Reversal of Heparin by Novel Synthetic Antagonist PMX-60056 Exhibits a Linear Dose-Response Relationship

Abstract

AbstractAbstract 3329PMX-60056 is a small-molecule first-in-class new chemical entity designed to bind to the pentasaccharide group in unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), and reverse their anticoagulation effects. It has been shown to reverse UFH and the LMWH tinzaparin to date, and without rebound anticoagulation.When no UFH or LMWH is present, PMX-60056 dosing has been limited by transient hypotension at doses over 0.4 mg/kg in volunteers, but its use for heparin reversal should eliminate this effect as PMX-60056 preferentially binds to heparin. A study with UFH at 70 U/kg and reversal with 0.3 mg/kg PMX-60056 showed full efficacy, and mild blood-pressure reductions in half the subjects that suggested excess PMX-60056.Therefore, we examined the dose-response, efficacy, and safety at higher doses of UFH as used in cardiac surgery. Hemodynamic effects were recorded with lithium-dilution cardiac output, and blood pressures were continuous intra-arterial measurements. PMX-60056 dose was titrated using activated clotting times (ACTs), and protamine requirements were also estimated by heparin-protamine titrations to determine heparin levels.350 U/kg of heparin was reversed in 6 normal volunteers, after an initial 10-minute infusion of 0.7 mg/kg PMX-60056 and subsequent smaller doses as needed to normalize ACT. Hemodynamics were unaffected until total PMX-60056 dose exceeded 1 mg/kg – the initial dose of 0.7 mg/kg never produced a change. When a hemodynamic effect did occur (in 3 of the 6), it was initiated by a fall in systemic vascular resistance. Only 1 of these 6 subjects had a clinically significant hypotension, which lasted 15 minutes with pressor agents and limb elevation; this subject was subsequently found to have a past history suggestive of vaso-vagal instability. The other 5 subjects had no appreciable change in blood pressure.Per protocol the antagonist doses were in discrete amounts, so some overshoot was inevitable. Therefore, the total dose of PMX-60056 to the point immediately preceding full reversal of ACT was correlated with ACT, with initial protamine requirement according to heparin levels, and with estimated residual heparin (calculated from dose given and time elapsed). These data were highly correlated with a straight line from zero: R-squared was 0.90 with initial ACT, 0.96 with initial protamine requirement according to heparin levels, and 0.97 with estimated residual heparin (calculated).These data suggest that measurements routinely available during cardiac surgery are sufficient for predicting a single reversing dose of PMX-60056 that will safely and effectively neutralize UFH-induced anticoagulation.After reversal, the ability to re-anticoagulate is sometimes important. The same study also established that reversal of anticoagulation with PMX-60056 did not inhibit subsequent repeat anticoagulation with heparin a few minutes later, which was then also reversed with PMX-60056.This study was conducted according to cGCP at Duke University's Anesthesiology Research Unit. More results will be forthcoming as the analysis proceeds. Disclosures:McAllister:PolyMedix, Inc.: Employment.