Abstract

Based on previous studies showing the efficacy of FactorIXa (FIXa) blockade using an active site-blocked form of this coagulation enzyme, we speculated that partial inhibition of the intrinsic coagulation pathway would offer a novel approach to attenuate intravascular clot formation without promoting untoward bleeding. Here we describe the anticoagulant activity of TTP889, a small molecule partial inhibitor of FIXa activity. TTP889 is orally absorbed with a PK profile that is conducive to once daily dosing. It is selective for FIXa in that it shows little to no activity against several other proteases in the clotting cascade including FXa, FXIa, FXIIa or FVIIa in a unique clotting assay. In vivo, TTP889 inhibited fibrin deposition in a rat arteriovenous (A/V) shunt model. In this model, vehicle treated rats had 104mg ± 43 of fibrin deposited on a silk thread after a 15 minute shunt while TTP889 treated rats had significantly less fibrin deposited (39mg ± 18 p=<0.001). Furthermore, TTP889 inhibited clotting in a porcine A/V shunt model where pressure across a hemodialysis filter that was shunting the carotid artery to the jugular vein was used as an indirect marker of clot formation. In this model, TTP889 at 0.3mg/kg performed as well as 150U/kg of heparin over the 90-minute shunt. Of additional importance, TTP889 has no effect on bleeding times as measured by APTT or ACT assays ex-vivo or by bleeding time and volume from incisions in the skin or spleen in vivo. Together, these data support that TTP889 is a selective partial inhibitor of FIXa activity that offers a novel approach to attenuate clot formation associated with intravascular clotting without promoting untoward bleeding. TTP 889 is currently in Phase II and is being evaluated for the prevention of DVT in hip fracture patients with treatment starting one week post surgery and continued for 3 weeks.

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