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.

项目概要 与其他疾病相比，血栓作为一种临床实体导致最多的死亡和最高的发病率。 大多数主要心血管疾病，包括心肌梗塞、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，要么是 最近发现，大流行的 COVID-19 与血栓增加有关。 凝血障碍，可能导致急性呼吸窘迫甚至多器官衰竭的发生 检测这些患者的血栓栓塞及其来源血栓对于正确的患者至关重要。 目前，血栓是通过不同的解剖成像来检测的。 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 肾毒性对比剂，不能用于某些患者）。没有现有的方法可以用来评估不同的情况。 在一次多站检查中检查血栓的血管区域，而这在以下情况中非常有价值： 血栓栓塞性疾病，如深静脉血栓 (DVT)/肺栓塞 (PE) 或中风 重要的是，不仅检测栓子，而且还检测栓子来源，目前的方法无法提供信息。 血栓的成分和纤维蛋白含量，尽管治疗策略（例如，溶栓治疗纤维蛋白） 通过正电子发射断层扫描 (PET) 识别丰富的血块与机械血栓切除术比较，获得有组织的纤维蛋白 不良的慢性血栓）将从此类信息中受益。 Collagen Medical正在开发一种纤维蛋白特异性分子PET探针68Ga-CM500，可以识别血栓 通过单次静脉注射，然后进行 PET 成像，我们最终可以对身体的任何部位进行检测。 寻求监管部门批准“68Ga-CM500 检测血栓”适应症，该适应症需要证明 不同血管区域（例如深静脉、肺动脉和动脉）血栓检测的功效 使用密切相关的探头，我们有很好的初步人体数据表明 68Ga-CM500 可以准确识别心脏中的血栓 本次 CRP 资助的目的是提供资金。 1) 提交 68Ga-CM500 的 IND，2) 在健康人群中进行安全性、药代动力学和剂量测定评估 志愿者，以及 3) 获得了 68Ga-CM500 可以检测深静脉血栓的概念验证数据， 患有深静脉血栓和/或肺栓塞的患者的肺动脉。 探针 68Ga-CM500 在大鼠中表现出对纤维蛋白的高亲和力、快速的血液清除和高代谢稳定性。 和兔子模型中，它表现出了出色的检测血栓的能力，具有高目标背景比。 该商业化准备试点计划的目标是评估 68Ga-CM500，将其作为一种工具 我们已经制备了一批固体原料药。 已在两只动物中评估了 cGMP 条件下的清除、消除和生物分布。 种（大鼠和兔子），并在 GLP 条件下对大鼠进行了单剂量毒性研究。 PET 给予的微剂量的研究需要一个简短的非临床安全包 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 并获取志愿者和 PE/DVT 患者的关键初步数据 对于人体数据至关重要。 吸引投资并最终商业化。 首先，我们将进行68Ga-CM500用于人体所需的后期非临床活动 通过最终确定、组装和提交 IND 申请，我们将评估药代动力学， 68Ga-CM500 在健康志愿者中的分布和消除，以确定安全性、放射化学剂量，并 估计血栓成像的最佳时间，然后对已知深部血栓的患者进行概念验证研究 静脉血栓和/或肺栓塞。

项目成果

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

使用新型纤维蛋白结合正电子发射断层扫描探针对高风险动脉粥样硬化血栓形成进行成像。

• 发表时间: 2022-02
• 影响因子: 8.3
• 作者: Izquierdo;Diyabalanage, Himashinie;Ramsay, Ian A;Rotile, Nicholas J;Mauskapf, Adam;Choi, Ji;Witzel, Thomas;Humblet, Valerie;Jaffer, Farouc A;Brownell, Anna;Tawakol, Ahmed;Catana, Ciprian;Conrad, Mark F;Caravan, Peter
• 通讯作者: Caravan, Peter