• Thrombotic Disorders
• Hematology Clinical Trials
• Thrombophilia

• Thrombotic Disorders
• Hematology Clinical Trials
• Hematology
• Thrombophilia

An investigational synthetic antidote for the new oral anticoagulants (NOACs) and heparins demonstrated full reversal of anticoagulation in preclinical studies. The properties and mechanisms of action of the agent, PER977, and preclinical data were discussed by Bryan Laulicht, PhD, Perosphere Inc., Mt. Kisco, New York, USA.

Although new generation Factor Xa and Ha inhibitors offer significant advantages over heparins and warfarin in terms of their route of administration, drug interactions, and predictability of bioactivity, the NOACs lack a specific reversal agent. Thus, concern over the need for rapid reversal should a patient start to bleed or require an emergency procedure when taking an oral factor Xa or Ha inhibitor is heightened.

Dr. Laulicht described PER977, a synthetic small molecule designed as an anticoagulant antidote. PER977 showed no procoagulant effects in human blood on thromboelastography (TEG) ex vivo.

In silico modeling data predicted the sites of noncovalent hydrogen bonding between PER977 and new oral anticoagulants and heparins. Data from in vitro dynamic light scattering correlate the in silico-predicted noncovalent binding specificity of PER977 directly to the approved new generation oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban (approved in Japan only), and heparins.

PER977 bonds to 6 sites on heparins, preventing them from binding to antithrombin III. Dynamic light scattering of mixtures of PER977 and enoxaparin provides evidence for the formation of molecular complexes formed at a mass ratio of 1:1, increasing in size at 10:1 ratios, indicating a strong physical, noncovalent association between PER977 and enoxaparin that accounts for the enoxaparin reversal activity of PER977

TEG reaction time (TEG-R) measurements demonstrate a statistically significant decrease (p<0.01) back to normal TEG-R levels in enoxaparin-anticoagulated rats within 30 minutes of intravenous administration of PER977 at 30 mg/kg compared with rats receiving enoxaparin followed by a saline sham.

Preclinical in vivo anticoagulant (rat-tail transection bleeding) assays demonstrated improved reversal of enoxaparin with 30 mg/kg of PER977 compared with protamine sulfate (p<0.05).

PER977 binds to two sites on edoxaban, preventing it from inhibiting Factor Xa. Within 30 minutes of administration, 10 and 20 mg/kg of PER977 reversed edoxaban anticoagulation in rats measured by TEG in a dose-dependent manner (Figure 1), with full reversal at 20 mg/kg, compared with rats receiving edoxaban followed by a saline sham (p<0.05 with 10 mg/kg; p<0.001 with 20 mg/kg vs control). Blood loss mass in rats treated with 12.5 mg/kg of oral edoxaban was reduced significantly with administration of PER977 31.25 mg/kg (p<0.01).

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Figure 1.

PER 977 Reverses Edoxaban Anticoagulation in Measured by TEG

Reproduced with permission from B Laulicht, PhD.

PER977 binds to four sites on dabigatran, disallowing it from inhibiting Factor IIa. PER977 31.25 mg/kg significantly reduced blood loss mass in rats treated with dabigatran etexilate 15.5 mg/kg orally (p<0.001).

PER977 binds to a site on argatroban that does not interfere with argatroban's binding to Factor Ha. As such, rats administered argatroban 5 mg/kg subcutaneously followed by PER977 100 mg/kg intravenously remain anticoagulated.

PER977 showed no binding to common cardiac drugs such as lisinopril, propafenone, and digoxin, among others, or to antiepileptic drugs such as gabapentin, lamotrigine, Phenytoin, and valproate.

In conclusion, said Dr. Laulicht, PER977 reverses new generation oral anticoagulants ex vivo in human blood and decreases bleeding in vivo in a standard rat tail bleeding model.

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