The phase I clinical trial was a randomized, double-blind, 3-treatment period, 6-sequence crossover, multicentre study in which 577 healthy adult male and female volunteers were administered 6 mg/0.6 mL pegfilgrastim subcutaneously in a pre-filled syringe on the first day of each period. The study duration per subject was at least 25 weeks when fully completed.

The aim of the trial was to study the pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity of Sandoz’s pegfilgrastim biosimilar, Ziextenzo (LA‑EP2006), compared to US-licensed and EU-approved reference pegfilgrastim (Amgen’s Neulasta).

The three primary PK endpoints were area under the concentration curve from time of dosing and extrapolated to infinity (AUC0–inf); from time of dosing to the last measurable concentration (AUC0-last) and maximum concentration (Cmax). The two primary PD endpoints were absolute neutrophils count (ANC) area under the effect curve from time of dosing to the last sampling time point (ANC AUEC0-last); and maximum neutrophil count measured (ANC Emax). PK and PD biosimilarity was to be confirmed if the 90% confidence intervals (CI) of the ratio of geometric means for all primary PK and PD endpoint comparisons were contained within the predefined similarity margins of 0.80-1.25.

For all five endpoints, the 90% confidence intervals (CIs) of the ratio of the primary endpoints geometric means were entirely within 0.80−1.25 allowing biosimilarity between LA‑EP2006 and both reference biologicals to be demonstrated. Results comprised the following: the 90% CI for the AUC0-inf was 1.01−1.12 for Sandoz pegfilgrastim versus US-reference pegfilgrastim, 0.99−1.10 for Sandoz pegfilgrastim versus EU-reference pegfilgrastim, and 0.93−1.03 for US- versus EU-reference pegfilgrastim. The 90% CI for the ANC AUEC0-last was 0.99−1.01 for all three comparisons.

The safety profile was similar across all treatment groups with comparable incidence and patterns of treatment-emergent adverse events (TEAEs). The five most common TEAEs reported by subjects, and similar across all three treatments, were headache, back pain, bone pain, myalgia and pain in extremity.

The incidence of anti-drug antibodies was low and similar across all treatment groups; 6.1% for LA‑EP2006, 7% for US-reference pegfilgrastim and 7.8% for EU-reference pegfilgrastim.

The results of this large phase I PK/PD study demonstrate that Sandoz biosimilar pegfilgrastim is biosimilar to US-reference pegfilgrastim and EU-reference pegfilgrastim in terms of pharmacokinetic, pharmacodynamic, safety, and immunogenicity in healthy subjects after a single 6 mg subcutaneous administration.

Sandoz pegfilgrastim (pegfilgrastim-bmez) has been approved by the US Food and Drug Administration on 4 November 2019 [3] based on, but not limited to, the clinical results presented in this article.

Abstracted by Anne Bellon, Hexal AG, Holzkirchen, Germany. Hexal AG is an affiliate of Sandoz International, a Novartis division.

Conflict of interest
The authors of the research paper [1] reported conflict of interest, including being employees of Sandoz/Hexal. For full details of the authors’ conflict of interest, see the research paper [1].

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References
1. 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 Feb 5. doi:10.1111/bcp.14226.
2. European Medicines Agency. Ziextenzo summary of product characteristics [homepage on the Internet]. [cited 2020 Mar 20]. Available from: www.ema.europa.eu/en/documents/product-information/ziextenzo-epar-product-information_en.pdf
3. U.S. Food and Drug Administration. Ziextenzo highlights of prescribing information [homepage on the Internet]. [cited 2020 Mar 20]. Available from: www.accessdata.fda.gov/drugsatfda_docs/label/2019/761045lbl.pdf

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