Novel, Safe, Efficacious Heparin Reversal

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Abstract Anticoagulants and their reversal agents are key components of standard of care for managing thrombosis. Heparin in particular is used for thrombosis prevention in multiple clinical indications, including procedures such as cardiopulmonary bypass and catheter ablation, after which heparin’s anticoagulant activity requires prompt neutralization. In fact, around a million clinical cases annually require heparin reversal in the US alone. Protamine sulfate, the only FDA-approved reversal agent for heparin, is a 60-year-old drug with a Black Box Warning. Its clinical use is constrained by two major limitations: (i) requirement of titration because of its very narrow therapeutic safety window; and (ii) potentially life-threatening hypersensitivity reactions or anaphylaxis. Thus, there is an unmet medical need to discover novel heparin-reversal agents with a wider therapeutic window and better safety profile. Furthermore, although protamine can reverse the action of unfractionated heparin, it is ineffective in reversing the anticoagulant action of low molecular weight (MW) heparins. Therefore, a novel, effective reversal agent with a superior safety profile compared to protamine would not only improve current treatment paradigms, but has also the very attractive commercial potential to expand the clinical use of low MW heparins as a safer alternative to unfractionated heparin. We aim to develop a safer and more efficacious heparin-reversal drug to replace protamine. Our proprietary Polyanion Modulating Dendrimer (PoMoD) chemistry platform is ideal for creating drugs that selectively bind and inhibit relatively unstructured polyanionic substances such as heparins. The proposed research will provide preclinical proof-of-concept that our lead candidate, PoMoD-1.1, is a safe and effective heparin reversal therapeutic with properties that warrant full preclinical product development. We will demonstrate efficacy with intravenous administration in rat model, and establish the pharmacokinetic (PK) and pharmacodynamic (PD) relationship. In addition, we will assess the exploratory toxicology profile of PoMOD-1.1 in rats. These data will provide an initial estimate of the therapeutic window. Furthermore, our learnings from this research can be applied to the design and testing of other PoMoDs which bind polyphosphate or other poly-anions which are implicated in several disease states. The end result of this work will be a novel, best-in-class safe and effective heparin-reversal agent to provide superior treatment options to patients. We have assembled a team of expert advisors and collaborators to ensure successful completion of this research plan.