Development of an RNA-based anticoagulant and antidote for precise on/off coagulation control during cardiovascular procedures

开发基于 RNA 的抗凝剂和解毒剂，用于心血管手术期间精确的开/关凝血控制

• 批准号: 10603072
• 负责人: Abhichart Krissanaprasit
• 金额: $ 98.36万
• 依托单位: HELIXOMER, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603072
• 关键词: Acute; Address; Affect; Affinity; American; Anaphylaxis; Animal Model; Anticoagulants; Anticoagulation; Antidotes; Appearance; Base Pairing; Binding; Biodistribution; Biological; Biological Assay; Blood; Blood Coagulation Factor; Canis familiaris; Cardiac Surgery procedures; Cardiovascular system; Cessation of life; Clinical; Clinical Trials; Coagulation Process; DNA; Data; Deep Vein Thrombosis; Deposition; Detection; Development; Dialysis procedure; Dose; Endotoxins; Enzyme-Linked Immunosorbent Assay; Enzymes; Euthanasia; Event; Extracorporeal Membrane Oxygenation; Family suidae; Fibrin; Future; Genetic Transcription; Hemorrhage; Hemostatic Agents; Heparin; Hospitalization; Hour; Human; Hypersensitivity; Immune response; In Vitro; Industry Standard; Intravenous; Ischemia; Kinetics; Lead; Life; Liquid substance; Maximum Tolerated Dose; Medical; Medication Errors; Methods; Mus; Myocardial Infarction; Operative Surgical Procedures; Overdose; Patients; Pharmaceutical Preparations; Phase; Plasma; Polynucleotides; Postoperative Period; Preparation; Procedures; Production; Protamines; Pulmonary Embolism; RNA; Rattus; Reaction; Resistance; Risk; Safety; Saline; Shapes; Single-Stranded DNA; Small Business Innovation Research Grant; Stroke; Therapeutic; Thrombin; Thrombosis; Time; Tissues; Toxic effect; Toxicology; Work; analytical method; aptamer; assay development; clinical practice; detection assay; experience; first-in-human; heart valve replacement; heparin-induced thrombocytopenia; immunotoxicity; in vivo; innovation; large scale production; manufacture; manufacturing scale-up; meetings; nano; novel; novel therapeutics; patient variability; porcine model; preclinical development; preclinical study; prevent; response; safety assessment; side effect

PROJECT SUMMARY Each year, approximately one-third of all hospitalized patients in the US (corresponding to about 12 million Americans) receive unfractionated heparin (UFH) to prevent clotting during surgical and invasive medical procedures, such as open-heart surgery and transcatheter heart valve replacement, and to prevent postoperative clotting issues, such as deep vein thrombosis, and major ischemic events, such as pulmonary embolism, heart attack, and stroke. UFH is a fast-acting, reversible, and inexpensive anticoagulant drug that indirectly inhibits several clotting factors, including thrombin and Xa. However, UFH is associated with serious acute side effects, including hypersensitivity reactions. The non-linear dose response to UFH and a high degree of patient-to-patient and batch-to-batch variability lead to medication errors related to improper dosing, and these errors are among the most common and serious in clinical practice. An estimated 1-5% of patients who receive UFH experience an immune response known as heparin-induced thrombocytopenia (HIT), which is considered life threatening or results in death in 20-30% of affected patients. Additionally, up to 26% of cardiac surgery patients experience “heparin resistance,” where achieving therapeutic anticoagulation requires excessive doses of UFH. As with any anticoagulant, treatment with UFH carries the risk of excessive bleeding, which can be fatal. UFH is reversed by protamine, which is also associated with serious side effects, including anaphylaxis and toxicity. Accurate determination of the dosing ratio of protamine to UFH is challenging, putting patients at risk for protamine overdose. In the context of medical procedures that require precise (i.e., immediate and titratable) hemostatic control, such as transcatheter heart valve replacement, these shortcomings are particularly challenging. Thus, there is a recognized, unmet medical need for new anticoagulant/reversal agent combinations that are safe and fast acting with a predictable dose response to enable more precise hemostatic control during medical procedures. Helixomer, Inc. is developing a novel polynucleotide-based anticoagulant/antidote combination for intravenous anticoagulation. In vitro and in vivo data have demonstrated that Helixomer’s anticoagulant drug, Hex01, and its antidote, Hex02, are highly specific and fast acting, with clear, predictable dose responses. Hex01 specifically binds to and directly inhibits thrombin, the enzyme responsible for fibrin deposition and clot formation. Hex02 base-pairs with and deactivates Hex01, reversing the anticoagulant effect by releasing thrombin. In this Direct-to-Phase II SBIR project, Helixomer will advance the preclinical development of Hex01 and Hex02 by i) validating bioanalytical assays for Hex01 and Hex02 in plasma to support preclinical development, ii) establishing scale-up manufacturing methods for Hex01, iii) determining a dosing strategy for Hex01 and Hex02 in a porcine large-animal model, and iv) defining safety and toxicity profiles for Hex01 and Hex02 and identifying the maximum tolerated dose through non-GLP dose range finding studies in rats and dogs. Successful completion of these critical preclinical studies will support subsequent pivotal GLP toxicology studies and IND submission.

项目摘要 每年，美国约有三分之一的住院患者（相当于约1200万人） 美国人）接受普通肝素（UFH），以防止在手术和侵入性医疗过程中凝血 手术，如心脏直视手术和经导管心脏瓣膜置换术，并防止术后 凝血问题，如深静脉血栓形成，和主要缺血性事件，如肺栓塞，心脏 攻击和中风。UFH是一种快速、可逆、廉价的抗凝药物，可间接抑制 几种凝血因子，包括凝血酶和Xa。然而，UFH与严重的急性副作用有关， 包括过敏反应。UFH的非线性剂量反应和高度的患者间 批次间的差异导致与剂量不当相关的用药错误，这些错误 临床实践中最常见和最严重的。估计1-5%接受UFH治疗的患者 一种称为肝素诱导的血小板减少症（HIT）的免疫反应，被认为是危及生命或 导致20-30%的受影响患者死亡。此外，高达26%的心脏手术患者 “肝素抵抗”，其中实现治疗性抗凝需要过量的UFH。正如任何 由于UFH具有抗凝剂，因此UFH治疗存在出血过多的风险，这可能是致命的。UFH被逆转， 鱼精蛋白，它也与严重的副作用有关，包括过敏反应和毒性。准确 确定鱼精蛋白与UFH的剂量比具有挑战性，使患者面临鱼精蛋白的风险 服药过量在需要精确（即，立即且可滴定）止血 然而，在诸如经导管心脏瓣膜置换术的控制中，这些缺点尤其具有挑战性。因此，在本发明中， 对于新的抗凝剂/逆转剂组合存在公认的、未满足的医学需求，所述组合是安全的， 具有可预测的剂量反应的快速作用，以在医疗过程中实现更精确的止血控制 程序. Helixomer，Inc.正在开发一种新的基于多核苷酸的抗凝剂/解毒剂组合， 静脉抗凝体外和体内数据表明，Helixomer的抗凝药物， Hex 01及其解毒剂Hex 02具有高度特异性和快速作用，具有明确的可预测的剂量反应。Hex01 特异性结合并直接抑制凝血酶，凝血酶是负责纤维蛋白沉积和凝块形成的酶。 Hex 02与Hex 01碱基配对并使其失活，通过释放凝血酶逆转抗凝作用。在这 直接进入II期SBIR项目，Helixomer将通过i） 验证血浆中Hex 01和Hex 02的生物分析测定以支持临床前开发，ii）建立 iii）确定Hex 01和Hex 02在猪中的给药策略 大动物模型，和iv）定义Hex 01和Hex 02的安全性和毒性特征，并确定 通过大鼠和犬的非GLP剂量范围探索研究确定最大耐受剂量。成功完成 这些关键的临床前研究将支持后续的关键GLP毒理学研究和IND提交。