Development of a non-factor small molecule,… (R43HL162336) – Project Grant to Yewsavin, Inc.

Abstract: Hemophilia, a, b, c, and VWF are inherited bleeding disorders resulting from a partial or complete deficiency of factor VIII (fviii) or factor IX (fix), respectively. Factor-based therapies involve the administration of exogenous 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 therapeutic agents, rendering treatments ineffective. Current investigational therapies seek to diminish the anti-clotting natural control factors protein c, anti-thrombin and tissue factor protein inhibitor (tfpi-inhibitor) in order to enhance clotting in patients with impaired clotting. This approach has significant challenges since the coagulation process must remain extremely well-balanced and is important to make sure that prevention of hemorrhage by enhancing clotting does not result in inadvertent thrombosis. Furthermore, most of these therapies are administered in BI-weekly injections, subcutaneous or intravenous, and adverse events relating to injectables remain a concern. Our overarching goal was to understand the remarkable effects of traditionally used plant extracts on wound healing and the balance between hemostasis and thrombosis, and their application in developing an oral treatment for hemophilia. Yewsavin's plant-derived pair of coagulant and anti-coagulant molecules result in the best balance of hemostasis and thrombosis. This small molecule oral, the first in such class, treatment strategy, 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 and thrombotic 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 towards identifying single molecule entities that promoted clotting and healing. We triangulated molecules for hemophilia treatment and accelerated healing using our proprietary artificial intelligence (AI), structure match (SAR), and experimental verification by bioassay guided fractionation ability. Using a factor VIII knockout (KO) mouse model, we demonstrated that our identified CC_2 molecules cause significant improvement in clotting time, in normal rats and in factor VIII KO mice. These results demonstrate that CC_2 is not factor VIII dependent and is also more efficient than the first line therapy currently used, injection of factor VIII. Finally, there are currently no known anti-thrombin small molecule agents. According to our preliminary results, the mechanism of action seems 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 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.

Action	Obligated	Date
Amendment	$0	Mar 1, 2024
Amendment	$300,000	Aug 25, 2022
Original award	$300,000	Aug 25, 2022

Development of a non-factor small molecule, oral, prophylactic and hemostasis balanced therapy for treatment of clotting disorders including hemophilia a/b

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