Thrombosis

Most antithrombotic/anticoagulant therapies target the final common pathway of coagulation, which involves the extrinsic pathway. A problem with this approach is the lack of an endogenous bypass mechanism capable of maintaining hemostasis at extravascular sites. Discovery of an ideal anti-thrombotic drug is one that protects its recipient from clotting within blood vessels without causing excessive bleeding.

TransTech Pharma is addressing thrombosis through the discovery of potent, safe, and selective modulators of precise intervention points in the thrombotic cascade. We are successfully utilizing our technology to discover orally active, potent, selective and safe modulators for the treatment of vascular disorders and heart disease.

The intrinsic pathway is activated and causes unwanted clotting when blood encounters foreign materials such as hemodialysis filters or artificial heart valves. It is also activated and causes unwanted clotting when venous blood is moving slowly (stasis), as occurs during and after major surgery. Inhibition of the intrinsic pathway should prevent venous thromboembolism (VTE) in these, and potentially other, circumstances. The extrinsic pathway is initiated by tissue factor released during tissue injury (trauma, surgery, stomach ulcers). It is desirable that this pathway remains functional to form clots that limit the amount of blood loss caused by tissue injury. Inhibition of this pathway, either directly or at the level of the common pathway, is likely responsible for the excessive bleeding associated with all currently available anticoagulants.

TTP889 is the only molecule in development that is an inhibitor of the intrinsic pathway in vitro and in vivo via FIX/IXa. TTP889 inhibits the ability of FIXa to form a fully functional tenase complex with FVIIIa. FIXa plays an integral role in the intrinsic coagulation pathway and a lesser role in the extrinsic pathway.

TTP889 is entering its second Phase 2 trial, in patients with VADs, vascular assist devices. The initial Phase 2 trial examining the effect of TTP889 on the venous system was in patients post-hip fracture surgery. While safe and well tolerated, TTP889 did not show significant efficacy in the primary endpoint.