Novel, Safe, Efficacious Heparin Reversal

新颖、安全、有效的肝素逆转

基本信息

批准号：
10545133
负责人：
Elke Lipka
金额：
$ 39.44万
依托单位：
TSRL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545133
关键词：
Anaphylaxis Anions Anticoagulants Binding Biodistribution Black race Blood specimen Cardiac ablation Cardiopulmonary Bypass Cations Cells Charge Chemistry Clinical Complex Data Dendrimers Disease Dose Drug Kinetics Engineering Ensure Evaluation Excretory function FDA approved Feces Generations Hemorrhage Heparin Heparin Binding Human Hypersensitivity Hypotension In Vitro Label Lead Learning Life Low-Molecular-Weight Heparin Maximum Tolerated Dose Measures Medical Modeling Mus Operative Surgical Procedures Organ Patients Pharmaceutical Preparations Pharmacodynamics Physiological Plasma Plasma Proteins Polymers Polyphosphates Positioning Attribute Pre-Clinical Model Prevention Procedures Property Protamine Sulfate Protamines Pulmonary Edema Pulmonary Hypertension Radioactivity Rattus Reaction Research Resistance Risk Safety Sampling Tail Testing Therapeutic Thrombosis Time Titrations Toxic effect Toxicology Urine Validation Work base cardiovascular collapse clinical development design efficacy validation improved in vivo intravenous administration intravenous injection lead candidate novel pharmacokinetics and pharmacodynamics phase 1 study polyanion pre-clinical product development protonation pulmonary vasoconstriction standard of care

项目摘要

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.

抽象的抗凝剂及其逆转剂是治疗血栓形成护理标准的关键组成部分。肝素尤其用于多种临床适应症的血栓形成预防，包括诸如此类的手术如体外循环和导管消融，之后肝素的抗凝活性需要及时事实上，仅在美国，每年就有大约一百万个临床病例需要肝素逆转。硫酸盐是 FDA 批准的唯一肝素逆转剂，是一种有 60 年历史的药物，带有黑框警告。临床使用受到两个主要限制：（i）由于其范围非常窄，因此需要滴定治疗安全窗；和（ii）可能危及生命的过敏反应或过敏反应。发现具有更宽治疗窗的新型肝素逆转剂的医疗需求尚未得到满足此外，虽然鱼精蛋白可以逆转普通肝素的作用，但它是更好的安全性。不能有效逆转低分子量（MW）肝素的抗凝作用。与鱼精蛋白相比，具有优越安全性的有效逆转剂不仅可以改善目前的情况治疗范例，但也具有非常有吸引力的商业潜力，可以扩大低分子量的临床使用肝素作为普通肝素的更安全替代品。我们的目标是开发一种更安全、更有效的肝素逆转药物来替代我们的专有鱼精蛋白。聚阴离子调节树枝状聚合物 (PoMoD) 化学平台非常适合创建选择性结合和抑制相对非结构化的聚阴离子物质，例如肝素。拟议的研究将提供。临床前概念证明我们的主要候选药物 PoMoD-1.1 是一种安全有效的肝素逆转剂具有保证全面临床前产品开发的特性的治疗方法，我们将证明其疗效。大鼠模型静脉给药，建立药代动力学（PK）和药效学（PD）此外，我们将评估 PoMOD-1.1 在大鼠中的探索性毒理学特征。提供治疗窗口的初步估计此外，我们从这项研究中学到的知识可以是应用于结合多磷酸盐或其他聚阴离子的其他 PoMoD 的设计和测试与多种疾病状态有关。这项工作的最终结果将是一种新颖的、同类最佳的安全有效的肝素逆转剂，以提供我们组建了一个由专家顾问和合作者组成的团队，以确保为患者提供优质的治疗选择。顺利完成本研究计划。