INTRODUCTIONEP217609 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.PURPOSEThe 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.METHODSHealthy 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.RESULTSOverall, 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.CONCLUSIONSThese results will allow further investigation in patients requiring a neutralizable anticoagulant as those undergoing cardiac surgery.STUDY REGISTRATIONEudraCT number 2010-020216-10.

01 Dec 2016·Future Medicinal ChemistryQ4 · MEDICINE

Structure–Activity Relationship Studies for Multitarget Antithrombotic Drugs

Q4 · MEDICINE

Review

Author: Pinto, Madalena ; Neves, Ana R ; Sousa, Emília ; Correia-da-Silva, Marta

Thrombosis is a complex process involving multiple pathways. Currently, therapy relies on the combination of two or more antithrombotic drugs, showing that inhibiting more than one target provides benefits in the prevention and treatment of thrombosis. This review focuses on structure–activity relationship studies of molecules possessing multiple actions against thrombosis, namely, dual inhibitors of coagulation, dual inhibitors of coagulation and platelet aggregation, and also dual inhibitors of platelet aggregation. EP217609 has just entered clinical trials, which raise the expectations on the multitarget strategy to prevent or treat thrombosis.

01 Dec 2016·Translational ResearchQ2 · MEDICINE

Inhibition of coagulation proteases Xa and IIa decreases ischemia–reperfusion injuries in a preclinical renal transplantation model

Q2 · MEDICINE

Article

Author: Jerôme Cau ; Thibaut Saint-Yves ; Sandrine Joffrion ; Maurice Petitou ; Thomas Kerforne ; Gérard Mauco ; Jean-Michel Goujon ; Thierry Hauet ; Sébastien Giraud ; Solenne Tillet

Coagulation is an important pathway in the pathophysiology of ischemia-reperfusion injuries. In particular, deceased after circulatory death (DCD) donors undergo a no-flow period, a strong activator of coagulation. Hence, therapies influencing the coagulation cascade must be developed. We evaluated the effect of a new highly specific and effective anti-Xa/IIa molecule, with an integrated innovative antidote site (EP217609), in a porcine preclinical model mimicking injuries observed in DCD donor kidney transplantation. Kidneys were clamped for 60 minutes (warm ischemia), then flushed and preserved for 24 hours at 4°C in University of Wisconsin (UW) solution (supplemented or not). EP217609-supplemented UW solution (UW-EP), compared with unfractionated heparin-supplemented UW solution (UW-UFH) or UW alone (UW). A mechanistic investigation was conducted in vitro: addition of EP217609 to endothelial cells during hypoxia at 4°C in the UW solution inhibited thrombin generation during reoxygenation at 37°C in human plasma and reduced tumor necrosis factor alpha, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 messenger RNA cell expressions. In vivo, function recovery was markedly improved in the UW-EP group. Interestingly, levels of thrombin-antithrombin complexes (reflecting thrombin generation) were reduced 60 minutes after reperfusion in the UW-EP group. In addition, 3 months after transplantation, lower fibrosis, epithelial-mesenchymal transition, inflammation, and leukocyte infiltration were observed. Using this new dual anticoagulant, anti-Xa/IIa activity during kidney flush and preservation is protected by reducing thrombin generation at revascularization, improving early function recovery, and decreasing chronic lesions. Such an easy-to-deploy clinical strategy could improve marginal graft outcome.

100 Deals associated with EP-217609

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 2	-	Endotis Pharma SARL	-
Thrombosis	Phase 2	FR	Endotis Pharma SA	-
Thrombosis	Phase 2	-	Merck Sharp & Dohme Corp.	-

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