Abstract 19503: An Improved Potent Direct Thrombin Inhibitor Shows Efficacy With Low Bleeding Risk

Introduction: The advent of the novel oral anticoagulants (NOACs) has had a profound impact on the treatment of venous and arterial thrombotic diseases, which are major clinical concerns with high prevalence and often fatal outcome. While the NOACs offer advantages such as more convenient dosing regimens, more predictable anticoagulant responses, and less frequent monitoring than the traditional options warfarin and heparins, their bleeding liability remains high. Methods and Results: We have developed a novel class of highly selective oral direct thrombin inhibitors that show significantly lower bleeding compared to the NOACs in preclinical testing. Previously, we presented data for an advanced lead compound, VE-1902. Here we will present VE-2851, another lead compound with good liver microsome and plasma stability, improved pharmacokinetic profile in rats, and better combined in vitro and in vivo activity. In contrast to the NOACs, VE-2851, like VE-1902, is preferentially excreted through the feces. In rodent models of venous stasis and arteriovenous shunt thrombosis, VE-2851 demonstrated efficacy comparable to the NOACs, and it is 5x more potent than VE-1902. Despite its strong anticoagulant properties, VE-2851 showed >15x lower blood cell loss relative to apixaban in a rodent tail bleeding time test and less extension of the bleeding time compared to the NOACs. This distinctive bleeding profile is associated with an approx. 200-fold reduced potency in inhibiting thrombin-mediated platelet activation in vitro compared to other direct thrombin inhibitors, while VE-2851 inhibits fibrinogen cleavage, TAFI activation, and protein C activation with similar potency to the NOACs. In vivo , VE-2851 also shows >5x higher maximum platelet activation in the arteriovenous shunt thrombosis model compared to apixaban. Conclusions: The ability of VE-2851 to prevent thrombosis while preserving hemostasis could lead to a new anticoagulant therapy with lower bleeding risk when administered either as a monotherapy or as dual or triple therapy with antiplatelet agents. In addition, a favorable excretion profile with low renal clearance could provide benefits for patients with impaired kidney function.