Novel, Safe, Efficacious Heparin Reversal

新颖、安全、有效的肝素逆转

• 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
• 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

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.

摘要 抗凝剂及其逆转剂是管理血栓形成的标准治疗的关键组成部分。 肝素尤其用于多种临床适应症中的血栓形成预防，包括诸如 如心肺转流术和导管消融术，之后肝素的抗凝活性需要及时 中和事实上，仅在美国，每年就有大约一百万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剂，是一种有60年历史的药物，带有黑匣子警告。其 临床应用受到两个主要局限性的限制：（i）由于其非常狭窄， 治疗安全窗;和（ii）潜在危及生命的超敏反应或过敏反应。因此，在本发明中， 发现具有更宽治疗窗的新型肝素逆转剂的医学需求尚未得到满足， 更好的安全性。此外，虽然鱼精蛋白可以逆转普通肝素的作用，但它是不稳定的。 在逆转低分子量（MW）肝素的抗凝作用方面无效。因此，一部小说， 与鱼精蛋白相比具有上级安全性特征有效的逆转剂不仅可以改善电流 治疗范例，但也有非常有吸引力的商业潜力，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，以取代鱼精蛋白。我们专有 聚阴离子调节树枝状聚合物（PoMoD）化学平台是创造选择性结合和 抑制相对非结构化的聚阴离子物质如肝素。该研究将提供 临床前概念验证表明，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 具有保证完全临床前产品开发的特性的治疗剂。我们将证明有效性， 在大鼠模型中静脉给药，并建立药代动力学（PK）和药效学（PD） 关系此外，我们将评估PoMOD-1.1在大鼠中的探索性毒理学特征。这些数据将 提供治疗窗的初始估计。此外，我们从这项研究中学到的东西可以 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， 与多种疾病有关。 这项工作的最终结果将是一种新的，一流的安全和有效的肝素逆转剂，提供 为患者提供上级治疗选择。我们组建了一个专家顾问和合作者团队，以确保 顺利完成了这项研究计划。