Abstract
With regards to route of administration, drug interactions and predictability of bioactivity, the new oral anticoagulants (NOACs; direct factor Xa and IIa inhibitors) offer significant advantages over heparins and warfarin therapies. However, concern over serious bleeding, emergency procedures and potential over-dosage is heightened with the current lack of a specific reversal agent. PER977 is a synthetic small molecule rationally designed anticoagulant antidote. Reversal of anticoagulation induced bleeding was demonstrated in a rat tail transection model: weight-matched rats were overdosed with rivaroxaban, edoxaban, dabigatran, or apixaban, resulting in large increases in blood loss volume. PER977 was administered IV and after thirty minutes, blood loss volume was quantified. PER977 significantly decreased bleeding in vivo in rats treated with NOAC (Figure 1a). PT (for edoxaban, rivaroxaban, and apixaban) or aPTT (for dabigatran) and thromboelastography (TEG) (TEG- for edoxaban, Figure 1b) were also used to quantify NOAC anticoagulation reversal in vivo in rats; PER977 restored these laboratory values to baseline levels within 20 minutes of administration. Importantly, PER977 has also shown no pro-coagulant properties as measured by TEG, PT and aPTT in rat and human whole blood, nor any interaction with circulating coagulation factor proteins. 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 is underway. In conclusion, PER977 is a synthetic small molecule new chemical entity under development that reverses NOAC anti-coagulation in vivo as measured by TEG, PT, and aPTT, and also by bleeding volume in a rat tail transection model.
Published Version
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