Prevention and mitigation of acute traumatic coagulopathy and bleeding

预防和减轻急性创伤性凝血病和出血

• 批准号: 10700402
• 负责人: Laurent O Mosnier
• 金额: $ 29.5万
• 依托单位: HEMATHERIX, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10700402
• 关键词: Accident and Emergency department; Acute; Address; Advanced Development; Affect; Age; Anticoagulants; Blood Coagulation Disorders; Blood Component Transfusion; Blood Vessels; Cause of Death; Cessation of life; Characteristics; Clinical; Coagulation Process; Complex; Data; Development; Diagnosis; Disulfides; Drug Targeting; Emergency Situation; Engineering; Etiology; Factor V; Factor VIII; Factor Va; Fibrinogen; Generations; Goals; Health; Hemorrhage; Hemostatic Agents; Hour; Iatrogenesis; Intercept; Ions; Light; Link; Modeling; Molecular; Multiple Organ Failure; Mus; Mutation; Operative Surgical Procedures; Organ; Organ failure; Outcome; Pathway interactions; Patients; Phase; Phenotype; Plasma; Positioning Attribute; Prevention; Property; Protein C; Protein Isoforms; Reporting; Resistance; Risk; Safety; Shock; Site; Structure; Surface; Syndrome; Therapeutic; Thrombin; Thrombosis; Tranexamic Acid; Transfusion; Trauma; Trauma patient; Traumatic Hemorrhage; Variant; Vascular Permeabilities; activated Protein C; clinically relevant; cofactor; commercialization; disability; driving force; drug development; glycosylation; high risk; improved; mortality; mouse model; pre-clinical; prevent; prophylactic; protein activation; response; risk/benefit ratio; success; targeted treatment; thrombogenesis; thrombotic; thrombotic complications; trauma induced coagulopathy; young adult

Project Summary/Abstract Hematherix is developing superFVa for the treatment of acute traumatic coagulopathy (ATC). Mortality rates with traumatic hemorrhage often exceed 40%, exposing an unmet clinical need for targeted drug development. ATC develops early on as the consequence of severe trauma and shock, prior to additional iatrogenic effects. ATC is distinct from other coagulopathies and is characterized by the selective diminishment of factor V, factor VIII, and fibrinogen levels due to the exaggerated activation of the protein C and fibrinolytic pathways following vascular disruption due to trauma and shock. The presence of ATC is associated with uncontrollable bleeding and increased transfusion requirements, especially during emergency surgery, resulting in increased risks of organ failure and death. Activated factor V (FVa) is an essential co-factor in the prothombinase complex, enhancing the rate of thrombin generation approximately 10,000-fold, but is readily inactivated by activated protein C (APC). SuperFVa is a stable engineered variant of the activated coagulation cofactor factor V and poses a unique targeted therapy to prevent and correct ATC. Key features of superFVa are its resistance to inactivation by APC due to mutation of the APC cleavage sites (Arg506/306/679Gln) and its increased specific activity and stability due to an engineered disulfide link between the A2 and A3 domains. The unique characteristics of superFVa differentiate it from existing prohemostatic and other experimental anti-APC approaches in development and makes superFVa inimitably positioned as a targeted strategy for ATC. Data in murine models of ATC support the concept that APC is a major instigator of ATC. We recently reported that superFVa efficiently prevented ATC when given prophylactically and corrected ATC when given therapeutically in 2 murine models where ATC was induced either by trauma and shock or by trauma and bleeding. These data provide strong support for superFVa as a targeted approach for the treatment of ATC. The objectives for this project are: 1) To provide proof of concept that correction of ATC by superFVa improves clinically relevant outcomes after trauma such as organ damage and survival, and 2) To demonstrate that superFVa has a favorable thrombogenicity risk/benefit ratio due to its unique characteristics. Proof of concept that correction of ATC by superFVa improves survival and organ health outcomes will have an unprecedented scientific and clinical impact for treatment and rescue of trauma patients with ATC and provides strong preclinical support for the next IND-enabling development phase of superFVa for treatment of ATC that will be the subject of a phase 2 application.

项目总结/摘要 Hematherix正在开发用于治疗急性创伤性凝血病（ATC）的superFVa。死亡率 创伤性出血常常超过40%，暴露了对靶向药物开发的未满足的临床需求。ATC 在其他医源性影响之前，作为严重创伤和休克的后果早期发展。atc被 与其他凝血病不同，其特征在于因子V、因子VIII和 纤维蛋白原水平由于过度激活的蛋白C和纤溶途径后血管 由于创伤和休克造成的破坏。ATC的存在与无法控制的出血有关， 输血需求增加，特别是在急诊手术期间，导致器官移植风险增加 失败和死亡。活化因子V（FVa）是凝血酶原酶复合物中的必需辅因子，增强凝血酶原酶的活性。 凝血酶的生成速率约为10，000倍，但很容易被活化蛋白C（APC）灭活。 SuperFVa是活化的凝血辅因子V的稳定的工程化变体，并且对人的凝血辅因子V的表达构成独特的靶向调节。 预防和纠正ATC。superFVa的关键特征是其对APC失活的抗性，这是由于 APC切割位点（Arg506/306/679Gln）的突变及其由于以下原因而增加的比活性和稳定性： A2和A3结构域之间的工程化二硫键。superFVa分化的独特特征 它从现有的促止血剂和其他正在开发的实验性抗APC方法中产生superFVa， 作为ATC的有针对性的战略，其定位是独一无二的。ATC小鼠模型中的数据支持以下概念： APC是ATC的主要煽动者。我们最近报道，当给予 在诱导ATC的2种小鼠模型中进行治疗性给药时， 要么是外伤和休克，要么是外伤和出血这些数据为superFVa作为一种抗肿瘤药物提供了强有力的支持。 有针对性的方法来治疗ATC。该项目的目标是：1）提供概念验证 通过superFVa校正ATC改善了创伤后的临床相关结果，例如器官损伤， 存活率，以及2）证明superFVa因其独特的血栓形成风险/受益比而具有有利的血栓形成风险/受益比 特色通过superFVa校正ATC改善存活率和器官健康结果的概念证明 将对ATC创伤患者的治疗和抢救产生前所未有的科学和临床影响 并为下一个IND使能开发阶段的superFVa提供了强有力的临床前支持， ATC将成为第二阶段应用的主题。