A study comparing Sandoz’s filgrastim biosimilar (Zarzio) with originator filgrastim (Neupogen) has shown that they are highly similar in terms of their structure and function [1].
Filgrastim is used for the prevention of neutropenia following chemotherapy treatment for cancer, as well as for the mobilization of haematopoietic stem cells. Following confirmation of its biosimilarity to the originator product based on extensive protein characterization and clinical studies, Zarzio was approved in Europe in 2009 [2]. While filgrastim biosimilars are widely used in Europe, no biosimilar filgrastim had, until March 2015, been approved in the US [3].
During the development of a biosimilar, comprehensive characterization of the drug at both the physicochemical and biological level is required. Owing to recent advances in analytical methods, such detailed protein characterization is now entirely feasible. Analytic similarity is now regarded as the most robust scientific basis for comparing different biological drug products, and is considered more sensitive than clinical endpoints for identifying minor differences between products. Pharmacodynamic (PD) and pharmacokinetic (PK) studies in healthy volunteers also provide crucial data as part of a stepwise comparability exercise.
FDA guidance for biosimilar approval in the US states the need for adequate comparison of the proposed biosimilar directly with the US-licensed reference product [4]. In this study, an array of protein analytical techniques was used to compare the physicochemical properties of Zarzio with EU-approved and US-licensed originator filgrastim. The authors reported no differences with respect to the primary, secondary or tertiary protein structure, mass, size, purity, charge or hydrophobicity.
Furthermore, the authors observed no differences between the biosimilar and originator drugs in G-CSF (granulocyte colony-stimulating factor) receptor binding affinity, and all samples demonstrated comparable biological activity in an in vitro cell proliferation assay.
The researchers also carried out a randomized, double-blind, two-way crossover phase I study in 28 healthy volunteers. This study assessed the PD, PK and safety profiles of Zarzio and originator US-licensed filgrastim (administered as a single 10 µg/kg subcutaneous injection). The results of the study showed no statistically significant differences between Zarzio and the US-licensed originator in terms of PD parameters, which included absolute neutrophil count and CD34+ cell count as surrogate markers of filgrastim efficacy, nor in PK parameters, which included mean filgrastim serum concentration-time profiles. All confidence intervals were within the predefined equivalence boundaries.
Zarzio and the US-approved originator filgrastim also had similar safety profiles. The incidence of adverse events (AEs) was similar between the two treatments, and most reported events were mild. No relevant differences in the severity, type or pattern of AEs were reported between the two treatments.
Based on the results, the authors concluded that Zarzio is highly similar to the EU- and US-approved originator filgrastim. These data provide robust evidence of the structural and functional similarity between Zarzio and the US-licensed originator filgrastim, and provided part of the successful submission that led to FDA approval of Zarzio as the first biosimilar in the US [3].
Conflict of interest
The authors of the research paper [1] declared that Sörgel and Kinzig have conducted analytical and clinical research funded by Sandoz, and Sörgel has received honoraria for presenting at Sandoz-sponsored symposia at international congresses. Schwebig and Singh are employees of Hexal AG/Sandoz Biopharmaceuticals. Holzmann and Prasch are employees of Sandoz GmbH.
Editor’s comment
Readers interested to learn more about the comparable efficacy and safety of biosimilar filgrastim are invited to visit www.gabi-journal.net to view the following manuscript published in GaBI Journal:
Mobilization of stem cells in healthy donors by G-CSF biosimilars shows comparable efficacy and safety to Neupogen
Readers interested in contributing a research or perspective paper to GaBI Journal – an independent, peer reviewed academic journal platform – please send us your submission here.
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References
1. Sörgel F, Schwebig A, Holzmann J, Prasch S, Singh P, Kinzig M. Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics. BioDrugs. 2015;29(2):123-31.
2. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 May 8]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe
3. GaBI Online - Generics and Biosimilars Initiative. FDA approves its first biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 May 8]. Available from: www.gabionline.net/Biosimilars/News/FDA-approves-its-first-biosimilar
4. GaBI Online - Generics and Biosimilars Initiative. US guidelines for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 May 8]. Available from: www.gabionline.net/Guidelines/US-guidelines-for-biosimilars
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