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Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care

1651 - A large multi-center, randomized, double-blind, crossover study in healthy volunteers to compare pharmacokinetics and pharmacodynamics of a proposed biosimilar pegfilgrastim with EU and US reference pegfilgrastim: methodological approach

Date

22 Oct 2018

Session

Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care

Presenters

Roumen Nakov

Citation

Annals of Oncology (2018) 29 (suppl_8): viii603-viii640. 10.1093/annonc/mdy300

Authors

R. Nakov1, S. Schussler2, S. Schier-Mumzhiu3, A. Skerjanec4, A. Bellon4, J. Wang5, A. Krendyukov6, G. Otto3

Author affiliations

  • 1 Hematology, Hexal AG, D-83607 - Holzkirchen/DE
  • 2 Clinical research, Sandoz Inc., Princeton/US
  • 3 Clinical research, Hexal AG, Holzkirchen/DE
  • 4 Clinical Pharmacology, Hexal AG, Holzkirchen/DE
  • 5 Biostatistics, Sandoz Inc., Princeton/US
  • 6 Medical Oncology/hematology, Hexal AG, Holzkirchen/DE
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Resources

Abstract 1651

Background

Biosimilar development applies a totality of evidence approach, in which Phase I (pharmacokinetic [PK]/pharmacodynamics [PD]) studies have a pivotal role. Phase I studies are particularly important in biosimilar pegfilgrastim development due to high inter-subject variability (ISV) mainly linked to target-mediated clearance.1 A pivotal Phase I study confirmed that Sandoz proposed biosimilar pegfilgrastim (LA-EP2006) and EU-reference biologic have matching PK/PD profiles.2 For FDA approval of LA-EP2006, a bridging study is necessary to confirm that PK/PD properties of LA-EP2006 match EU and US reference pegfilgrastim. This Phase I bridging study is ongoing and here we present the methodology.

Methods

To meet FDA requirements of LA-EP2006, EU and US reference pegfilgrastim PK/PD similarity, and to address ISV, a three-way crossover design was chosen following FDA advice. The study was sufficiently powered (90%) to achieve confidence intervals within margins 0.8–1.25 in co-primary endpoints pairwise comparisons.

Results

Due to historically known high intra- and inter-subject variabilities with reference biologic (CV: 45% and ∼80%, respectively)3 in AUC0-inf, a randomized, double-blind, single-dose, 3-treatment, 6-sequence crossover, Phase I study in healthy volunteers is suitable to demonstrate similarity of PK/PD, safety and immunogenicity between LA-EP2006, EU and US reference pegfilgrastim. Multiple centers, regions, contract research organizations and medicine batches are required, which further amplifies operational complexity of study conduct and scientific standards. The study is ongoing in 5 US and 1 Dutch study sites.

Conclusions

Phase I methodology applying a 3-way crossover design addresses known high ISV with pegfilgrastim and establishes the scientific bridge between proposed biosimilar and reference US and EU biologics. References 1. Yang et al. Clin Pharmacokinet 2011;50:295–306. 2. Nakov et al. Poster presented at SABCS 2017 (P3-14-10). 3. Yang et al. Cancer Chemother Pharmacol 2015;75:1199–206.

Clinical trial identification

Legal entity responsible for the study

Hexal AG, Holzkirchen, Germany.

Funding

Hexal AG, Holzkirchen, Germany.

Editorial Acknowledgement

Caroline McGown, Spirit Medical Communications.

Disclosure

R. Nakov, S. Schier-Mumzhiu, A. Skerjanec, A. Bellon, A. Krendyukov, G. Otto: Employee: Hexal AG. S. Schussler, J. Wang: Employee: Sandoz Inc.

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