A synthetic small molecule antidote for anticoagulants

Abstract

The new oral anticoagulants (NOACs) offer significant advantages over the heparins and warfarin therapies with regards to route of administration, drug interactions and predictability of bioactivity. However, the NOACs currently lack a specific reversal agent. As such concern over serious bleeding, emergency procedures and potential overdosage is heightened. We set out to rationally design, synthesize, and characterize a synthetic small molecule anticoagulant antidote (PER977). Blood was drawn from healthy human volunteers. Plasma was immediately collected and spiked with rivaroxaban or apixaban at 1x and 2x the therapeutic Cmax. Factor Xa activity was measured before and after PER977 addition using a chromogenic anti-Xa kit (Hyphen-BioMed, France). PER977 completely reversed the anti-Xa activity of rivaroxaban and apixaban in a dose-dependent fashion ex vivo in human plasma, and no pro-coagulant effects were observed. Additionally, in a rat tail transection bleeding assay, weight-matched rats were overdosed with edoxaban (see figure), rivaroxaban, apixaban, or dabigatran as confirmed by large increases in blood loss volume. PER977 or sham was administered and after thirty minutes, blood loss volume was quantified. PER977 significantly decreased bleeding in vivo in rats treated with NOACs, reducing it to within the normal range for naive rats and no pro-coagulant effects were observed. In vivo and in vitro toxicology and safety studies have been completed and a first-in-human clinical trial to demonstrate safety and efficacy in healthy human volunteers with PER977 and edoxaban will follow. In conclusion, PER977 is a synthetic small molecule new chemical entity under development that reverses NOACs ex vivo in human blood and decreases bleeding in vivo in a rat tail transection bleeding model. ![Figure][1] [1]: pending:yes