Novel, Safe, Efficacious Heparin Reversal

摘要 抗凝剂及其逆转剂是管理血栓形成的标准护理的关键组成部分。 肝素尤其用于在多种临床适应症中预防血栓形成，包括 如体外循环和导管消融，在此之后肝素的抗凝活性需要及时 中和。事实上，仅在美国，每年就有大约100万例临床病例需要肝素逆转。鱼精蛋白 硫酸盐是FDA批准的唯一肝素逆转药，是一种有60年历史的药物，有黑匣子警告。它的 临床应用受到两个主要限制：(I)由于滴定的范围很窄，所以对滴定的要求 治疗安全窗口；和(Ii)潜在威胁生命的过敏反应或过敏反应。因此， 发现具有更宽治疗窗口的新型肝素逆转药物的医学需求尚未得到满足 更好的安全状况。此外，尽管鱼精蛋白可以逆转普通肝素的作用，但它是 不能逆转低分子肝素的抗凝作用。因此，一部小说， 与鱼精蛋白相比，具有更高安全性的有效逆转剂不仅可以改善电流 治疗模式，但也具有非常诱人的商业潜力，扩大低分子量的临床应用 肝素作为普通肝素更安全的替代品。 我们的目标是开发一种更安全、更有效的肝素逆转药物来取代鱼精蛋白。我们的专有 聚阴离子调制树状大分子(Pomod)化学平台是创造选择性结合和 抑制相对无结构的聚阴离子物质，如肝素。拟议的研究将提供 临床前概念验证，我们的主要候选药物Pomod-1.1是一种安全有效的肝素逆转药物 具有治疗性的特性，保证全面的临床前产品开发。我们将通过以下方式展示其有效性 大鼠静脉给药模型，建立药代动力学(PK)和药效学(PD) 两性关系。此外，我们还将评估Pomod-1.1在大鼠身上的探索性毒理学特征。这些数据将 提供治疗窗口的初步估计。此外，我们从这项研究中学到的东西可以是 应用于结合聚磷酸盐或其他聚阴离子的其他POMOD的设计和测试，这些聚磷酸盐或其他聚阴离子 牵涉到几种疾病状态。 这项工作的最终结果将是一种新型的、同类中最好的安全有效的肝素逆转试剂来提供 为患者提供更好的治疗选择。我们已经组建了一支由专家顾问和合作者组成的团队，以确保 圆满完成这项研究计划。

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.