Molecular Imaging Agent to Detect Thrombus

项目摘要 血栓作为一种临床实体，与以下疾病相比，造成的死亡人数和发病率最高 是否有其他病理改变。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 会导致血栓形成。最近，新冠肺炎大流行被发现与增加的 凝血障碍，可能导致急性呼吸窘迫，甚至多器官 这些患者都失败了。血栓栓子及其来源血栓的检测对正确的患者至关重要 对所有这些疾病的管理。目前，血栓是通过不同的解剖成像来检测的 方法取决于血管范围，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 在一次多站检查中发现血栓的血管范围，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子，还要检测栓子的来源。目前的方法不会通知 血栓的组成和纤维蛋白含量，尽管治疗策略(例如，纤维蛋白的溶栓 通过正电子发射断层扫描(PET)识别丰富的凝块，与机械血栓切除术相比，有组织的，纤维蛋白... 贫穷、慢性血栓)将从这些信息中受益。 胶原医学公司正在开发一种可识别血栓的纤维蛋白特异性分子PET探针68Ga-CM500 在一次静脉注射后进行PET成像后，可以在身体的任何地方进行检查。最终，我们是 寻求监管机构批准“68Ga-CM500检测到血栓”的指示，这需要证明 不同血管区域血栓检测的有效性，如深静脉、肺动脉和 心房室。使用一个密切相关的探测器，我们有很好的初步人类数据表明 68Ga-CM500能准确识别心脏血栓。这笔奖助金的目的是提供资金 1)提交68Ga-CM500的IND，2)在健康人群中进行安全性、药代动力学和剂量学评估 志愿者，以及3)获得概念证明数据，68Ga-CM500可以检测深静脉血栓和 深静脉血栓形成和/或肺栓塞患者的肺动脉。 68Ga-CM500探针对纤维蛋白亲和力高，血液清除快，代谢稳定性高。在大鼠中 在兔模型中，它表现出了很好的检测血栓的能力，具有很高的目标背景比。 此商业化准备试点计划的目标是评估68Ga-CM500作为一种工具 无创性地诊断患者的血栓形成。我们已经制备了一批固体药材 CGMP条件下的前体。清除性、排除性和生物分布在两种动物身上进行了评估 物种(大鼠和兔)，在GLP条件下进行大鼠单次给药毒性研究。因为 在PET给予的微量剂量中，需要一种简化的非临床安全包来进行研究 新药(IND)申请，我们已经满足了这些要求。此CRP计划将使我们能够 提交IND并获得志愿者和PE/DVT患者的关键初步数据。人类数据对于 招商引资和最终商业化。 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。然后我们将评估药物动力学， 68Ga-CM500在健康志愿者体内的分布和消除，以建立安全性、放射化学剂量和 评估血栓成像的最佳时间，然后对已知的深静脉血栓患者进行概念性研究 静脉血栓形成和/或肺栓塞。

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.