New Agent PER977 Shows Promise in Reversing Anticoagulation

Although newer target-specific oral anticoagulants represent great advances in the prevention and treatment of blood clots, their use is limited by a lack of effective reversal agents. Severe or life-threatening bleeding thus remains a dangerous complication of these agents. In a trial reported in The New England Journal of Medicine, a new small, synthetic molecular agent holds promise as an antidote to bleeding associated with the factor Xa inhibitor edoxaban.

In this early-stage study, the synthetic agent, called PER977, brought patients’ whole-blood clotting time (a measure of anticoagulation) back to within 10 percent of an individual’s baseline value within 10 minutes of administration.

Jack E. Ansell, MD, from Hofstra North Sore-LIJ School of Medicine, and colleagues assessed the safety, side-effect profile, and ability to reverse anticoagulation in 80 healthy subjects. In the double-blind placebo-controlled trial, PER977 was administered in escalating, single intravenous (IV) doses (5-300 mg) either alone or after a 60-mg oral dose of edoxaban.

After administration of edoxaban, the mean whole-blood clotting time increased by 37 percent over the baseline value. In patients who received a single IV dose of PER977 (100-300 mg) three hours after edoxaban, the drug’s anticoagulant effect was effectively reversed. In the placebo-treated group, on the other hand, it took approximately 12 to 15 hours to reach a level within 10% of baseline.

The reversal effect lasted for 24 hours, and the authors found no evidence of procoagulant activity after administration of PER977. Adverse events potentially related to the study drug included episodes of mild headache and transient mild periorial and facial flushing.

PER977’s effect may not be limited to just edoxaban, Dr. Ansell and coauthors noted. PER977 is designed to bind specifically to unfractionated heparin and low-molecular-weight heparin through noncovalent hydrogen bonding and charge–charge interactions. According to researchers, PER977 should bind in a similar way to the other new oral factor Xa inhibitors, rivaroxaban and apixaban, and to the oral thrombin inhibitor, dabigatran.

Future phase 2 studies will confirm these findings in larger patient populations.


Reference

    Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141-2.

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