Molecular Imaging Agent to Detect Thrombus

检测血栓的分子成像剂

• 批准号: 10158327
• 负责人: Valerie Humblet
• 金额: $ 49.68万
• 依托单位: COLLAGEN MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158327
• 关键词: Adult Respiratory Distress Syndrome; Affinity; Animals; Atrial Fibrillation; Biodistribution; Blood; Blood Coagulation Disorders; Blood Vessels; COVID-19 pandemic; Cardiac; Cardiovascular Diseases; Cessation of life; Chronic; Clinical; Clinical Protocols; Coagulation Process; Collagen; Cyclic GMP; Data; Deep Vein Thrombosis; Detection; Development; Disease; Dose; Drug Kinetics; Embolism; Evaluation; Fibrin; Formulation; Funding; Goals; Grant; Healthcare; Heart; Human; Image; Institutional Review Boards; Investigational Drugs; Investigational New Drug Application; Investments; Mechanics; Medical; Metabolic; Methods; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Myocardial Infarction; Oryctolagus cuniculus; Pathology; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Pulmonary Embolism; Pulmonary artery structure; Rattus; Readiness; Safety; Sedation procedure; Solid; Source; Stroke; Techniques; Therapeutic; Thrombectomy; Thrombosis; Thrombus; Time; Toxic effect; Writing; acute coronary syndrome; anatomic imaging; commercialization; deep vein; dosimetry; healthy volunteer; human data; imaging agent; imaging modality; intravenous injection; molecular imaging; nephrotoxicity; noninvasive diagnosis; programs; radiochemical; standard of care; thrombolysis; tool; uptake; volunteer

Project Summary Thrombus as a clinical entity is responsible for the largest number of deaths and greatest morbidity compared to any other pathology. Most major cardiovascular diseases, including myocardial infarction, atrial fibrillation, acute coronary syndrome, stroke, pulmonary embolism, and deep vein thrombosis, are either a result of thrombosis or can cause thrombosis. Recently, the pandemic COVID-19 has been found to be associated with increased coagulopathy, which likely contributes to the development of acute respiratory distress and even multi-organ failure in these patients. Detection of thromboemboli and their source thrombus are vital to proper patient management across all of these diseases. Currently thrombi are detected by different anatomical imaging methods depending on the vascular territory, but all techniques have limitations (e.g. require sedation, require nephrotoxic contrast, cannot be used in certain patients). No existing method can be used to assess different vascular territories for thrombus in a single multistation exam, while this would be extremely valuable in thromboembolic diseases like deep vein thrombosis (DVT) / pulmonary embolism (PE) or stroke where it is important to not only detect the embolus but the embolic source as well. Current methods do not inform on composition of the thrombus and the fibrin content, although therapeutic strategies (e.g., thrombolysis for a fibrin rich clot identified by positron emission tomography (PET) vs. mechanical thrombectomy for an organized, fibrin- poor, chronic thrombus) would benefit from such information. Collagen Medical is developing a fibrin-specific molecular PET probe, 68Ga-CM500 that can identify thrombus anywhere in the body following a single intravenous injection followed by PET imaging. Ultimately, we are seeking regulatory approval for the indication “68Ga-CM500 detects thrombus” which require demonstration of efficacy for thrombus detection in different vascular territories, such as the deep veins, pulmonary arteries, and cardiac chambers. Using a closely related probe, we have excellent preliminary human data to suggest that 68Ga-CM500 can accurately identify thrombus in the heart. The purpose of this CRP grant is to provide funding to 1) file an IND for 68Ga-CM500, 2) perform safety, pharmacokinetic, and dosimetry evaluations in healthy volunteers, and 3) obtain proof of concept data that 68Ga-CM500 can detect thrombus in the deep veins and pulmonary arteries of patients with deep vein thrombosis and/or pulmonary embolism. The probe 68Ga-CM500 displays high affinity for fibrin, fast blood clearance, and high metabolic stability. In rat and rabbit models it demonstrated an excellent ability to detect thrombus with a high target-to-background ratio. The goal of this Commercialization Readiness Pilot program is to evaluate 68Ga-CM500, as a tool to noninvasively diagnose thrombosis in patients. We have already prepared a batch of solid drug substance precursor under cGMP conditions. Clearance, elimination and biodistribution have been assessed in two animal species (rat and rabbit), and a single dose toxicity study in rats was conducted under GLP conditions. Because of the microdose given with PET an abbreviated nonclinical safety package is required for an Investigational New Drug (IND) application and we have already met these requirements. This CRP program will enable us to file an IND and obtain key preliminary data in volunteers and patients with PE/DVT. Human data is crucial for attracting investment and ultimate commercialization. First, we will conduct late-stage nonclinical activities necessary for 68Ga-CM500 to be administered to humans by finalizing, assembling, and submitting an IND application. We will then assess the pharmacokinetics, distribution, and elimination of 68Ga-CM500 in healthy volunteers to establish safety, radiochemical dose, and to estimate an optimal time for thrombus imaging, followed by proof of concept studies in patients with known deep vein thrombosis and/or pulmonary embolism.

项目摘要 血栓作为一种临床实体，与其他疾病相比， 任何其他病理。大多数主要心血管疾病，包括心肌梗死、心房颤动、急性 冠状动脉综合征、中风、肺栓塞和深静脉血栓形成，要么是血栓形成的结果， 会导致血栓形成最近，发现COVID-19大流行与 凝血病，这可能有助于发展急性呼吸窘迫，甚至多器官 这些患者的失败。血栓栓塞及其血栓源的检测对正确选择患者至关重要 所有这些疾病的管理。目前，血栓通过不同的解剖成像检测 方法取决于血管区域，但所有技术都有局限性（例如，需要镇静，需要 肾毒性造影剂，不能用于某些患者）。现有的方法无法用于评估不同的 在单次多站检查中检查血栓的血管区域，而这在 血栓栓塞性疾病，如深静脉血栓形成（DVT）/肺栓塞（PE）或中风， 重要的是不仅要检测栓塞，而且要检测栓塞源。目前的方法不提供信息， 血栓的组成和纤维蛋白含量，尽管治疗策略（例如，纤维蛋白溶栓 通过正电子发射断层扫描（PET）与机械血栓切除术确定的富含血凝块的组织化纤维蛋白， 不良的慢性血栓）将受益于这些信息。 Collagen Medical正在开发一种纤维蛋白特异性分子PET探针，68 Ga-CM 500，可以识别血栓 在单次静脉注射后进行PET成像，最终，我们 寻求监管机构批准适应症“68 Ga-CM 500检测血栓”，需要证明 不同血管区域（如深静脉、肺动脉）中血栓检测的有效性， 心腔使用一个密切相关的探针，我们有很好的初步人类数据表明， 68 Ga-CM 500可以准确识别心脏内的血栓。该CRP赠款的目的是提供资金 1）提交68 Ga-CM 500的IND，2）在健康受试者中进行安全性、药代动力学和剂量测定评价 志愿者，以及3）获得68 Ga-CM 500可以检测深静脉中的血栓的概念验证数据， 深静脉血栓形成和/或肺栓塞患者的肺动脉。 探针68 Ga-CM 500显示出对纤维蛋白的高亲和力、快速血液清除和高代谢稳定性。大鼠 和兔模型，它表现出优异的检测血栓的能力，具有高的目标-背景比。 该商业化准备试点计划的目标是评估68 Ga-CM 500，作为一种工具， 非侵入性诊断患者血栓形成。我们已经制备了一批固体原料药 cGMP条件下的前体。在两只动物中评估了清除、消除和生物分布 种属（大鼠和兔），并在GLP条件下进行大鼠单次给药毒性研究。因为 在PET给予的微剂量中，研究性试验需要一个简化的非临床安全性包装。 新药（IND）申请，我们已经满足了这些要求。该CRP计划将使我们能够 提交IND并获得PE/DVT志愿者和患者的关键初步数据。人类数据对于 吸引投资并最终实现商业化。 首先，我们将进行68 Ga-CM 500用于人体所需的后期非临床活动 完成、组装和提交IND申请。我们会评估药代动力学， 在健康志愿者中测定68 Ga-CM 500的分布和消除，以确定安全性、放射化学剂量， 估计血栓成像的最佳时间，然后在已知深静脉血栓患者中进行概念验证研究。 静脉血栓形成和/或肺栓塞。

项目成果

Imaging High-Risk Atherothrombosis Using a Novel Fibrin-Binding Positron Emission Tomography Probe.

• DOI: 10.1161/strokeaha.121.035638
• 发表时间: 2022-03
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Izquierdo-Garcia D;Diyabalanage H;Ramsay IA;Rotile NJ;Mauskapf A;Choi JK;Witzel T;Humblet V;Jaffer FA;Brownell AL;Tawakol A;Catana C;Conrad MF;Caravan P;Ay I
• 通讯作者: Ay I