Credit: Kevin MacKenzie
An investigational anticoagulant reversal agent known as PER977 can restore hemostasis following edoxaban administration, according to a phase 1/2 trial.
The study included 80 healthy subjects who received PER977 or placebo 3 hours after they received a dose of edoxaban.
PER977 decreased anticoagulation to within 10% of baseline levels within 10 to 30 minutes of administration, an effect that took 12 to 15 hours in placebo-treated subjects.
Jack Ansell, MD, of Hofstra North Shore–LIJ School of Medicine in Hempstead, New York, and his colleagues reported these results in a letter to NEJM. The research was funded by Perosphere, the company developing PER977.
PER977 is a small molecule that can bind to unfractionated heparin, low-molecular-weight heparin, edoxaban, rivaroxaban, apixaban, and dabigatran. In preclinical studies, PER977 reversed anticoagulation with each of the new oral anticoagulants.
Dr Ansell and his colleagues wanted to determine the safety and efficacy of PER977 when given to healthy subjects after edoxaban. So the team enrolled 80 subjects and gave them placebo or single, escalating doses of PER977 (5 mg to 300 mg) 3 hours after a 60 mg dose of edoxaban.
After edoxaban administration, the mean whole-blood clotting time (WBCT) increased 37% from baseline. In placebo-treated subjects, it took 12 to 15 hours for the mean WBCT to return to within 10% above the baseline level.
In subjects who received PER977 at 100 mg to 300 mg, it took 10 minutes or less to reach the same level. And the WBCT remained within 10% above or below the baseline value for 24 hours, with no rebound and no infusions needed.
The researchers also assessed clots while measuring WBCT to determine the mean fibrin-fiber diameter. They found that edoxaban significantly reduced the mean fibrin-fiber diameter relative to baseline, from about 250 nm to about 125 nm (P<0.001).
But the mean fibrin-fiber diameter was restored to normal 30 minutes after subjects received 100 mg to 300 mg of PER977.
In addition, the researchers saw no evidence of procoagulant activity after PER977 administration, as assessed by levels of D-dimer, prothrombin fragment 1.2, and tissue factor pathway inhibitor.
The team noted a few adverse events that may have been related to PER977, including transient, mild perioral and facial flushing, dysgeusia, and moderate headache.
One subject experienced a moderate muscle cramp and elevation in creatinine phosphokinase levels, but the researchers believe this was not related to PER977.
“[T]he fact that PER977 was shown to be safe, well tolerated, and, most importantly, effective in reversing edoxaban, one of the new factor Xa oral anticoagulants, is a major step forward in developing a readily available and simple-to-use reversal agent for the new oral anticoagulants,” Dr Ansell said.
