Agarwala et al. have recently published a review on the totality of evidence (ToE) for the biosimilar pegfilgrastim Ziextenzo® (LA-EP2006) matching the European Union- (EU) and US-reference biological pegfilgrastim Neulasta® (marketed by Amgen) [1].
Ziextenzo® is a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) with a covalent conjugation of polyethylene glycol (PEG) indicated for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy [2, 3].
A critical assessment of quality attributes was carried out, focusing on the highest impact on clinical outcome to ensure desired biosimilar quality. The ToE was comprised of preclinical analysis including structural and functional attributes as well as clinical studies confirming matching results in efficacy, safety and immunogenicity to its reference medicine. State-of-the-art techniques assessed physiochemical attributes showing identical primary structure and pegylation site, indistinguishable higher-order structure, similar variant and impurity profiles covering end of shelf life, molecular size variants, and formulation. Similar biological activity was demonstrated including potency and binding affinity to the G-CSF receptor. Quantitative quality attributes were based on broader batch ranges to increase comprehensive statistical evaluation.
Clinical pharmacokinetic (PK) and pharmacodynamic (PD) similarity of biosimilar pegfilgrastim Ziextenzo with reference pegfilgrastim sourced from the EU and US was demonstrated by a key randomized, double‐blind, single‐dose, multicentre study using a three-way crossover six-sequence design with 576 healthy male and female subjects [4]. This was supplemented by two randomized, double-blind phase III confirmatory clinical studies in patients with breast cancer under chemotherapy matching the reference pegfilgrastim in terms of efficacy [5, 6]. The equivalence criteria with a defined margin of ±1 day were met for the primary endpoint (mean duration of severe neutropenia [DNS]) in both studies, the difference between biosimilar pegfilgrastim Ziextenzo and reference medicine comprising only 0.04 days [6]. Safety and immunogenicity profiles showed no clinically relevant differences, with similar incidences of treatment-related adverse events and no detection of treatment-related binding and neutralizing antibodies including a six-month follow up period (PROTECT-1) [5, 6].
According to Agarwala et al., the ToE of biosimilar pegfilgrastim Ziextenzo including extensive clinical data confirms equivalent efficacy and safety and biosimilarity between Ziextenzo® and its EU- and US-reference pegfilgrastim. Therefore, biosimilar pegfilgrastim Ziextenzo® could be used as a safe and effective treatment option in patients for all eligible indications, concluded the authors.
Conflict of interest
The authors of the research paper [1] declared that they are either current or former employees of Sandoz. For full details of the authors’ conflict of interest, see the research paper [1].
Abstracted by Dr Sebastian Howe, Global Medical Manager Oncology, Hexal AG, Germany; Spanish version translated by Daniel Freire, Head Medical Affairs Latin America, Sandoz Brazil.
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Pelmeg®, a biosimilar pegfilgrastim developed in the context of evolving regulatory guidelines
Perspectives on the future of pegfilgrastim biosimilars
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References
1. Sanjiv SA, Ulrich N, Xinghua G, et al. A review of the totality of evidence supporting the development and approval of a pegfilgrastim biosimilar (LA-EP2006). Curr Med Res Opin. 2022;38(6):999-1009.
2. European Medicines Agency. Summary of product characteristics. Ziextenzo [homepage on the Internet]. [cited 2022 Sep 9]. Available from: https://www.ema.europa.eu/en/documents/product-information/ziextenzo-epar-product-information_en.pdf
3. U.S. Food and Drug Administration. Ziextenzo prescribing information [homepage on the Internet]. [cited 2022 Sep 9]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761045lbl.pdf?msclkid=1994df54cf7511ec97566f9e44834a60
4. Bellon A, Wang J, Skerjanec A, et al. 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. Br J Clin Pharmacol. 2020;86(6):1139-49.
5. Harbeck N, Lipatov O, Frolova M, et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol. 2016;12(11):1359-67.
6. Blackwell K, Gascon P, Jones CM, et al. Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Ann Oncol. 2017;28(9):2272-7.
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