Summary

Recombinant Nematode Anticoagulant Protein c2 (rNAPc2) isa potent (K_I =10 pM), inhibitor of the factor VIIa/tissue factor(fVIIa/TF) complex that requires the prerequisite binding tozymogen or activated factor X (fX). In two double blind, placebo-controlled, sequential dose-escalation phase I studies,rNAPc2 was found to be safe and well tolerated following singleand repeat subcutaneous administrations in healthy humanmale volunteers at doses ranging from 0.3 to 5 µg/kg. Therewas a dose-dependent elevation of the prothrombin timereaching almost 4-fold above the baseline value in the highestdose group that directly correlated with rNAPc2 plasma concentration.In contrast, there was little or no effect on the activatedpartial thromboplastin time, thrombin time or templatebleeding time. The pharmacokinetic behavior of rNAPc2revealed a dose-independent and prolonged elimination half-life(t_1/2β) with a mean of >50 hours. A high affinity interactionbetween rNAPc2 and plasma fX was shown to be essential forthe prolonged t_1/2β in man using crossed immunoelectrophoresisand was confirmed by exploiting the considerably weakerinteraction between rNAPc2 and bovine fX which resulted inan attenuated t_1/2β of ~1.5 hours in calves. The accumulateddata suggests that rNAPc2 is safe and well tolerated followingrepeat subcutaneous administrations at doses up to 5 µg/kg inhealthy volunteers. In addition, the in vivo fate of rNAPc2 inman appears to be governed by its high affinity interaction withcirculating fX. This data supports the continued developmentof this novel anticoagulant for the prevention and treatment ofacute thrombotic disorders.