Research Project
10158327
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.
