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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要每年，美国约有三分之一的住院患者（相当于约 1200 万）美国人）接受普通肝素 (UFH) 以防止手术和侵入性医疗期间出现凝血手术，例如开心手术和经导管心脏瓣膜置换术，并防止术后凝血问题，例如深静脉血栓形成，以及重大缺血事件，例如肺栓塞、心脏病 UFH 是一种速效、可逆且廉价的抗凝药物，可间接抑制。多种凝血因子，包括凝血酶和 Xa。然而，UFH 与严重的急性副作用相关。包括超敏反应对 UFH 的非线性剂量反应和患者之间的高度差异。批次之间的差异会导致与剂量不当相关的用药错误，这些错误包括临床实践中最常见和最严重的情况是，接受 UFH 的患者中估计有 1-5% 有这种经历。称为肝素诱导的血小板减少症 (HIT) 的免疫反应，被认为危及生命或此外，高达 26% 的心脏手术患者会因此死亡。 “肝素抵抗”，与任何其他药物一样，实现治疗性抗凝需要过量的 UFH。 UFH 是一种抗凝剂，治疗存在过度出血的风险，而 UFH 可以逆转这种情况，这可能是致命的。鱼精蛋白，它也与严重的副作用有关，包括过敏反应和毒性。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在需要精确（即立即和可滴定）止血的医疗程序中。控制，例如经导管心脏瓣膜置换术，这些缺点特别具有挑战性。对于安全且可靠的新型抗凝剂/逆转剂组合存在着公认的、未得到满足的医疗需求。快速起效并具有可预测的剂量反应，可在医疗期间实现更精确的止血控制 Helixomer, Inc. 正在开发一种新型的基于多核苷酸的抗凝剂/解毒剂组合。静脉抗凝作用体外和体内数据表明，Helixomer 的抗凝药物， Hex01 及其解毒剂 Hex02 具有高度特异性和快速作用，具有清晰、可预测的剂量反应。特异性结合凝血酶并直接抑制凝血酶，凝血酶负责纤维蛋白沉积和凝块形成。 Hex02 与 Hex01 碱基配对并使 Hex01 失活，通过释放凝血酶来逆转抗凝作用。直接进入 II 期 SBIR 项目，Helixomer 将通过 i) 推进 Hex01 和 Hex02 的临床前开发验证血浆中 Hex01 和 Hex02 的生物分析检测以支持临床前开发，ii) 建立 Hex01 的放大生产方法，iii) 确定 Hex01 和 Hex02 在猪体内的给药策略大型动物模型，以及 iv) 定义 Hex01 和 Hex02 的安全性和毒性特征并确定通过非 GLP 剂量范围寻找大鼠和狗的最大耐受剂量研究成功完成。这些关键的临床前研究将支持后续关键的 GLP 毒理学研究和 IND 提交。