Randomized, double-blind, cross-over phase I study comparing pharmacokinetics, pharmacodynamics, safety and immunogenicity of a biosimilar pegfilgrastim with EU and US references

Abstract

Abstract Background The pharmacokinetic (PK)/pharmacodynamic (PD), safety and immunogenicity profiles of Sandoz biosimilar pegfilgrastim (Ziextenzo®) and EU reference pegfilgrastim were shown to be similar in a pivotal phase I study. Similarity of efficacy and safety to the reference was demonstrated in two phase III studies in breast cancer patients receiving myelosuppressive chemotherapy. This 3-way study aimed to confirm similarity of PK/PD, safety and immunogenicity to US reference pegfilgrastim, and to bridge between the EU and US reference medicines. Methods This randomized, double-blind, 3-treatment, 6-sequence crossover phase I study included healthy volunteers (HVs) administered pegfilgrastim (biosimilar, EU reference, or US reference) once per treatment period. Primary objectives were to demonstrate PK similarity in AUC0-inf, AUC0-last and Cmax, and PD similarity in ANC AUEC0-last and ANC Emax. The study was powered (90%) to achieve confidence intervals within biosimilarity margins 0.8–1.25 in pairwise comparisons (biosimilar vs US reference, biosimilar vs EU reference, and US reference vs EU reference). Secondary objectives were safety, immunogenicity and additional PK/PD parameters. Results The study included 577 male and female HVs. PK and PD similarity were demonstrated for primary PK and PD parameters between Sandoz biosimilar, US reference, and EU reference (Table). The safety profile of Sandoz biosimilar pegfilgrastim was similar across groups. Incidence of antidrug antibodies was similar across groups (biosimilar: 31/512 [6.1%]; US reference: 36/511 [7.0%]; EU reference: 39/501 [7.8%]). Secondary PK/PD parameters were also similar. Table . 1815P Summary of PK and PD similarity Ratio CI 90% Biosimilar / US-reference AUC0-last 1.0635 1.0087, 1.1213 AUEC0-last 0.9997 0.9912, 1.0082 Biosimilar / EU-reference AUC0-last 1.0469 0.9929, 1.1038 AUEC0-last 1.0012 0.9927, 1.0098 US-reference / EU-reference AUC0-last 0.9844 0.9336, 1.0380 AUEC0-last 1.0015 0.9930, 1.0101 Conclusions Sandoz biosimilar demonstrated similar PK/PD, safety, tolerability and immunogenicity to US reference and EU reference pegfilgrastim in this large 3-way crossover phase I study. Clinical trial identification EudraCT: 2016-003549-27. Editorial acknowledgement Caroline McGown of Spirit Medical Communications Ltd, supported by Hexal AG. Legal entity responsible for the study Hexal AG. Funding Hexal AG. Disclosure M. Velinova: Full / Part-time employment: PRA; Honoraria (self), compensation as lead Principal Investigator in the study: Sandoz Biopharmaceuticals. A. Bellon: Full / Part-time employment: Hexal AG. R. Nakov: Full / Part-time employment: Hexal AG. S. Schussler: Full / Part-time employment: Sandoz Inc. S. Schier-Mumzhiu: Full / Part-time employment: Hexal AG. C. Schelcher: Full / Part-time employment: Hexal AG. S.D. Koch: Full / Part-time employment: Hexal AG. A. Skerjanec: Full / Part-time employment: Novartis. J. Wang: Full / Part-time employment: Sandoz Inc. A. Krendyukov: Full / Part-time employment: Hexal AG. G.P. Otto: Full / Part-time employment: Hexal AG.