SynthoPlate: Intravenous Hemostatic Nanotechnology to Mitigate Bleeding in Thrombocytopenia

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Project Summary/Abstract The normal platelet count in human blood is 150,000-400,000/μL, and these platelets are responsible for efficient hemostatic surveillance and bleeding mitigation in the body. Thrombocytopenia (TCP, low platelet count) is a condition caused by a decrease in platelet production, increase in platelet destruction or consumption, or increase in splenic sequestration. The age-adjusted prevalence of immune thrombocytopenic purpura (ITP) is estimated to be 3.3 per 100,000 persons in the USA, while drug-induced TCP affects 1-2 per 100,000 persons. The majority (>95%) of TCP cases result from autoimmune disorders or are induced by chemo- and radiotherapies as well as other pharmaceuticals. At platelet counts <50,000/μL, surgical procedures are complicated by high bleeding risks and any minor injury may lead to excessive bleeding. At counts <10,000/μL, spontaneous bleeding becomes a major concern. Therefore, frequent therapeutic and prophylactic platelet transfusions are required to increase platelet counts and mitigate bleeding risks. However, the availability of natural platelet products is severely limited by a near-static pool of donors and a very short shelf-life (3-5 days) due to high risks of bacterial contamination and storage-related platelet activation and degranulation. Therefore, there exists a significant unmet clinical need for a therapeutic agent that can mitigate bleeding complications intravenously in TCP patients, while allowing reduced contamination and long shelf-life without compromising function. To this end, we have developed a synthetic hemostatic nanotechnology, called SynthoPlateTM, that mimics platelet’s ability to adhere and aggregate specifically at a site of injury in the body. In Phase I of this SBIR, we demonstrated platelet-mimetic hemostatic functions in vitro as well as in vivo in proof-of-concept TCP murine models of bleeding. Building on this in the proposed Phase II studies, we aim to: 1) Establish appropriate clinical biomarkers for monitoring SP efficacy in thrombocytopenic (TCP) patient blood samples, 2) determine the effective pharmacodynamic (PD) dosing window of SynthoPlateTM in a rabbit bleeding model of thrombocytopenia, and 3) establish the pharmacokinetic (PK) profile of SP in healthy and thrombocytopenic (TCP) rabbits. Altogether, these experiments will establish and correlate PK with ex vivo functional assays and in vivo PD to guide clinical evaluation. Success in this Phase II proposal will be used to generate a Target Product Profile (TPP), which will guide clinical protocol design, as well as aid in raising follow-on-funding and partnerships for product development from multiple potential sources. Building on these results, Phase III will implement defined dosage guidelines for IND-enabling Pharm/Tox studies with GMP-manufactured SP and thereby progress towards submitting an IND application for clinical evaluation.