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 suchas cardiopulmonary bypass and catheter ablation, after which heparin's anticoagulant activity requires promptneutralization. In fact, around a million clinical cases annually require heparin reversal in the US alone. Protaminesulfate, the only FDA-approved reversal agent for heparin, is a 60-year-old drug with a Black Box Warning. Itsclinical use is constrained by two major limitations: (i) requirement of titration because of its very narrowtherapeutic 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 andbetter safety profile. Furthermore, although protamine can reverse the action of unfractionated heparin, it isineffective 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 currenttreatment paradigms, but has also the very attractive commercial potential to expand the clinical use of low MWheparins as a safer alternative to unfractionated heparin.We aim to develop a safer and more efficacious heparin-reversal drug to replace protamine. Our proprietaryPolyanion Modulating Dendrimer (PoMoD) chemistry platform is ideal for creating drugs that selectively bind andinhibit relatively unstructured polyanionic substances such as heparins. The proposed research will providepreclinical proof-of-concept that our lead candidate, PoMoD-1.1, is a safe and effective heparin reversaltherapeutic with properties that warrant full preclinical product development. We will demonstrate efficacy withintravenous 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 willprovide an initial estimate of the therapeutic window. Furthermore, our learnings from this research can beapplied to the design and testing of other PoMoDs which bind polyphosphate or other poly-anions which areimplicated in several disease states.The end result of this work will be a novel, best-in-class safe and effective heparin-reversal agent to providesuperior treatment options to patients. We have assembled a team of expert advisors and collaborators to ensuresuccessful completion of this research plan.
Public Health Relevance Statement: Project Narrative
Anticoagulants and their reversal agents are key components of standard of care for managing thrombosis, in
particular during surgical procedures. TSRL and their collaborators are developing a safe and effective heparin-
reversal agent to provide superior treatment options to patients.
Project Terms: |
