Neulasta®. F-627 was non-inferior compared to Neulasta® for the duration of Grade 4 neutropenia in chemotherapy cycle 1 with a mean difference of 0.0 days (95% CI: -0.1, 0.1), utilizing a non-inferiority margin of 0.6 days. The incidence of Grade 4 neutropenia in chemotherapy cycle 1 was comparable between F-627 and Neulasta®, 11.7% for both treatment groups. For chemotherapy cycles 2, 3, and 4, the incidence and duration of Grade 4 neutropenia was generally lower than in chemotherapy cycle 1. The mean durations of Grade 4 neutropenia were 0.1, 0.0, and 0.0 days for F-627 and 0.1, 0.1, and 0.1 days for Neulasta® in chemotherapy cycles 2,3,4, respectively. The incidence of Grade 4 neutropenia was 4.6%, 2.6%, and 1.6% for F-627 and 5.1%, 6.3%, and 5.3% for Neulasta® in chemotherapy cycles 2, 3, and 4, respectively. Across all chemotherapy cycles and for each chemotherapy cycle, the mean duration and the incidence of IV antibiotic use and hospitalization due to febrile neutropenia or any infection were low and comparable between F-627 and Neulasta®. The depth of ANC nadir was comparable in each chemotherapy cycle between F-627 and Neulasta®. For each chemotherapy cycle, time to ANC nadir was slightly longer for patients treated with F-627 than those with Neulasta®; the mean time to ANC nadir was 6.4, 6.1, 6.2, and 6.2 days for F-627, compared to 6.1,5.3, 5.7, and 5.5 days for Neulasta® in cycles 1, 2, 3, and 4, respectively. F-627 was well tolerated, with a low incidence of serious AEs and AEs leading to discontinuation, comparable to the profile for Neulasta®. There were 3 deaths during the study (1 for F-627 and 2 for Neulasta®). None of the deaths were related to study drug treatment. Clinical laboratory abnormalities were observed to be similar between the two treatment groups. Conclusion - Once-per-cycle F-627, given as a fixed 20 mg dose, was non-inferior to Neulasta® in reducing the duration of severe neutropenia following TC chemotherapy. F-627 was well tolerated during the study with an overall safety profile comparable to that for Neulasta®. F-627 is a safe, effective, and easy to use alternative to current CIN therapy. Disclosures Daley: Evive: Current Employment, Current holder of stock options in a privately-held company. Chen: Evive: Current Employment.
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&NA;. "New Indication for Neulasta." Oncology Times 27, no. 21 (2005): 15. http://dx.doi.org/10.1097/01.cot.0000291276.70786.2f.
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Ertan-Ahmed, Senem, Michael G. Kiehl, Atanas Radinoff, et al. "GX-G3, a long-acting G-CSF, compared with pegfilgrastim in reducing duration of severe neutropenia after chemotherapy for non-Hodgkin’s lymphoma." Journal of Clinical Oncology 37, no. 15_suppl (2019): e19065-e19065. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e19065.
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e19065 Background: G-CSF is used in patients at significant risk for developing severe neutropenia (neutrophil count < 0.5 × 109/L or grade 4 neutropenia) following myelosuppresive chemotherapy. GX-G3, human G-CSF fused to hyFc is a proposed alternative to Neulasta. Methods: An open-label, randomized, phase II study was designed to compare the effects of subcutaneous (SC) injection of GX-G3 (a long-acting G-CSF) at doses of 150, 250 and 350 μg/kg with Neulasta 6 mg administered SC in patients receiving R-CHOP for advanced NHL (n = 65). The primary objective was to assess the duration of severe neutropenia after 1st cycle of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). The following parameters were also assessed: duration of severe neutropenia after 2nd cycle of chemotherapy, optimal time for GX-G3 intervention (two GX-G3 250 μg/kg cohorts; administered 24 and 72 hours after R-CHOP), incidence of severe neutropenia and febrile neutropenia post R-CHOP, pharmacokinetics, and safety. Patients were randomly assigned to receive GX-G3 or reference drug, Neulasta, one dose after 1st and 2nd cycle of R-CHOP for a total of 2 doses. Results: The mean duration of severe neutropenia after 1st cycle was shortest in GX-G3 350 μg/kg group [GX-G3 150, 250 (24h, 72h), 350 μg/kg and Neulasta®; 3.2, 2.3, 2.0, 1.3 and 2.4 days, respectively]. The results of all GX-G3 groups and Neulasta were not significantly different for duration of severe neutropenia after 2nd cycle of R-CHOP, incidence of severe neutropenia and febrile neutropenia, or toxicity profile. The elimination half-life of GX-G3 and Neulasta ranged from 29.8 to 66 hours and 19.2 to 76.8 hours, respectively. Conclusions: GX-G3, in all tested dosage regimen, was safe and well tolerated in this patient population. A single injection of GX-G3 per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by Neulasta. GX-G3 administration after 24 hours, compared to 72 hours post R-CHOP treatment resulted in relatively shorter duration of severe neutropenia. Clinical trial information: 2015-002693-20.
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Roth, Karsten, Barbara Gastl, Dirk Lehnick, Karin Jacob, and Ruediger Jankowsky. "Demonstration of Pharmacokinetic and Pharmacodynamic Equivalence in Healthy Volunteers for B12019, a New Proposed Pegfilgrastim Biosimilar." Blood 128, no. 22 (2016): 5079. http://dx.doi.org/10.1182/blood.v128.22.5079.5079.
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Abstract B12019 is being developed as a biosimilar to Neulasta® (INN pegfilgrastim), a long-acting, pegylated form of recombinant human granulocyte-colony stimulating factor (r-metHuG-CSF, INN filgrastim) for the prevention of chemotherapy-induced neutropenia. A comprehensive analytical, functional and preclinical comparability program has already demonstrated a high degree of similarity of B12019 as compared to Neulasta®. In order to confirm the similarity on the clinical level, a pharmacokinetics/pharmacodynamics (PK/PD) study was conducted with B12019 in comparison to EU-authorised Neulasta®. The study was designed as a single-dose, randomized, double-blind, two-way crossover study. The study statistics were based on a two-stage design derived from to Potvin et al, 2007 to address potential high variability for the PK endpoints. 172 healthy male volunteers were enrolled in stage 1 of the study, whereas stage 2 would allow the recruitment of additional 102 subjects. The subjects received B12019 as well as Neulasta®. The primary PK endpoints were the Area Under the Curve for concentration (AUC0-last) and maximum concentration (Cmax). The primary PD endpoint was the Area Under the Effect Curve (AUEC) for Absolute Neutrophil Count (ANC). PK endpoints were assessed with a 94.32% confidence interval (CI) accounting for the two-stage study design, whereas the PD endpoint was assessed with a 95% CI. Furthermore, safety and immunogenicity were investigated. 161 subjects were eligible to contribute to the model-based PK and PD comparison based upon the first stage of the study. For the PK endpoints, the 94.32% CIs for the geometric mean ratios were 86.60-104.73% for AUC0-last and 84.36-102.18% for Cmax. Both PK endpoints fulfilled the predefined acceptance criteria of being within the range of 80-125%. For the PD endpoint, the 95% CI for the geometric mean ratio of the ANC AUEC was 98.67-101.75%, also falling within the predefined acceptance criteria of 80-125%. Since the primary PK endpoints were met in stage 1 of the study, stage 2 was not required. The safety profile of B12019 did not show any clinically meaningful difference as compared to Neulasta®. Neither anti-G-CSF nor neutralising antibodies were detected for both, B12019 and Neulasta®. The study demonstrated PK and PD comparability as well as comparable safety and immunogenicity profiles of B12019 as compared to EU-authorised Neulasta®. No clinically meaningful differences were detected between B12019 and Neulasta®. The high analytical and functional similarity of B12019 was confirmed on clinical level. Disclosures Roth: Cinfa Biotech: Employment. Gastl:Cinfa Biotech: Consultancy. Lehnick:Nuvisan GmbH: Employment. Jacob:Cinfa Biotech: Employment. Jankowsky:Cinfa Biotech: Employment.
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Deshmukh, Arati, Rishank Goyal, Kalyana Sundaram, et al. "Analytical sameness methodology for the evaluation of structural, physicochemical, and biological characteristics of Armlupeg: A pegfilgrastim biosimilar case study." PLOS ONE 18, no. 8 (2023): e0289745. http://dx.doi.org/10.1371/journal.pone.0289745.
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Pegfilgrastim is administered as an adjunct to chemotherapy to reduce the incidence of febrile neutropenia and associated infectious complications. Lupin’s Pegfilgrastim is a proposed biosimilar to the U.S.-referenced Neulasta®. Demonstration of biosimilarity requires extensive physicochemical and functional characterization of the biosimilar, and demonstration of analytical similarity to the reference product, in addition to clinical studies. This work is a case study for demonstrating the analytical similarity of Armlupeg (Lupin’s Pegfilgrastim) to Neulasta® with respect to structural and physicochemical attributes using several robust, orthogonal, and state-of-the-art techniques including high-end liquid chromatography, mass spectrometry, and spectroscopy techniques; circular dichroism; differential scanning calorimetry; nuclear magnetic resonance; analytical ultracentrifugation; and micro-flow imaging. Functional similarity was demonstrated using an in vitro cell proliferation assay to measure relative potency and surface plasmon resonance to measure receptor binding kinetics. Furthermore, comparative forced-degradation studies were performed to study the degradation of the products under stress conditions. The product attributes were ranked based on a critical quality attributes risk score according to their potential clinical impact. Based on criticality, all analyses were statistically evaluated to conclude analytical similarity. Lupin’s Pegfilgrastim was comparable to Neulasta® as demonstrated via structural, functional, and purity analyses. Lupin’s Pegfilgrastim complied with the quality and statistical ranges established using Neulasta®. Both products follow the same degradation pathways under stress conditions as observed in the forced-degradation studies. No new impurity or degradation product was observed in Lupin’s Pegfilgrastim. These data conclusively demonstrate the analytical similarity of Lupin’s Pegfilgrastim and Neulasta®.
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Wessels, Hendrik, Dirk Lehnick, Josef Höfler, Ruediger Jankowsky, Paul Chamberlain, and Karsten Roth. "Pharmacodynamics, safety, and immunogenicity of Pelmeg, a pegfilgrastim biosimilar in healthy subjects." Pharmacology Research & Perspectives 7, no. 5 (2019): 1, 9. https://doi.org/10.5281/zenodo.4588564.
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A pharmacodynamics (PD) and immunogenicity study was conducted to investigate biosimilarity of Pelmeg®, a pegfilgrastim biosimilar to EU‐authorized Neulasta®. The multiple‐dose, randomized, double‐blind, two‐sequence, and three‐period cross‐over study comprised 96 healthy male subjects, receiving Pelmeg (Test [T]) and Neulasta (Reference [R]) in a sequential manner (T‐T‐R vs R‐R‐T). Subjects were dosed with 3 mg pegfilgrastim, as this dose was previously shown to be in the ascending part of the dose‐response curve for PD. The primary PD endpoint was the area under the effect curve (AUEC0‐last) for absolute neutrophil count (ANC). The primary immunogenicity endpoint was proportion of anti‐drug antibody (ADA)‐positive subjects at the end of Period 2 (ie, after administration of two doses of the same study drug). Comparability was demonstrated for the PD endpoint, with the geometric mean ratio (T/R) of AUEC0‐last being 101.59%, with a corresponding 95% CI of [99.58; 103.63]. Of note, when using tighter acceptance limits (90.00%‐111.00%), comparability between test and reference was shown as well. Only two confirmed ADA positive samples were detected, one after treatment with Pelmeg and one after Neulasta. These had a low ADA titer, no filgrastim reactivity, and no neutralizing capacity. No clinically meaningful differences in safety between Pelmeg and Neulasta were observed. Overall, the results from this study confirmed the biosimilarity of Pelmeg and Neulasta for PD and immunogenicity, as shown already at the bioanalytical level and in the pivotal PK/PD study with Pelmeg.
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Piedmonte, Deirdre Murphy, and Michael J. Treuheit. "Formulation of Neulasta® (pegfilgrastim)." Advanced Drug Delivery Reviews 60, no. 1 (2008): 50–58. http://dx.doi.org/10.1016/j.addr.2007.04.017.
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Fiegl, Michael A., Wolfgang Hiddemann, and Jan Braess. "Pegylated Recombinant G-CSF after Sequential High Dose Cytarabine Based Induction Chemotherapy in AML - Analysis of Pharmakokinetics and Effect on Neutrophil Recovery of Pegfilgrastim." Blood 108, no. 11 (2006): 4551. http://dx.doi.org/10.1182/blood.v108.11.4551.4551.
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Abstract BACKGROUND: The use of hematopoetic growth factors after conventional induction chemotherapy in acute myeloid leukemia (AML) remains controversial. Yet from former studies with sequential high dose AraC (S-HAM) in relapsed and refractory AML it was shown that the use of G-CSF reduced the early death rate significantly in this clinical setting. Pegylated filgrastim (NEULASTA©, Amgen) has shown to have a sustained-duration effect compared to conventional filgrastim due to decreased renal clearance. This analysis focuses on pegfilgrastim pharmacokinetics and effect on neutrophil recovery in AML. MATERIAL AND METHODS: The ongoing AML CG pilot trial uses sequential high dose AraC as accelerated dose dense induction therapy in AML. It comprises 66 % of the established HAM-HAM double induction regimen (HAM: AraC 3 g/m2 bid for 3 days and mitoxantron 10 mg/m2 for 3 days) given within 2 weeks instead of four. 6 mg of Neulasta© was applied subcutaneously to all patients with complete blast clearance on day 18 after start of S-HAM. Blood samples for measurement of Neulasta plasma levels were obtained before application and afterwards daily up to day 21. Plasma concentrations of pegfilgrastim were measured by ELISA technique. Leukocyte count was obtained daily. RESULTS: Analyses were performed in 19 patients at two institutions. After injection, peak plasma levels with a mean of 174 ng/ml were achieved within 48 hours after injection and t ½ was 6 days. 7 of these patients received a second injection of Neulasta 10 – 15 days later due to insufficient neutropenic recovery. Here plasma levels of &gt; 200 ng/ml were achieved. Effective plasma levels of Neulasta (&gt; 2.0 ng/ml) were observed up to 14 days after injection. In those patients who remained neutropenic, Neulasta plasma levels were observed even longer (t ½ &gt; 6 days). Pegfilgrastim clearance was significantly correlated to neutrophil recovery (r=−0.91, p=0.001). Median time to leukocyte recovery of &gt; 1 G/l was 9 days after injection of the first dose in all evaluable patients. CONCLUSION: In our study, time to neutrophil recovery in primary AML was shortened to 26 days by use of an accelerated, dose dense regimen plus pegfilgrastim application as compared historically to standard double induction therapy (median time to neutrophil recovery 45 days). Figure Figure
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Sykes, Alison, Louise Ingram, Ulrich Kronthaler, and Laurent Chevalet. "Demonstration of physicochemical and functional similarity between Stimufend (pegfilgrastim-fpgk) and Neulasta (pegfilgrastim): A comparative analytical assessment." PLOS ONE 19, no. 10 (2024): e0309480. http://dx.doi.org/10.1371/journal.pone.0309480.
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Background Pegfilgrastim is a long-acting recombinant human granulocyte colony-stimulating factor biologic that is indicated to reduce the incidence of infections, manifested by febrile neutropenia, in patients receiving myelosuppressive anti-cancer drugs and to increase survival in patients acutely exposed to myelosuppressive doses of radiation. Due to the high cost of biologic therapy and the scarcity of biosimilar alternatives, there is an unmet medical need for targeted biologics. Objective This comparative analytical investigation aimed to confirm the similarity of biosimilar Stimufend® (pegfilgrastim-fpgk) to reference product Neulasta® (pegfilgrastim). Methods The analysis was designed using state-of-the-art orthogonal techniques and side-by-side testing to compare the physicochemical and biological properties of these two products. The measured quality attributes included the primary structure and higher order structure of the molecule, purity/impurity profiles, product variants, process-related impurities, composition, content, and biological activity. The statistical analysis was based on risk ranking of the critical quality attributes (very low, low, moderate, high, very high), and scientific considerations in combination with the characteristics of the assay (sensitivity, selectivity, and variability). In addition, non-quantitative parameters were compared using a descriptive assessment of the product profile. Analytical similarity was concluded by quality attributes falling within the defined range of the originator product. Results The results of this study confirm that Stimufend® is biosimilar to Neulasta® for all measured quality attributes. There are no clinically significant differences between Stimufend® and Neulasta®, which was confirmed by the marketing approval for Stimufend® by the Food and Drug Administration and the European Medicines Agency. Conclusion The findings of this study provide robust evidence supporting the structural and functional biosimilarity between Stimufend® and Neulasta®.
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Singh, Aditi, Morgan M. Bailey, Neha J. Patel, and Danae Hamouda. "Pegfilgrastim-induced leukocytosis and hyperleukocytosis." Case Reports in Internal Medicine 8, no. 1 (2021): 5. http://dx.doi.org/10.5430/crim.v8n1p5.
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Objective: To report a case of leukocytosis (LCT) and hyperleukocytosis (HLCT) episodes post Pegfilgrastim (Neulasta) administration.Case Summary: A 74-year-old female presented with several episodes of LCT and HLCT following administration of Pegfilgrastim while undergoing adjunct dose dependent chemotherapy for adenocarcinoma of the gallbladder. The patient had completed cycle 6, day 8 of chemotherapy and subsequently received Neulasta 48 hours later. Two days later, she presented to the ER with white blood cell (WBC) count of 110K. Prior to Neulasta administration, her WBC counts were within normal range and after each episode of leukocytosis, the patient’s WBC count trended downward. Upon consultation, hematology considered Pegfilgrastim as a likely cause for this patient’s WBC cycling and HLCT.Discussion: Pegfilgrastim-induced HLCT occurs in less than 1% of patient cases. Dose-dependent chemotherapy combined with Pegfilgrastim treatment is an optimal treatment option to reduce the length of chemotherapy schedules and risk of febrile neutropenia. Following the dosing of Pegfilgrastim, the drug clearance is mediated by neutrophil receptors which results in a reduction of ANC values.Conclusions: Further studies are needed to determine the optimum timing and dosage of Pegfilgrastim to offer maximum myeloprotective benefit while also minimizing the risks of adverse events such as leukocytosis and hyperleukocytosis experienced by our patient.
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Roth, Karsten, Dirk Lehnick, Hendrik Wessels, Josef Höfler, Barbara Gastl, and Ruediger Jankowsky. "Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of Pelmeg, a pegfilgrastim biosimilar in healthy subjects." Pharmacology Research & Perspectives 7, no. 5 (2019): 1, 9. https://doi.org/10.5281/zenodo.4626851.
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A pharmacokinetics (PK)/pharmacodynamics (PD) study (EudraCT number 2015‐002966‐21) was conducted to investigate the biosimilarity of Pelmeg® (pegfilgrastim), a biosimilar to EU‐authorized Neulasta®, which is used in the clinic for prevention of chemotherapy‐induced neutropenia. The single‐dose, randomized, double‐blind, two‐way crossover study comprised 171 healthy male subjects, receiving Pelmeg and Neulasta (6 mg as subcutaneous injection) in a sequential manner. Primary PK endpoints were the area under the concentration curve from time zero to last measurable concentration (AUC0‐last) and the maximum concentration (Cmax). The primary PD endpoint was the area under the effect curve (AUEC0‐last) for absolute neutrophil count (ANC). Safety and immunogenicity were also assessed. Comparability was demonstrated for both PK endpoints, with geometric mean ratios (test/reference) for AUC0‐last and Cmax of 95.2% and 92.8%, respectively. The corresponding confidence intervals (CIs; 94.3%) were [86.6%;104.7%] for AUC0‐last and [84.4%;102.2%] for Cmax, both being within the equivalence margin of 80.0% to 125.0%. Likewise, PD comparability was demonstrated, with the geometric mean ratio (test/reference) of AUEC0‐last of 100.2%, with a corresponding CI (95%) of 98.7%‐101.8%. No clinically meaningful differences were observed for safety and immunogenicity between Pelmeg and Neulasta. Pelmeg was found to be highly similar to the reference product.
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Jaiswal, Nikhil, Undergraduate Pre-Med, Ahsan Khan, Undergraduate Pre-Med, and Zahida Yasin. "Hyperleukocytosis Caused By Neulasta Complicated By Leukostasis Versus Asymptomatic Uncomplicated Hyperleukocytosis In AML. Two Cases and When To Leukapherese." Blood 122, no. 21 (2013): 4832. http://dx.doi.org/10.1182/blood.v122.21.4832.4832.
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We describe two cases of hyperleukocytosis, one resulting from growth factor use with complications and the other a case of asymptomatic acute myeloid leukemia with high blast count; literature was reviewed to identify similar cases and how to treat them. Introduction Hyperleukocytosis may be complicated by intravascular leukostasis. 5-13% of adults diagnosed with acute myeloid leukemia (AML) present with hyperleukocytosis (Porcu P, Cripe LD et al Hyperleukocytic leukemias and leukostasis: Leukemia Lymphoma. 2000; 39:1–18). Leukapheresis is performed to treat complications of hyperleukocytosis in AML. No cell count cutoffs exist to prevent leukostasis with timely leukapheresis. Literature review Neupogen (filgrastim) and Neulasta (pegfilgrastim) are used to reduce the duration of neutropenia in selected patients. Pegfilgrastim has reduced renal clearance, is more potent, and possesses a much longer half-life in vivo compared to filgrastim. Predicting leukocytic response to initial growth factor exposure is difficult. Asymptomatic hyperleukocytic responses may result. Symptomatic hyperleukocytosis with sequelae of leukostasis is rarely encountered with the use of growth factors (JCO, Antonio C. Wolff, Volume 24, Number 15 May 20 2006). We could find only one case report where leukapheresis was used to treat growth factor induced leukostasis (From FDA reports: Neulasta and Leukapheresis, eHealthMe August 7 2013). There are no guidelines to treat cell count cutoffs for leukapheresis in symptomatic patients with hyperleukocytosis resulting from growth factors. Shown below is data taken from FDA reports: eHealthMe 2013). Summarizing data in tables above Growth factor induced leukocytosis is directly proportional to age (Table 1). Females are more susceptible to leukocytic response than males (Table 2). Leukostasis is rare with growth factors, Neulasta > Neupogen (Table 3, 4). Cases Case #1 is that of an asymptomatic 69 year old male with AML, hyperleukocytosis, and white blood cell (WBC) counts of 270,000 with 98% circulating blasts. Cell counts trended down with Hydroxyurea. Case #2 is an elderly octogenarian male patient with MDS (IPSS 1) renal insufficiency (creatinine clearance = 31.9), a small serum IgA lambda M Spike, grade 3/4 neutropenia, and pancytopenia given 6 mg subcutaneous Neulasta. Within 7 hours, the patient became symptomatic (chest pain, dizziness, and headache). On presentation to the hospital the next day, WBC count was up to 130,000, complicated by intraocular flame hemorrhage, documented troponin elevation, and an EKG that confirmed a non ST elevation myocardial infarction (NSTEMI). Cell counts trended down to 50,000 range in approximately 3 days without treatment for hyperleukocytosis. Conclusion Neulasta should be used very cautiously in elderly patients, especially those with renal insufficiency. Patients who have symptomatic hyperleukocytosis should be seriously considered for interventions such as leukapheresis to prevent life threatening complications, regardless of the cause, growth factor or acute leukemia. Evidence-based guidelines for prevention of leukostasis are desperately needed. Disclosures: No relevant conflicts of interest to declare.
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Webster, Jennifer, Jeffrey A. Scott, Helen Smith, et al. "Udenyca has equivalent efficacy to the pegfilgrastim originator in breast cancer patients receiving highly myelosuppressive chemotherapy." Journal of Clinical Oncology 38, no. 15_suppl (2020): e19273-e19273. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e19273.
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e19273 Background: In late 2019, the Center for Medicare and Medicaid Innovation (CMMI) issued a request for information (RFI) for the Oncology Care First (OCF) program, which will extend the evaluation of value-based care in the community oncology setting for an additional five years, through 2026. We have learned through the Oncology Care Model (OCM) that there are savings to be found by reducing inpatient admissions and emergency department visits and controlling for things such as duplicate labs. However, it has become increasingly clear that further savings will require practices to evaluate their use of both cancer-directed therapy and supportive therapy. To this end, Integra Connect has developed a tool, the Value Monitor, that allows for statistically rigorous comparative effectiveness research at scale, using real world data. As an initial proof of concept, we used the Value Based Care Monitor to compare the efficacy for febrile neutropenia prophylaxis between two pegfilgrastims: Udenyca, a biosimilar, and Neulasta, the originator. Methods: The Integra Connect Value Monitor was used to perform a matched cohort analysis of breast cancer patients receiving Udenyca vs patients receiving Neulasta from 1/1/2017 – 8/31/2019. Patients were matched on age (within 5 years), gender, OCM participation status and date of treatment (within 90 days). Each Udenyca patient (n = 496) was matched to 5 Neulasta patients. The efficacy endpoint was neutropenia rate, where neutropenia was defined as the presence of a neutropenia ICD-10 code (D70*), and/or an Absolute Neutrophil count less than 1,500. We are in the process of adding grade IV neutropenia (ANC < 500) to the tool. Results: Udenyca and Neulasta showed similar rates of neutropenia at 28.6% and 29.1% respectively (McNemar’s p-value 0.82). These rates are likely higher than those reported in the literature due to the very broad definition of neutropenia used in this study. Follow up will include neutropenia rates by grade. Conclusions: This proof of concept study established two key findings. First, that it is possible to do comparative effectiveness research at scale in order to drive value-based decisions in oncology care. Secondly, it confirms that we are seeing equivalent pegfilgrastim efficacy for neutropenia prophylaxis when comparing Udenyca, a biosimilar, to the originator agent.
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Waller, C. F., R. Tiessen, T. Lawrence, et al. "A pharmacokinetics and pharmacodynamics equivalence trial of proposed pegfilgrastim biosimilar, MYL-1401H vs EU neulasta® and US neulasta®." Annals of Oncology 27 (October 2016): vi503. http://dx.doi.org/10.1093/annonc/mdw390.19.
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Waller, C., R. Tiessen, T. Lawrence, et al. "A pharmacokinetics and pharmacodynamics equivalence trial of proposed pegfilgrastim biosimilar, MYL-1401H vs EU-Neulasta ® and US-Neulasta ®." European Journal of Cancer 72 (February 2017): S41. http://dx.doi.org/10.1016/s0959-8049(17)30215-0.
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Bhanushali, Charmi, Maya Gogtay, Vidhi Bhanushali, Kalaivani Babu, Srinishant Rajarajan, and Nihar Desai. "Patterns of Medicare Utilization and Spending on Granulocyte Colony-Stimulating Factors: Filgrastim, Pegfilgrastim, and Their Biosimilars." Blood 144, Supplement 1 (2024): 7572. https://doi.org/10.1182/blood-2024-211978.
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Introduction: Granulocyte colony-stimulating factors (G-CSF) are pivotal for aiding in neutrophil production in patients post-chemotherapy. They represent a substantial part of Medicare expenditure. The emergence of biosimilars promises reduced costs and enhanced accessibility without compromising efficacy. However, the adoption of biosimilars in clinical practice has varied, influenced by factors such as physician preferences, patient awareness, and healthcare policies. In this study, we aim to examine Medicare part B spending and utilization trends for Filgrastim, Pegfilgrastim, and their biosimilars from 2018-2022. Methodology: We analyzed publicly available datasets from Centers for Medicare & Medicaid Services (CMS) within Medicare Part B and extracted total spending, the number of beneficiaries, and spending per beneficiary. Data for Neupogen and its biosimilars (Zarxio, Nivestym, Granix) and Neulasta and its biosimilars (Fulphila, Udenyca, Ziextenzo and Nyvepria) was extracted. All costs were adjusted for inflation (using Inflation Calculator based on the average Consumer Price Index data) and represented in US dollars. Results Filgrastim: From 2018 to 2022, total spending on Neupogen dropped 69%, from $47.63M to $14.52M. Spending on both Granix and Zarxio showed a 70% reduction (from $14.61M to $4.37M and $46.64M to $13.76M respectively).The spending on Nivestym (approved in June 2018) increased from $2.13M in 2019 to $4.19M in 2022. Average spending per beneficiary for Neupogen decreased by 17% from $3,209 in 2018 to $2,654 in 2022. Average spending per beneficiary decreased by 41% for Granix (from $1,745 in 2018 to $1,025 in 2022), 68% for Zarxio (from $2,404 in 2018 to $764 in 2022) and 57% for Nivestym ($2,441 in 2018 to $1,055 in 2022). PEGfilgrastim: The total spending on Neulasta was highest in 2022 at $342M. The total spending on Nyvepria, Ziextenzo and Fulphila showed an increase since their introduction from $29M in 2021 to $52M in 2022, $18M in 2019 to $79.5M in 2022 and $19.83 in 2018 to $66.30M in 2022 respectively. Total spending on Udencya decreased by 47% from $167M in 2019 to $89M in 2022. Average spending per beneficiary for Neulasta was $6,935 in 2022. The average spending per beneficiary for biosimilars has decreased since their introduction (by 46% for both Fulphila and Udencya, from $11,510 in 2018 to $6,942 in 2002 and from $14,444 in 2019 to $7,742 in 2022 respectively) and by 36% for both Ziextenzo and Nyvepria (from $11,672 in 2020 to $7,402 in 2022 and from $13,981 in 2021 to $8,937 in 2022). Conclusion Total spending on Filgrastim and its biosimilars has notably decreased with increased adoption of more cost-effective alternatives like Nivestym. Neupogen is a high-cost option, with its spending declining but still notable compared to its biosimilars. Neulasta continues to dominate total spending, although its biosimilars have shown substantial growth in utilization. Neulasta maintains the lowest average spending per beneficiary, highlighting its ongoing value proposition despite the increasing role of biosimilars in the treatment landscape. In conclusion, by leveraging the market competition from biosimilars, the healthcare system can achieve a more balanced approach to delivering high-quality care while managing costs effectively.
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Kasi, Pashtoon Murtaza, Mrinal M. Patnaik, and Prema P. Peethambaram. "Safety of Pegfilgrastim (Neulasta) in Patients with Sickle Cell Trait/Anemia." Case Reports in Hematology 2013 (2013): 1–4. http://dx.doi.org/10.1155/2013/146938.
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Pegfilgrastim (Neulasta) is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and risk for febrile neutropenia. Prescribing information available on manufacturer’s website for the drug warns us about possible severe sickle cell crises related to the medication but does not report the actual incidence or the use in patients with sickle cell trait. Caution is advised when using it in patients with sickle cell disease. Here we present a case of a Caucasian female with known sickle cell trait (SCT) with no prior complications who developed a presumed sickle cell crisis after getting Neulasta, as a part of the chemotherapy regimen used to treat her breast cancer. Based on our literature review, this appears to be the first case report of a patient with SCT developing a sickle cell crisis with the pegylated form of recombinant filgrastim. Given the dearth of literature regarding the use of G-CSF and its related pegylated forms in patients with sickle cell anemia and sickle cell trait, a discussion of potential mechanisms and review of current literature and guidelines is also presented.
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Molineux, G. "The Design and Development of Pegfilgrastim (PEG-rmetHuG-CSF, Neulasta®)." Current Pharmaceutical Design 10, no. 11 (2004): 1235–44. http://dx.doi.org/10.2174/1381612043452613.
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Cohen, Michael R. "Fatal Potassium Errors Linked to Pharmacy Processes Neumega, Neulasta and Neupogen." Hospital Pharmacy 39, no. 6 (2004): 519–21. http://dx.doi.org/10.1177/001857870403900604.
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Schmidt, Sarah (Hopps), Katherine Newman, Michael Machiorlatti, Sara K. Vesely, Jennifer Holter Chakrabarty, and George B. Selby. "Pegfilgrastim (Neulasta®) Vs. Tbo-Filgrastim (Granix®) Post Autologous Transplant." Biology of Blood and Marrow Transplantation 24, no. 3 (2018): S331—S332. http://dx.doi.org/10.1016/j.bbmt.2017.12.273.
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McBride, Ali, Ivo Abraham, Karen MacDonald, Kim Campbell, Mohan Bikkina, and Sanjeev Balu. "Cost savings of conversion from filgrastim or pegfilgrastim to biosimilar filgrastim-sndz for chemotherapy-induced (febrile) neutropenia (CIN/FN) prophylaxis and expanded access to biosimilar GCSF on a budget neutral basis." Journal of Clinical Oncology 35, no. 15_suppl (2017): e18334-e18334. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e18334.
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e18334 Background: Biosimilar filgrastim (Zarxio) provides a more cost-efficient alternative to reference and pegylated filgrastim for CIN/FN prophylaxis. Using biosimilar conversion rates, we determined savings achieved, number needed to convert (NNC) to purchase additional Zarxio, and the incremental number (n) of patients (pts) that could be provided Zarxio on a budget neutral basis using various filgrastim cycle/treatments scenarios. Prior real-world practice studies have shown variations in GCSF duration including shorter durations (Weycker 2006; Gascon 2016) relative to registration trials and guideline recommendations. Methods: Calculations were done for a panel of 20000 pts; chemotherapy of 1 or 6 cycles with 5, 7 or 11 filgrastim injections; cost of medicines using average selling price (Zarxio $245.08, Neupogen $283.87, Neulasta $3761.22) and subcutaneous administration per Current Procedural Terminology ($42.31 hospital outpt). NNC is the n to be converted to Zarxio to purchase 1 additional Zarxio dose or the full regimen. This yielded the incremental n that could receive any of the 6 prophylaxis scenarios budget neutrally. Results: See table below. Conclusions: A 20000 pt panel yields expanded access to Zarxio, on a budget-neutral basis, to 2699 additional pts if 100% are converted from Neupogen; and to 4063 to 32939 additional pts, depending on cycles/treatments, if converted from Neulasta. Weycker et al, Ann Pharmacother 2006;40:402-7. Gascon et al, Support Care Cancer 2016;24:911-25. [Table: see text]
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CRAWFORD, J. "Once-per-cycle pegfilgrastim (Neulasta) for the management of chemotherapy-induced neutropenia." Seminars in Oncology 30 (August 2003): 24–30. http://dx.doi.org/10.1016/s0093-7754(03)00314-2.
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Legesse, Betre, Amandeep Kaur, Doreswamy Kenchegowda, Bernadette Hritzo, William E. Culp, and Maria Moroni. "Neulasta Regimen for the Hematopoietic Acute Radiation Syndrome: Effects Beyond Neutrophil Recovery." International Journal of Radiation Oncology*Biology*Physics 103, no. 4 (2019): 935–44. http://dx.doi.org/10.1016/j.ijrobp.2018.11.043.
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Rice, R. D., L. B. Baker, and C. H. Moskowitz. "95: Neulasta™ as Growth Factor Support After Autologous Stem Cell Transplantation." Biology of Blood and Marrow Transplantation 14, no. 2 (2008): 37. http://dx.doi.org/10.1016/j.bbmt.2007.12.104.
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&NA;. "Pegfilgrastim [Neulasta] may lower the incidence of infection in patients with breast cancer." Inpharma Weekly &NA;, no. 1444 (2004): 11. http://dx.doi.org/10.2165/00128413-200414440-00030.
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Biganzoli, Laura, Michael Untch, Tomas Skacel, and José-Luis Pico. "Neulasta (pegfilgrastim): a once-per-cycle option for the management of chemotherapy-induced neutropenia." Seminars in Oncology 31 (June 2004): 27–34. http://dx.doi.org/10.1053/j.seminoncol.2004.04.002.
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Peshin, Supriya, Chirag Kapadia, and Ravitharan Krishnadasan. "Insights into Neulasta-Associated Splenic Infarction: Unveiling a Rare Complication in Chemotherapy for Chronic Myelomonocytic Leukemia." Clinical Lymphoma Myeloma and Leukemia 24 (September 2024): S187. http://dx.doi.org/10.1016/s2152-2650(24)00617-7.
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Garcia Arroyo, F. R., J. Herrero, M. Provencio, J. Gómez-Codina, A. Rueda, and M. Llanos. "Safety analysis of a phase II study of cyclophosphamide, vincristine, non-pegilated liposomal doxorubicin (Myocet), and prednisone + rituximab in biweekly regimen (R-COMP-14) as primary treatment of non-Hodgkin lymphoma." Journal of Clinical Oncology 24, no. 18_suppl (2006): 17532. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.17532.
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17532 Background: Gold standard treatment of CD20+ aggressive B-cell non-Hodgkin lymphoma, R-CHOP, has been suggested to improve outcome when administered as dose-dense regimen supported with G-CSF. The non-pegylated liposomal doxorubicin (Myocet) has an improved safety profile compared to standard formulations of doxorubicin. Standard R-CHOP regimen has been modified replacing doxorubicin with Myocet, administered on a biweekly basis (R-COMP-14) looking for an increase in efficacy without impairing tolerability Methods: Single arm, multicentric, 2-step (Simon design) phase II trial. Newly diagnosed, diffuse large B-cell lymphoma, stages III, IV or I, II with IPI ≥ 1, CD20+, eligible patients (Pt) were treated with Myocet 50 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 (max. 2 mg), rituximab 375 mg/m2 and prednisone 100 mg/d d1–5 in biweekly cycles. Pegilated filgastrim (Neulasta™) was administered on day 2 of the cycle. Response was assessed after 3 cycles, and patients with PR or CR received 5 additional cycles. A safety analysis was planned by protocol with data of first patients included Results: The median age of the 13 Pt included was 59 (range 28–64). At baseline 53.9% Pt had III-IV stage and 41.7% had extraganglionar involvement. Median basal LVEF was 66% (range 44–79). A median of 7 cycles of R-COMP were administered. The median relative dose intensity per week for Myocet was 94.9%. 6.2% of the cycles were delayed and 8.6% of the cycles were dose reduced. There were 2 episodes of febrile neutropenia. G3 asthenia, G3 neurotoxicity and G3 related infection were found in one cycle each. One patient had G3 hepatic toxicity resolved with dose reduction. At the end of treatment the median LVEF was 65.52% (range 52–76), there was no cardiac event related to the treatment. 84.6% of Pt had complete or partial response (7 RC, 2 uRC, 2 PR, 1 SD, 1 PD) at the end of the study Conclusions: In this small safety group of Pt that received the dose-dense regimen, the preliminary results suggest that R-COMP-14 supported with Neulasta is a well tolerated and effective regimen. Recruitment will proceed as planned (75 Pt). No significant financial relationships to disclose.
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Wang, Weijia, Sanjeev Balu, and Kim Campbell. "Cost-minimization analysis for biosimilar pegfilgrastim in the prophylaxis of chemotherapy induced (febrile) neutropenia and expanded access based on budget neutral basis." Journal of Clinical Oncology 37, no. 15_suppl (2019): 6645. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6645.
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6645 Background: Pegfilgrastim (pegfil) injection is 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. Assuming biosimilarity of biosim-pegfil and pegfil in the prevention of febrile neutropenia, we estimated cost minimization of conversion from pegfil to biosim-pegfil and subsequent potential expanded access due to cost savings. Methods: A cost minimization model was conducted based on a hypothetical panel of 20,000 patients using average selling price (ASP) for one chemotherapy cycle. ASP was obtained from 1Q 2019 payment allowance limits. The simulation included two steps: 1) cost minimization was calculated per cycle (biosim-pegfil and pegfil is administered 1 dose per cycle) when patients were converted to biosim-pegfil from pegfil on ratio of 10% to 100% at 10% intervals and at a discount from 15% to 35% at 5% intervals, and 2) expanded access to biosim-pegfil was calculated based on budget neutrality. Since pegfil has two forms of availability (Neulasta and Neulasta-Onpro) with the same price, results were to either conversion scenario. Results: Per-cycle per-patient cost minimization from converting pegfil to biosim-pegfil ranged from $702.27 (15% discount) to $1,638.63 (35% discount). For 20,000 patients, this yields savings of over $14 million (15% discount) to $32 million (35% discount) at 100% conversion rate. When half the patients were converted to biosim-pegfil, savings could range from > $7 million (15% discount) to > $16 million (35% discount). With 100% conversion rate and 15% discount, 3,529 additional patients could be treated with the savings generated. At 50% conversion rate, cost savings could be applied to another 1,765 patients with 15% discount, 3,333 patients with 25% discount, and 5,385 patients with 35% discount, respectively. Conclusions: Conversion from pegfil to biosim-pegfil can lead to potential cost savings and these savings can be applied to offer increased access to supportive care with biosim-pegfil for patients receiving chemotherapy on a budget-neutral basis. For payers with larger populations, savings can be substantial. More studies are warranted to evaluate such potential cost savings due to use of biosim-pegfil over reference pegfil.
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Sanzari, Jenine K., Gabriel S. Krigsfeld, Anne L. Shuman, et al. "Effects of a granulocyte colony stimulating factor, Neulasta, in mini pigs exposed to total body proton irradiation." Life Sciences in Space Research 5 (April 2015): 13–20. http://dx.doi.org/10.1016/j.lssr.2015.03.002.
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Schaub, Felix, Birgit Federmann, Lothar Kanz, and Robert Möhle. "Daily G-CSF (filgrastim) and a Single Dose Of Pegylated G-CSF (pegfilgrastim) After Chemotherapy Result In Different Kinetics Of Circulating Hematopoetic Progenitors: Implication For Potential Stem Cell Harvesting." Blood 122, no. 21 (2013): 4513. http://dx.doi.org/10.1182/blood.v122.21.4513.4513.
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Several studies have shown that a single dose of pegylated G-CSF (pegfilgrastim, Neulasta®) administered after chemotherapy allows sufficient collection of hematopoietic progenitor cells (HPC) for autologous transplantation. Pegfilgrastim has not been approved for HPC mobilization, but the decision for stem cell harvesting may be made after pegG-CSF has already been given. In this case, particular kinetics of circulating HPC after pegG-CSF must be taken into account to guide stem cell harvesting. In an intra-individual analysis, we compared mobilization of HPC in 12 lymphoma patients undergoing two identical cycles of salvage chemotherapy (etoposide, ifosfamide, cisplatin, ± epirubicin, ± rituximab) within a clinical trial (ClinicalTrials.gov: NCT00306111). G-CSF (filgrastim, Neupogen® 5 ug/kg/d) was given daily after the 1st cycle starting at day 3, while a single dose of pegfilgrastim (Neulasta®, 6 mg) was administered after the 2nd cycle. Circulating HPC were analyzed by flow cytometry and colony assays. We found that neutrophil recovery was remarkably pronounced after pegG-CSF resulting in a significant higher white blood count at day 12 compared with filgrastim (WBC: 6.8 ± 1.9 G/l vs. 3.2 ± 0.8 G/l, mean ± SEM), but a similar WBC at day 14 and day 16. However, kinetics of circulating HPC were markedly different: A trend to higher numbers of CD34+ progenitors was observed after pegfilgrastim at day 12 compared to filgrastim, followed by a sharp drop at day 14: 25 ± 12 /μl (pegfilgrastim) vs. 69 ± 22 /μl (filgrastim). Particularly the number of more primitive CD34+CD38- progenitors was significantly reduced at day 14: 3.7 ± 3.0 /μl (pegfilgrastim) vs. 11.7 ± 6.3 /μl (filgrastim). Similar results were found for the more primitive CD34+CD133+ und CD34+CD90+ populations. The colony formation (cloning efficiency) of the HPC was not different. Also, coexpression of homing-related receptors (CXCR4, CD62L/L-selectin) was similar in both groups. We conclude that after chemotherapy and pegG-CSF, sufficient numbers of HPC are circulating which allows for HPC collection during the early recovery phase. However, the HPC count is rapidly dropping once the WBC has recovered, in line with the known elimination of pegGCSF by binding to neutrophils. Thus, when a stem cell harvest is scheduled after neutrophil recovery in these patients, daily addition of non-pegylated G-CSF should be considered. Disclosures: Kanz: Amgen GmbH: Research Funding. Möhle:Amgen GmbH: Research Funding. Off Label Use: Pegfilgrastim is not approved for stem cell mobilization.
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Cardonick, Elyce, Farhana Irfan, and Natalie Torres. "The Use of Neupogen (Filgrastim) or Neulasta (Pegfilgrastim) during Pregnancy When Chemotherapy Is Indicated for Maternal Cancer Treatment." Journal of Cancer Therapy 03, no. 02 (2012): 157–61. http://dx.doi.org/10.4236/jct.2012.32021.
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Peshin, Supriya, Chirag Kapadia, and Ravitharan Krishnadasan. "CML-401 Insights into Neulasta-Associated Splenic Infarction: Unveiling a Rare Complication in Chemotherapy for Chronic Myelomonocytic Leukemia." Clinical Lymphoma Myeloma and Leukemia 24 (September 2024): S372. http://dx.doi.org/10.1016/s2152-2650(24)01314-4.
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Romieu, G., M. Clemens, P. Fargeot, W. Brugger, V. Easton, and P. Bacons. "P110 Pegfilgrastim (Neulasta®) Enables Delivery of FEC 100 Chemotherapy in Elderly Subjects with High Risk Breast Cancer." Breast 14 (February 2005): S46. http://dx.doi.org/10.1016/s0960-9776(05)80146-8.
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Mandanas, R. A., B. J. Underwood, B. V. Geister, and J. W. Smith. "Pegfilgrastim (neulasta™) following chemotherapy leads to successful mobilization of hematopoietic progenitor cells among transplant patients with various diagnoses." Biology of Blood and Marrow Transplantation 10 (February 2004): 14. http://dx.doi.org/10.1016/j.bbmt.2003.12.047.
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Roth, Karsten, Hendrik Wessels, Josef Höfler, Ulrike Scholz, and Dirk Lehnick. "Pelmeg, a biosimilar pegfilgrastim developed in the context of evolving regulatory guidelines." Generics and Biosimilars Initiative Journal 9, no. 3 (2020): 125, 131. https://doi.org/10.5281/zenodo.4724798.
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Pelmeg® is a biosimilar pegfilgrastim, which obtained European Union (EU) regulatory approval in September 2018, with market- ing beginning in January 2019. A comprehensive analytical, functional and preclinical comparability programme demonstrated a high degree of similarity between Pelmeg® and its reference product Neulasta®. A targeted clinical development programme was conducted with Pelmeg®, consisting of two comparative pharmacokinetic (PK)/pharmacodynamic (PD) studies in healthy subjects. Since a surrogate endpoint for efficacy (absolute neutrophil count [ANC]) was available, efficacy and safety studies in patients were waived by the regulatory authorities. Clinical studies with Pelmeg® were designed in close dialogue with regulatory authorities in Europe. During the development process for Pelmeg®, the EU biosimilar guidelines, in particular relating to granu- locyte colony-stimulating factor (G-CSF), were modified. The development of Pelmeg® demonstrates that regular discussions with regulators, in the form of scientific advice or other interactions, are valuable opportunities for dialogue regarding scientific progress related to the comparability of biosimilars. Regulators – at least in the area of biosimilar development – were found to be open to improvements and to deviate from existing guidelines if there was agreement that the scientific state-of-the-art has superseded some aspect of the guidelines. Overall, we suggest that abridged development programmes waiving the need for phase III studies, as described for Pelmeg®, are possible, in particular if good surrogate endpoints are available. In line with this, the number of waivers for phase III studies in biosimilar development has increased in recent years.
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Jason, Xu, Sussman Jonathan, Xu Jessica, Zhao Xing, and Yan Xiao Qiang. "Using recombinant human G-CSF to treat chemotherapy-induced neutropenia over 3 decades: What is next?" Annals of Bone Marrow Research 8, no. 1 (2023): 001–4. http://dx.doi.org/10.17352/abmr.000010.
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Chemotherapy-Induced Neutropenia (CIN) is a potentially fatal side effect of cancer treatment, affecting > 50% of cancer patients treated with chemotherapy. Clinical use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) has allowed for primary and secondary prophylaxis of CIN and its sequela (i.e., febrile neutropenia, fatal infection) during myelosuppressive chemotherapy. Here, we review the translation and properties of first, second, and third-generation rhG-CSF molecules, including filgrastim (Neupogen, FDA approved in 1991) and biosimilars, pegfilgrastim (Neulasta, FDA approved in 2002) and biosimilars, and F-627 (Ryzneuta, NMPA approved in 2023), a novel long-acting rhG-CSF agent developed this past decade. Even with the development of increasingly personalized and targeted cancer therapy, chemotherapy, and stem cell transplantation remains a backbone for the majority of patients with advanced cancers, especially in the hematopoietic system. As such, more than 20 million cancer patients have been treated with rhG-CSF drugs since the first approval of filgrastim. In the next decade, we envision third-generation rhG-CSF products such as Ryzneuta lowering costs to patients and healthcare providers, expanding access to this essential medication for cancer patients worldwide, particularly for patients who require more aggressive chemotherapy treatment.
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Stevenson, Dustin E., James Splichal, and David Ririe. "Single Dose of Pegfilgrastim (Neulasta™) Is Effective in Mobilizing CD34+ Stem Cells in Patients Undergoing Autologous Stem Cell Transplant." Blood 104, no. 11 (2004): 5000. http://dx.doi.org/10.1182/blood.v104.11.5000.5000.
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Abstract Introduction: Numerous methods of stem cell mobilization for autologous donors are utilized. These strategies include the use of chemotherapy with growth factor support or growth factors alone. All strategies involve multiple injections, lab draws, and patient discomfort and inconvenience. The addition of the PEG molecule to the N-terminus of filgrastim (G-CSF) increases its serum half-life, thereby requiring less frequent dosing. Pegfilgrastim has been found to be safe and effective for patients with chemotherapy-induced neutropenia. Pegfilgrastim in healthy donors mobilizes stem cells in a dose-dependent fashion. A previous study has shown that 12mg of pegfilgrastim given after chemomobilization with cyclophosphamide mobilized sufficient stem cells for auto-grafting. In this study, we evaluated whether a single 12mg injection of pegfilgrastim could mobilize a sufficient number of CD34+ stem cells in autologous donors who did not receive chemomobilization. Methods: Six patients intending to undergo high-dose chemotherapy with stem cell transplant were enrolled onto the study. Four of the subjects had multiple myeloma and had received prior treatment. Two of these patients had previously undergone HDC/ASCT. One patient had mantle cell lymphoma and another had AL amyloidosis. All participants received a 12mg injection of pegfilgrastim. Four days after pegfilgrastim administration, a CD34 level was checked. If this level was greater than 10 cells per uL, stem cell apheresis was initiatiated. Results: Results are presented in the table below. Five of the six participants achieved a day four CD34+ level greater that 10 cells per uL and underwent successful stem cell apheresis. The one participant that failed to mobilize had been heavily pre-treated to include a prior autologous stem cell transplant. This patient underwent a repeat stem cell transplant with cells stored from a previous collection. All of the patients with multiple myeloma or amyloidosis proceeded onto high dose chemotherapy with melphalan and autologous stem cell rescue. The patient with mantle cell lymphoma received high-dose chemotherapy with cyclophosphamide, busulfan and vincristine followed autologous stem cell rescue. The most commonly reported side effect from the pegfilgrastim was bone pain. No serious side effects were noted. Conclusions: A single, 12mg injection of pegfilgrastim is capable of mobilizing sufficient numbers of stem cells in autologous donors. This regimen is convenient to both the patient and institution. Hematologic reconstitution is similar to other stem cell mobilization regimens. Alternative mobilization strategies should be considered in patients who have been heavily pretreated. Patient # Dx: Prev Tx: Day 4CD34 Count # of Apheresis sessions # of cells collected/kg Day of neutrophil recovery post transplant Day of platelet recovery post-transplant 1 MM VAD, HDC/ASCT 6.5 N/A N/A N/A N/A 2 Mantle Cell Lymphoma HyperCVAD 36.5 1 2.94 x 10(6) 10 67 3 MM VAD 47.5 2 10.36 x 10(6) 11 11 4 MM VAD 27.5 4 7.70 x 10(6) 12 15 5 MM VAD, HDC/ASCT, Thalidomide 25.0 2 3.27 x 10(6) 11 16 6 AL Amyloidosis prednisone 29.5 4 6.28 x 10(6) 11 13
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Vadhan-Raj, Saroj, Carlos E. Bueso-Ramos, G. Hangoc, K. Christopherson, M. Collard, and H. E. Broxmeyer. "Expansion of Bone Marrow (BM) Progenitors and Mobilization of Multilineage Progenitor Cells Associated with Once Per Cycle Administration of Long-Acting Growth Factors Neulasta and Aranesp with Chemotherapy (CT): Biology and Nature of Response." Blood 104, no. 11 (2004): 2905. http://dx.doi.org/10.1182/blood.v104.11.2905.2905.
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Abstract Hematopoietic growth factors (HGF) G-CSF and GM-CSF have been utilized widely to facilitate mobilization of progenitor cells that can be used to support high dose CT. Recently long-acting HGF neulasta (pegfilgrastim) and aranesp (darbepoetin alfa) were developed to reduce the frequency of administration. While these agents are effective in reducing CT-induced neutropenia and anemia similar to their parent compounds, very little is known about their efficiency in mobilizing progenitor cells. The purpose of this study was to evaluate biologic effects of these agents, used in combination with CT, on progenitor cells. Chemo-naïve sarcoma patients receiving adriamycin and ifosfamide (AI) were treated once per cycle with aranesp (500 mcg) SC prior to initiating CT (day 0) and neulasta (6 mg) SC after completion of CT (day 4). BM and peripheral blood (PB) samples were studied at the baseline and around day 14 (at the time of WBC recovery) for progenitors and mediators of response. The treatment was associated with a significant increase in PB CD 34 + cells (median increase 36-fold, p=0.005) and marked mobilization (p=0.003) of CFU-GM (24-fold), BFU-E (22-fold), and CFU-GEMM (62-fold) (n=14). To better understand the biology and nature of response, we examined BM before and at the time of mobilization (n=12). There was an expansion of multi-lineage BM progenitors (p=0.06) and CD 34+ cells (P=0.001). BM exam at the time of recovery showed increased cellularity (2-fold) with increased granulopoietic elements. An increased expression of MMP-9 but unchanged expression of TIMP-1 was observed by Immunohistochemistry (IHC). c-kit ligand level by Elisa was decreased in the BM supernatant. In addition, phospho c-kit (phospho site 568) was increased in the myeloid and erythroid precursors by IHC but phospho site 823 was unaltered, indicating the specificity of activation of the downstream pathway in response to c-kit ligand-receptor activation, possibly leading to expansion of progenitor cells. Interestingly, expression of CXCR4 at the protein level (flow cytometry and western blot) and RNA level (RT-PCR) was decreased (p&lt;0.05) in the BM at the time of mobilization (day 14) as compared to the baseline. These findings indicate that long-acting HGFs, administered once per cycle of CT, are a potent stimulus for mobilization of myeloid, erythroid, and multipotential progenitors. Our findings also suggest that increased myelopiesis in the regenerating BM may be associated with increased protease activity such as MMP-9 that may result in the cleavage of c-kit leading to activation of c-kit receptors and expansion of progenitors, and the cleavage of CXCR-4 leading to release of progenitors from the BM anchorage and mobilization into PB.
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Younes, Anas, Luis Fayad, Jorge E. Romaguera, Barbara Pro, and Michael Wang. "ABVD with Pegfilgrastim (Neulasta) Support in Newly Diagnosed Hodgkin Lymphoma: Long-Term Safety and Efficacy Results of a Phase-II Study." Blood 106, no. 11 (2005): 4790. http://dx.doi.org/10.1182/blood.v106.11.4790.4790.
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Abstract The safety and efficacy of pegfilgrastim (Neulasta) has been established in association with chemotherapeutic regimens that are repeated every 3 weeks. However, the long-term safety of pegfilgrastim in patients receiving chemotherapy regimens every 2 weeks remains under investigation. Of concern is the possibility of stem cell damage because of the long half-life that may overlap with subsequent courses of chemotherapy. ABVD chemotherapy is widely used for the treatment of patients with Hodgkin lymphoma (HL). Up to 65% of patients receiving ABVD will require growth factor support to maintain dose intensity, prevent neutropenic fever, and to prevent delays in chemotherapy administration. In this study, we used primary prophylaxis of 6 mg pegfilgrastim in first and subsequent cycles of ABVD. Patients were eligible if they were older than 16 years and had previously untreated HL patients who are scheduled to receive standard ABVD chemotherapy, adequate bone marrow reserve (ANC &gt; 1,000/uL, Platelet &gt; 100,000/uL, left ventricular ejection fraction &gt; 50%, serum creatinine &lt; 2 mg/dl, serum bilirubin &lt; 2 mg/dl. They were excluded if they had HIV infection, were pregnant women and women or child bearing age who are not practicing adequate contraception, had prior chemotherapy, severe pulmonary disease including COPD and asthma, or history of prior sensitivity to E. coli derived products. All patients received one fixed dose of 6 mg pegfilgrastim approximately 24 hours after ABVD therapy. CBC was performed on a weekly basis, until completion of therapy, and then was monitored every 3–4 months thereafter. Twenty-five patients are enrolled, all of whom are evaluable for efficacy and toxicity. Median age is 26 (range; 19 – 81 years). Men = 14, women = 11. Twenty three pts completed at least 3 full cycles (6 doses of ABVD), and thirteen Pts completed 6 cycles. A total of 225 doses of ABVD are administered. Day 14 ANC count below 1,000/uL occurred in only 5 doses of ABVD (2%). Non-neutropenic infection developed with 7 doses (3%) requiring delay in the subsequent dose of ABVD beyond day 14. Long-term safety is available on 11 pts who had a follow-up ANC counts beyond one year after completion of ABVD treatment. The median ANC after at least one year of follow up was 2,790/uL (range 1,350 to 7,060/uL). Five pts had a follow up beyond 18 months after completion of ABVD therapy, and their median ANC was 2,300/uL (range: 1,570 to 3,360/uL). Furthermore, PK data from 5 unselected patients were performed on day 14 following the first cycle of ABVD. In all 5 patients, serum pegfilgrastim levels were below clinically significant levels. Our data demonstrate the efficacy of single dose per cycle of pegfilgrastim in maintaining ABVD dose intensity, keeping therapy on schedule, and preventing neutropenic fever. Furthermore, our preliminary long-term follow up data demonstrate the safety of pegfilgrastim administration in conjunction with standard dose ABVD chemotherapy given every 2 weeks.
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Lickliter, Jason, Radmila Kanceva, Emmanuelle Vincent, et al. "Pharmacokinetics and Pharmacodynamics of a Proposed Pegfilgrastim Biosimilar MSB11455 Versus the Reference Pegfilgrastim Neulasta in Healthy Subjects: A Randomized, Double-blind Trial." Clinical Therapeutics 42, no. 8 (2020): 1508–18. http://dx.doi.org/10.1016/j.clinthera.2020.05.020.
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Ravasio, Roberto, Lorenzo Antonuzzo, Marco Danova, and Paolo Pronzato. "A Budget impact analysis of pegfilgrastim biosimilar in the treatment of febrile neutropenia in Italy." AboutOpen 7, no. 1 (2020): 4–8. http://dx.doi.org/10.33393/abtpn.2020.2030.
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Introduction: Granulocyte-colony stimulating factors (G-CSFs) can significantly reduce the risk of febrile neutropenia (FN) among certain patients receiving chemotherapy. FN is associated with significant clinical and nonclinical complications. At present, the patent protection of pegfilgrastim (Neulasta®) has expired, and a biosimilar (Ziextenzo®) has been approved. Since the biosimilar price is expected to be lower as compared with the originator’s, the present Drug Budget Impact analysis tries to evaluate whether and how much profitable the biosimilar availability will be for the Italian NHS, in terms of cost containment (savings).Methods and Results: The model time horizon extends to five years. The initial overall number of treatments with pegfilgrastim is estimated based on the number of pegfilgrastim packages (assuming a recommended dose of 6 mg is administered after each cytotoxic chemotherapy) and kept constant in time. The model assumes that, year by year, the number of treatments with the originator will partly switch to the biosimilar (according to an uptake rate assumed). The results show that the availability of the biosimilar would provide an €6.4 million cumulated savings to the NHS in the five years.Conclusions: According to the present analysis, the availability of the biosimilar would generate cumulated savings (in five years) as high as €6.4 million for the Italian NHS. 
 (HTA & Market Access)
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Waller, C. F., C. Blakeley, E. Pennella, et al. "Phase 3 efficacy and safety trial of proposed pegfilgrastim biosimilar MYL-1401H vs EU-neulasta® in the prophylaxis of chemotherapy-induced neutropenia." Annals of Oncology 27 (October 2016): vi497. http://dx.doi.org/10.1093/annonc/mdw390.01.
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Brackett, Craig M., Kellee Greene, Bojidar Kandar, et al. "A Toll-like Receptor 5 agonist entolimod mitigates radiation damage through a neutrophil-dependent mechanism." Journal of Immunology 202, no. 1_Supplement (2019): 182.70. http://dx.doi.org/10.4049/jimmunol.202.supp.182.70.
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Abstract The increased risk of exposure to life-threating nuclear and radiation emergencies warrants the development of FDA-approved medical radiation countermeasures (MRC) as radio mitigators, which can be used after exposure to total body irradiation. Currently, Neupogen and Neulasta are the only FDA-approved radio mitigators but are unfortunately limited by adverse side effects and the need for additional medical supportive care. Bacterial flagellin, the natural agonist of Toll-like receptor (TLR) 5, and apharmacologically optimized derivative entolimod developed by us have powerful activity as a single agent MRC in rodents and non-human primates. Currently entolimod is being developed as a MRC under the FDA’s Animal Efficacy Rule, which guides development of drugs for which efficacy testing in humans would be unethical. The lack of induction of cytokine storm post systemically administered entolimod was demonstrated in rodents, non-human primates, and Phase I clinical trials involving nearly 200 subjects. Entolimod stimulates TLR5 on hepatocytes followed by activation of immunoregulatory signaling pathways, production of pro-inflammatory cytokines, and rapid recruitment of immune cells to the liver. Neutrophils are among the first immune cells that are rapidly recruited to both non-lymphoid and lymphoid tissues post-entolimod. We found that this entolimod-elicited neutrophil response was essential to mitigating radiation damage by promoting the recovery of hematopoietic stem cells in the bone marrow. This work underscores the underappreciated importance of TLR5-elicited neutrophils in promoting there generation of hematopoiesis following total body irradiation.
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Waller, C., C. Blakeley, E. Pennella, et al. "Phase 3 efficacy and safety trial of proposed pegfilgrastim biosimilar MYL-1401H vs EU-Neulasta ® in the prophylactic treatment of chemotherapy-induced neutropenia." European Journal of Cancer 72 (February 2017): S42. http://dx.doi.org/10.1016/s0959-8049(17)30217-4.
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Duncan, R., M. J. Vicent, F. Greco, and R. I. Nicholson. "Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer." Endocrine-Related Cancer 12, Supplement_1 (2005): S189—S199. http://dx.doi.org/10.1677/erc.1.01045.
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The last decade has seen successful clinical application of polymer–protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer–anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80–320 mg/m2, consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.
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Roth, Karsten, Hendrik Wessels, Josef Hoefler, Ulrike Scholz, and Dirk Lehnick. "Pelmeg®, a biosimilar pegfilgrastim developed in the context of evolving regulatory guidelines." Generics and Biosimilars Initiative Journal 9, no. 3 (2020): 125–31. http://dx.doi.org/10.5639/gabij.2020.0903.021.
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Pelmeg® is a biosimilar pegfilgrastim, which obtained European Union (EU) regulatory approval in September 2018, with marketing beginning in January 2019. A comprehensive analytical, functional and preclinical comparability programme demonstrated a high degree of similarity between Pelmeg® and its reference product Neulasta®. A targeted clinical development programme was conducted with Pelmeg®, consisting of two comparative pharmacokinetic (PK)/pharmacodynamic (PD) studies in healthy subjects. Since a surrogate endpoint for efficacy (absolute neutrophil count [ANC]) was available, efficacy and safety studies in patients were waived by the regulatory authorities. Clinical studies with Pelmeg® were designed in close dialogue with regulatory authorities in Europe. During the development process for Pelmeg®, the EU biosimilar guidelines, in particular relating to granulocyte colony-stimulating factor (G-CSF), were modified. The development of Pelmeg® demonstrates that regular discussions with regulators, in the form of scientific advice or other interactions, are valuable opportunities for dialogue regarding scientific progress related to the comparability of biosimilars. Regulators – at least in the area of biosimilar development – were found to be open to improvements and to deviate from existing guidelines if there was agreement that the scientific state-of-the-art has superseded some aspect of the guidelines. Overall, we suggest that abridged development programmes waiving the need for phase III studies, as described for Pelmeg®, are possible, in particular if good surrogate endpoints are available. In line with this, the number of waivers for phase III studies in biosimilar development has increased in recent years.
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Toy, Edmond L., Francis Vekeman, François Laliberté, et al. "Comparison of Infection-Related Hospitalization Risk and Associated Costs among Patients Receiving Sargramostim (Leukine®), Filgrastim (Neupogen®), and Pegfilgrastim (Neulasta®) for Chemotherapy-Induced Neutropenia." Blood 112, no. 11 (2008): 665. http://dx.doi.org/10.1182/blood.v112.11.665.665.
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Abstract Background: Neutropenia is a main side effect of cancer treatment and leads to increased risk of serious infections. Myeloid growth factors, including the granulocyte colony-stimulating factors (G-CSFs) filgrastim (Neupogen®) and pegfilgrastim (Neulasta®) and the granulocyte-macrophage colony stimulating factor (GM-CSF) sargramostim (Leukine®), stimulate neutrophil production and are commonly used as supportive care with myelosuppressive chemotherapy. GM-CSF also stimulates the production and activity of macrophages and dendritic cells, and it is hypothesized that the additional immune protection conferred by GM-CSF might reduce infection risk compared with the G-CSFs. We tested this hypothesis by comparing infection-related hospitalization rates and costs in patients using sargramostim, filgrastim, and pegfilgrastim for chemotherapy-induced neutropenia (CIN). Methods: This retrospective matched cohort study analyzed a large, nationally representative managed care claims database from over 30 health plans in the US during 2000 to 2007. CIN patients were identified as having ≥2 claims of sargramostim or filgrastim or ≥1 claim of pegfilgrastim; ≥1 cancer claim within 120 days prior to the start of a G/GM-CSF treatment episode (index date); and ≥1 chemotherapy claim within 60 days prior to the index date. The treatment episode began with the first G/GM-CSF claim satisfying the 120 day washout period and ended on the last claim date for sargramostim and filgrastim episodes; pegfilgrastim episodes ended on the last claim date plus a mean therapeutic duration of 19 days due to its long-acting nature. A G/GM-CSF claim more than 28 days after a prior claim was considered to be a new treatment episode. This analysis only considered the first treatment episode. Patients had to be ≥18 years old as of the index date and have continuous enrollment. Sargramostim patients were 1:1 matched with filgrastim and pegfilgrastim patients based on gender and year of birth. Outcomes included infection-related hospitalization rates and the associated cost per patient per month. Hospitalization rates were analyzed using univariate and multivariate Poisson methods. Covariates included the Charlson comorbity index, the number of chemotherapy agents received, whether the patient received myleosuppressive agents, and indicator variables for the presence of heart disease, renal disease, liver disease, metastasis, breast cancer, lung cancer, non-Hodgkin’s lymphoma, history of anemia, and neutropenia diagnosis on index date. Results: A total of 990 sargramostim-filgrastim and 982 sargramostim-pegfilgrastim matched pairs were analyzed. Cohorts had similar baseline characteristics, although differences were observed for the fraction of patients with a diagnosis of neutropenia at index date (sargramostim 65%, filgrastim 57%, pegfilgrastim 45%) and the percentage of patients who received myelosuppressive agents (sargramostim 54%, filgrastim 48%, pegfilgrastim 77%). Sargramostim patients experienced infection-related hospitalizations about half as often as patients using filgrastim (p=0.04) or pegfilgrastim (p=0.06). Multivariate analyses adjusted for confounding factors and found that sargramostim patients were 56% less likely to have infection-related hospitalizations compared to filgrastim and pegfilgrastim patients (p=0.03 for both). Infection-related hospitalization costs for sargramostim patients were $728/patient/month ($8,736/patient/year) and $226/patient/month ($2,712/patient/year) less compared to filgrastim (p=0.04) and pegfilgrastim patients (p=0.01), respectively. Conclusions: Among patients with CIN, use of sargramostim is associated with a reduced risk of infection-related hospitalization and lower associated costs compared to filgrastim or pegfilgrastim. Incidence Rate Ratios and Costs of Infection-Related Hospitalizations Univariate Multivariate IRR (95% CI) p-value Adjusted IRR (95% CI) p-value Sargramostim vs. Filgrastim 0.46 (0.22–0.97) 0.0422 0.44 (0.20–0.94) 0.0333 Sargramostim vs. Pegfilgrastim 0.52 (0.26–1.04) 0.0628 0.44 (0.21–0.90) 0.0256 Cost/patient/month Sargramostim Mean (SD) Comparison Group Mean (SD) Incremental Cost p-value Sargramostim vs. Filgrastim $138 ($2,534) $866 ($22,234) −$728 0.0380 Sargramostim vs. Pegfilgrastim $139 ($2,544) $365 ($5,557) −$226 0.0100
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Medvedev, Yu V., M. A. Kolganova, O. A. Sas, et al. "Immunogenicity Assessment of Pegfilgrastim in Patients with Breast Cancer." Drug development & registration 9, no. 2 (2020): 140–44. http://dx.doi.org/10.33380/2305-2066-2020-9-2-140-144.
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Introduction. Neutropenia, which is an abnormally low concentration of neutrophils in the blood, is one of the common side effects in patients receiving radio- or chemotherapy. Neutropenia usually leads to higher risks of severe bacterial and fungal infections. Such medicines as colonystimulating factor filgrastim (and its conjugates) are used to prevent and treat neutropenia in oncology patients. Immunogenicity is a potential concern for any biological product, thus, its assessment is one of the most critical necessities during the development and registration of such products.Aim. The main aim of this study was to validate the ELISA method for anti-pegfilgrastim antibodies detection in human serum samples and to apply the validated method to pegfilgrastim drugs immunogenicity assessment.Materials and methods. To assess pegfilgrastim immunogenicity, the commercial ELISA kit «PEGylated Filgrastim (Neulasta®) ADA ELISA» was used for screening, confirmatory and titer assay. Moreover, to confirm the chosen commercial kit suits the study aims it was revalidated. The absorbance values were obtained using plate immunoassay analyzer Stat Fax 3200, plate washing was performed using an automatic twochannel plate washer.Results and discussion. The ELISA method for anti-pegfilgrastim antibodies determination in human serum samples was validated and applied to the analytical part of the comparative, multicenter, blind, randomized study of pegfilgrastim efficacy and safety in patients with breast cancer, receiving myelosuppressive chemotherapy. Human serum samples were first screened for anti-drug antibodies, then «screening positive» samples were analyzed in confirmatory assay with % inhibition calculation for each sample. The «confirmed positive» samples were further characterized in titer assay.Conclusions. The ELISA method for anti-pegfilgrastim antibodies determination in human serum samples was successfully validated and applied for pegfilgrastim drugs immunogenicity assessment.