VE-1902—A direct thrombin inhibitor with reversible covalent mechanism of action shows efficacy with reduced bleeding in rodent models of thrombosis. Issue 190 (June 2020)

• Record Type: Journal Article
• Authors: Sivaraja, Mohanram; Clemens, Daniel M.; Sizikov, Sivan; Dash, Subhadra; Xu, Chengpei; Rienzo, Matthew; Yang, Bo; Ryan, Molly; Chattopadhyay, Madhuri; Igoudin, Lev; Chang, Stephanie S.; Keutzer, Samuel; Zalicki, Piotr; Estiarte, M. Angels; Shiau, Timothy P.; Short, Kevin M.; Williams, David C.; Datta, Anirban; Pozzi, Nicola; Di Cera, Enrico; Gibson, C. Michael; Fox, Keith A.A.; Kita, David B.
• Is Part Of: Thrombosis research. Issue 190(2020)
• Page Start: 112
• Page End: 121
• Publication Date: 2020-06
• Subjects: Direct thrombin inhibitor -- Anticoagulants -- Thrombosis -- Thrombin -- Reduced bleeding; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2020.04.020
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: Introduction: High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated combination antithrombotic therapy. Here, we report on VE-1902, a member of a novel class of precision oral anticoagulants (PROACs) that combines effective anticoagulation with reduced bleeding in preclinical testing. Methods and results: Acting through covalent, reversible active-site modification of thrombin similar to a previously described molecule [1 ], VE-1902 shows potency and selectivity for thrombin inhibition in human plasma comparable to clinically relevant direct thrombin inhibitors (DTI) such as argatroban and dabigatran (thrombin generation assay ETP EC50 = 1.3 μM compared to 0.36 μM and 0.31 μM for argatroban and dabigatran; >100-fold selectivity against related serine proteases). Unlike the current anticoagulants, VE-1902 does not significantly inhibit thrombin-mediated platelet activation in in vivo models of thrombosis. In the thrombin generation assay, the compound inhibits thrombin formation without significantly delaying the initiation phase of the clotting cascade. These features are possibly responsible for the observed reduced bleeding in tail bleeding and saphenous vein bleeding models. Consistent with this novel pharmacological profile, VE-1902 shows efficacious anticoagulation in several fibrin-driven animal models of thrombosis (arteriovenous shunt, venous stasis thrombosis, and thrombin-induced thromboembolism models), whereas it does not significantly prevent arterial occlusion in the platelet dependent FeCl3 model. Conclusions: By leaving platelet activation following vascular injury mostly unaffected, VE-1902, and the PROACs more generally, represent a new generation of precision anticoagulants with reduced bleeding risk. Highlights: VE-1902 represents a novel class of precision oral anticoagulants (PROACs) that are reversible covalent thrombin inhibitors. VE-1902 combines potent inhibition of thrombin-mediated fibrin clot formation while preserving platelet function in in vivo thrombosis models. VE-1902 displays reduced bleeding compared to other Novel Oral Anticoagulants (NOACs) in in vivo bleeding models. PROACs have the potential to provide anticoagulation with reduced bleeding risk.