Hemophilia, A, B, C, and vwF are inherited bleeding disorders resulting from a partial or complete deficiency ofFactor VIII (FVIII) or Factor IX (FIX), respectively. Factor-based therapies involve the administration ofexogenous clotting factor concentrates with the aim of achieving the necessary levels of circulating protein. However, factor-based therapies present the complication of inhibitors (antibodies) inactivating the therapeuticagents, rendering treatments ineffective. Current investigational therapies seek to diminish the anti-clottingnatural control factors Protein C, Anti-thrombin and Tissue Factor Protein Inhibitor (TFPI-inhibitor) in order toenhance clotting in patients with impaired clotting. This approach has significant challenges since the coagulationprocess must remain extremely well-balanced and is important to make sure that prevention of hemorrhage byenhancing clotting does not result in inadvertent thrombosis. Furthermore, most of these therapies areadministered in bi-weekly injections, subcutaneous or intravenous, and adverse events relating to injectablesremain a concern.Our overarching goal was to understand the remarkable effects of traditionally used plant extracts on woundhealing and the balance between hemostasis and thrombosis, and their application in developing an oraltreatment for hemophilia. YewSavin's plant-derived pair of coagulant and anti-coagulant molecules result in thebest balance of hemostasis and thrombosis. This small molecule oral, the first in such class, treatmentstrategy, two Complementary Components (CC_2), consisting of Chalcones (pro-coagulant) and Flavones (anti-coagulant), that could potentially revolutionize hemophilia and anti-thrombotic treatments for clotting andthrombotic disorders alike by promoting blood clotting processes without causing thrombosis.In preliminary studies, bio-assays of clotting and healing times guided our initial fractionation assays towardsidentifying single molecule entities that promoted clotting and healing. We triangulated molecules for hemophiliatreatment and accelerated healing using our proprietary artificial intelligence (AI), structure match (SAR), andexperimental verification by bioassay guided fractionation ability. Using a Factor VIII knockout (KO) mousemodel, we demonstrated that our identified CC_2 molecules cause significant improvement in clotting time, innormal rats and in Factor VIII KO mice. These results demonstrate that CC_2 is not Factor VIII dependent andis also more efficient than the first line therapy currently used, injection of Factor VIII. Finally, there are currentlyno known anti-thrombin small molecule agents. According to our preliminary results, the mechanism of actionseems to be the dose-dependent reversal of the Heparin-Antithrombin complex that blocks coagulation.This project proposed by YewSavin, Inc. will apply knowledge of clotting processes gained from plantmolecules to address the challenges of hemostasis-thrombosis balanced therapy and to advance discovery of aclass of small molecule, non-immunogenic, compounds for oral prophylactic treatment in hemophilia.
Public Health Relevance Statement: NARRATIVE
This project proposed by YewSavin, Inc. will apply knowledge of clotting processes gained from plant molecules
to address the challenges of hemostasis-thrombosis balanced therapy and to advance discovery of a class of
small molecule, non-immunogenic, compounds for oral prophylactic treatment in hemophilia. Yewsavin's small
molecule oral, the first in such class treatment strategy, consisting of two complementary components, could
potentially revolutionize hemophilia and anti-thrombotic treatments for clotting disorders and thrombotic
disorders alike by promoting blood clotting processes without causing thrombosis.
Project Terms:
