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

项目总结 每年，美国约三分之一的住院患者(相当于约1200万人) 美国人)在外科手术和侵入性医疗中接受普通肝素(UFH)以防止凝血 手术，如心内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，以及重大缺血事件，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，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病人对病人 批次之间的可变性会导致与不适当剂量相关的用药错误，这些错误包括 在临床实践中最常见和最严重的。据估计，接受UFH治疗的患者中有1%-5%的人有过这样的经历 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 结果20%-30%的受影响患者死亡。此外，高达26%的心脏手术患者经历过 “肝素抵抗”，达到治疗性抗凝需要过量的UFH。就像任何 在使用抗凝剂的情况下，使用UFH治疗有出血过多的风险，这可能是致命的。UFH被反转为 鱼精蛋白，这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的剂量比例具有挑战性，使患者面临鱼精蛋白的风险 服药过量。在需要精确(即，立即和可滴定)止血的医疗程序的背景下 控制，如经导管心脏瓣膜置换术，这些缺点尤其具有挑战性。因此， 有一种公认的、尚未得到满足的医学需求，即安全和安全的新型抗凝剂/逆转剂组合 具有可预测的剂量响应的快速反应，在医疗过程中实现更精确的止血控制 程序。Helixmer，Inc.正在开发一种新的基于多核苷酸的抗凝剂/解毒剂组合，用于 静脉抗凝。体外和体内数据表明，Helixmer的抗凝药物， Hex01及其解毒剂Hex02具有高度特异性和快速起效，具有明确、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血栓形成的酶。 Hex02碱基对与Hex01失活，通过释放凝血酶逆转抗凝作用。在这 直接到第二阶段SBIR项目，Helixmer将推动Hex01和Hex02的临床前开发 验证血浆中Hex01和Hex02的生物分析方法以支持临床前开发，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的安全性和毒性分布，并确定 通过在大鼠和狗身上进行的非GLP剂量范围查找研究来确定最大耐受量。成功完成 这些关键的临床前研究将支持随后的关键GLP毒理学研究和IND提交。

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.