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Neutralization of EP217609, a new dual-action FIIa/FXa anticoagulant, by its specific antidote avidin: a phase I study

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Abstract

Introduction

EP217609 is a representative of a new class of synthetic parenteral anticoagulants with a dual mechanism of action. It combines in a single molecule a direct thrombin inhibitor and an indirect factor Xa inhibitor. EP217609 can be neutralized by a specific antidote avidin, which binds to the biotin moiety of EP217609.

Purpose

The primary objective was to assess the neutralization of EP217609 by avidin in healthy subjects. Secondary objectives were to define the optimal avidin monomer/EP217609 molar ratio to achieve an adequate neutralization of EP217609 and to assess the safety and tolerability of EP217609 and avidin.

Methods

Healthy subjects (n = 36) were randomized to a 3 by 3 replicated Latin square design between 3 EP217609 doses (4, 8, 12 mg) and 3 avidin monomer/EP217609 molar ratios (1:1; 2:1; 3:1). EP217609 was administered as a single intravenous bolus, and avidin as a 30-min intravenous infusion, starting 90 min after EP217609 administration.

Results

Overall, EP217609 and avidin were well tolerated. One subject experienced a benign and transient typical pseudo-allergic reaction. The administration of EP217609 resulted in dose-dependent increases in pharmacodynamic markers. Avidin triggered a rapid and irreversible neutralization of EP217609 without rebound effect. Adequate neutralization of the anticoagulant activity was achieved with both 2:1 and 3:1 avidin monomer/EP217609 molar ratios. All safety parameters did not show any treatment-emergent clinically relevant changes or abnormalities in any dose group.

Conclusions

These results will allow further investigation in patients requiring a neutralizable anticoagulant as those undergoing cardiac surgery.

Study registration

EudraCT number 2010-020216-10.

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Acknowledgments

The clinical part of the study was conducted at Biotrial, Rennes, France, with Marie-Claude Homery, acting as the principal investigator. Special thanks to Isabelle Gouin Thibault at University hospital Pontchaillou, Rennes, for the careful proofreading of the manuscript.

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Authors and Affiliations

  1. Haemostasis Department, University Hospital Pontchaillou, 2 rue Henri Le Guilloux, 35033, Rennes Cedex, France

    P. Gueret

  2. University Hospital Cochin, Paris, France

    S. Combe

  3. Endotis Pharma, Romainville, Paris, France

    C. Krezel, M. Petitou & E. Neuhart

  4. EMF Consulting, Aix en Provence, France

    E. Fuseau

  5. Van Giersbergen Consulting, Wuenheim, France

    P. L. M. van Giersbergen

  6. GETBO EA 3878, Brest, France

    P. Gueret

Authors
  1. P. Gueret
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  2. S. Combe
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  3. C. Krezel
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  4. E. Fuseau
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  5. P. L. M. van Giersbergen
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  6. M. Petitou
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  7. E. Neuhart
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Corresponding author

Correspondence to P. Gueret.

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Conflict of interest

The study was funded by Endotis Pharma, Romainville, France. EN, CK and MP were full-time employees of Endotis Pharma at the time of study conduct and reporting. PG, SC, EF and PvG received financial compensation for their involvement in the study. All authors are fully responsible for content and editorial decisions regarding this paper.

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Gueret, P., Combe, S., Krezel, C. et al. Neutralization of EP217609, a new dual-action FIIa/FXa anticoagulant, by its specific antidote avidin: a phase I study. Eur J Clin Pharmacol 73, 15–28 (2017). https://doi.org/10.1007/s00228-016-2143-9

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  • DOI: https://doi.org/10.1007/s00228-016-2143-9

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