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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 Hematherix 正在开发用于治疗急性创伤性凝血病 (ATC) 的 superFVa。死亡率与创伤性出血通常超过 40%，暴露出靶向药物开发的临床需求未得到满足。空中交通管制在其他医源性影响之前，由于严重创伤和休克而早期发生。空中交通管制是与其他凝血病不同，其特征是因子 V、因子 VIII 和因子选择性减少由于血管后蛋白 C 和纤溶途径的过度激活导致纤维蛋白原水平升高由于创伤和休克而造成的破坏。 ATC 的存在与无法控制的出血有关输血需求增加，特别是在紧急手术期间，导致器官损伤的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重要辅助因子，可增强凝血酶的生成速度约为 10,000 倍，但很容易被活化蛋白 C (APC) 灭活。 SuperFVa 是活化凝血辅因子 V 的稳定工程变体，具有独特的靶向作用预防和纠正 ATC 的治疗。 superFVa 的主要特征是其对 APC 失活的抵抗力，这是由于 APC 裂解位点 (Arg506/306/679Gln) 突变及其比活性和稳定性增加 A2 和 A3 结构域之间的工程化二硫键。 superFVa 的独特特性与众不同它来自现有的促止血剂和其他正在开发的实验性抗 APC 方法，并使得 superFVa 被独特地定位为 ATC 的目标战略。 ATC 小鼠模型中的数据支持这样的概念： APC是ATC的主要推动者。我们最近报道了 superFVa 在给予时可有效预防 ATC 在 2 种诱发 ATC 的小鼠模型中进行治疗时，可以预防和纠正 ATC 要么是由于外伤和休克，要么是外伤和出血。这些数据为superFVa作为 ATC 治疗的针对性方法。该项目的目标是： 1) 提供概念验证通过 superFVa 校正 ATC 可改善器官损伤等创伤后的临床相关结果生存率，以及 2) 证明 superFVa 由于其独特的特性而具有良好的血栓形成风险/效益比特征。概念证明通过 superFVa 校正 ATC 可提高生存率和器官健康结果将对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 superFVa 的下一个 IND 开发阶段提供强有力的临床前支持，用于治疗 ATC 将成为第二阶段申请的主题。