BACKGROUNDEP42675 is a first-in-class, synthetic, parenteral, anticoagulant combining in a single molecule a direct thrombin inhibitor and an indirect factor Xa(FXa) inhibitor.OBJECTIVESTo investigate the safety, pharmacokinetics, and pharmacodynamics of EP42675 and its interaction with aspirin, clopidogrel, and unfractionated heparin (UFH).SUBJECTS AND METHODSIn study 1, healthy male subjects were administered intravenously single-ascending doses (1-10 mg) of EP42675 or placebo. In study 2, healthy male subjects were administered intravenously a single dose of 5 mg EP42675 on day 1 followed by oral administration of aspirin (100 mg) and clopidogrel (75 mg) once daily from day 8 to 21. On day 15, a second dose of 5 mg EP42675 was administered, and subjects were then randomized to receive a single dose of UFH (30 or 60 IU kg(-1) ) or placebo.RESULTS AND CONCLUSIONSMild bleedings were the only drug-related adverse events. EP42675 pharmacokinetics were dose-proportional and characterized by a low clearance, a small volume of distribution, a long terminal half-life. EP42675 pharmacodynamics were characterized by a long-lasting, dose-dependent increase in activated clotting time, ecarin clotting time, thrombin time, anti-FXa activity, activated partial thromboplastin time, prothrombin time, and a decrease in endogenous thrombin potential, measured by a thrombin generation test. Dose-dependent additive effects were seen with UFH on coagulation tests. EP42675 had no additive effect on the inhibition of platelet aggregation induced by aspirin and clopidogrel. These results warrant further clinical development of this new class of anticoagulant.

01 Jan 2009·Thrombosis and HaemostasisQ2 · MEDICINE

From heparin to EP217609: The long way to a new pentasaccharide-based neutralisable anticoagulant with an unprecedented pharmacological profile

Q2 · MEDICINE

Review

Author: de Kort, Martin ; Vogel, Gerard M. T. ; Petitou, Maurice ; van Boeckel, Constant A. A. ; Nancy-Portebois, Vanessa ; Meuleman, Dick ; Dubreucq, Guy ; Motte, Vincent ; Wisse, Jeffry A. J.

SummaryThe elucidation of the structure of the antithrombin binding sequence in heparin has given a large impulse to the rational design of heparin related drugs. De novo chemical synthesis of the corresponding pentasaccharide as well as simplified analogues has provided very specific, antithrombin-mediated inhibitors of factor Xa with various pharmacokinetic profiles. Fondaparinux and idraparinux are examples of such compounds that have found clinical application as antithrombotics. Because of the very specific binding to antithrombin the pharmacokinetics of pentasaccharides can be predicted and transferred to other molecules covalently bound to them. The new chemical entities thus obtained display a wide array of antithrombotic activities, giving improved heparin molecules as well as new anticoagulants, devoid of the undesired side effects of heparin and with unprecedented pharmacological profiles. In this context, a direct thrombin inhibitor was covalently coupled to a pentasaccharide by an inert spacer.This compound, EP42675 exerts antithrombin mediated anti-factor Xa activity together with direct thrombin inhibiting capacity. It displays favourable pharmacokinetics as imposed by the pentasaccharide. EP42675 was further modified by the introduction of a biotin moiety in its structure.The new entity obtained, EP217609 exerts the same pharmacological profile as EP42675 and it can be instantaneously neutralised by injection of avidin. Due to this unprecedented mechanism of anticoagulant activity and its ability to be neutralised,EP217609 deserves to be investigated in clinical settings where direct thrombin inhibition is required.

01 Jun 2005·Drug Discovery TodayQ2 · MEDICINE

Synthetic heparin derivatives as new anticoagulant drugs

Q2 · MEDICINE

Review

Author: Martin de Kort ; Rogier C. Buijsman ; Constant A.A. van Boeckel

The journey towards a detailed mechanistic understanding of the anticoagulant action of heparin has resulted in synthetic mimetics with improved pharmacodynamic profiles. Inspired by the ternary complex formation of heparin with antithrombin III and thrombin, the active pentasaccharide fondaparinux has been succeeded by several clinical candidates, such as SR123781, that have tailor-made factor Xa and thrombin inhibitory activities combined with less aspecific binding (e.g. binding to platelet factor 4 involved in thrombocytopenia). Novel compounds with both antithrombin III-mediated inhibition of factor Xa and direct thrombin inhibition are emerging. Org42675 is one such compound, balancing dual inhibition of factor Xa and thrombin in one anticoagulant drug, with excellent pharmacokinetic properties and strong inhibitory activity toward clot-bound thrombin.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 1	-	Endotis Pharma SA	-
Thrombosis	Phase 1	-	Merck Sharp & Dohme Corp.	-
Thrombosis	Phase 1	-	Endotis Pharma SARL	-

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