Small molecule quickly reverses anticoagulant activity of edoxaban
American researchers have shared their safety and efficacy data with anticoagulant reversal agent PER977 in healthy volunteers in correspondence to the New England Journal of Medicine.
PER977 (developed by Perosphere) is a small, synthetic, water-soluble, cationic molecule that is designed to bind specifically to unfractionated heparin and low-molecular-weight heparin through noncovalent hydrogen bonding and charge–charge interactions. In addition, PER977 binds in a similar way to novel oral anticoagulants (NOACs), to both oral factor Xa inhibitors (edoxaban, rivaroxaban and apixaban), and to the oral thrombin inhibitor dabigatran.
PER977 had been shown to reverse anticoagulation with each of the NOACs in preclinical studies. The molecule did not bind to plasma proteins, nor to common cardiovascular, anti-epileptic and anaesthetic drugs.
This letter describes a pharmacokinetic and pharmacodynamics study of single intravenous doses of PER977 (5-300 mg) alone or administered after a 60 mg oral dose of edoxaban, in a double-blind, placebo-controlled set up. Whole-blood clotting time was used to monitor anticoagulation.
Administration of PER977 (100-300 mg single dose) 3 hours after administration of edoxaban, lowered whole-blood clotting time to within 10% above baseline in 10 minutes or less, while in subjects receiving placebo, the time to return to that level of whole-blood clotting time was approximately 12-15 hrs. Whole-blood clotting time remained stably within 10% above or below baseline for 24 hours after a single dose of PER977. In 30 minutes, PER977 also restored the mean fibrin-fiber diameter to normal, which had been reduced after edoxaban administration (as measured by scanning electron micrographs of clots).
There was no evidence of procoagulant activity after administration of PER977. Potentially related adverse events included transient mild perioral and facial flushing and dysgeusia, moderate headache (1 person). One person reported moderate muscle cramp and elevation in creatinine phosphokinine levels, which were not considered to be related to PER977.
Additional phase 2 clinical studies are ongoing.
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Ansell JE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; DOI: 10.1056/NEJMc1411800.