NCTX, a novel liposomal CT contrast agent for blood pool imaging

描述（由申请人提供）：Marval Therapeutics的创始人发明了一类新的用于计算机断层扫描（CT）的脂质体纳米颗粒造影剂，称为NCTX。在我们的第一阶段申请中，我们寻求资金支持这类药物的关键开发步骤：达到足够高的碘浓度，以便在合理的注射量下实现人体CT成像。在本II期提案中，我们通过研究NCTX使用3RO程序同时对胸部血管系统（右心/肺、左心/主动脉和冠状动脉血管系统）的所有区域进行成像的能力，寻求将NCTX平台快速转化为临床使用。首先，我们将比较NCTX（相对于传统造影剂）在大型动物模型（绵羊）中对胸部血管系统成像的能力。其次，我们将获得证明NCTX在人体中使用的关键药代动力学（PK）和毒性数据。虽然NCTX中使用的脂质体的器官分布已经很好地理解，但我们与有兴趣资助第3阶段的风险投资组织的对话表明，这些是他们提供第3阶段资金之前所需的2个关键信息。第二阶段申请的具体目的是：1。NCTX检测：比较常规增强CT和NCTX对（1）导管置入肺栓塞和（2）人工冠状动脉狭窄的检测。具体而言，将研究每种方法所需的造影剂剂量和X射线剂量。将通过CT成像测量药剂的器官分布。2.初步毒性试验：向FDA提交NCTX的IND（研究性新药）申请将需要在一只小动物和一只大动物模型中进行毒性和PK测试。小鼠和狗通常被推荐用于此类测试。在本研究中，我们将研究小鼠的毒性。将研究NCTX药物的消除途径、肾毒性和肝毒性，并与常规造影剂进行比较。Marval Therapeutics的创始人发明了一类新的用于计算机断层扫描（CT）的脂质体纳米颗粒造影剂，称为NCTX。在我们的第一阶段申请中，我们寻求资金支持这类药物的关键开发步骤：达到足够高的碘浓度，以便在合理的注射量下实现人体CT成像。在成功实现这一技术进步（1期申请的唯一具体目标）后，我们进行了转化研究，重点是开发NCTX的临床应用。虽然确定了几个临床上重要的应用，但我们专注于一个特别引人注目的适应症，目前的成像技术无法有效解决：急性胸痛-仅在美国，每年就有500 - 800万患者前往急诊室（ER）。从临床角度来看，急性胸痛有三种不同的危及生命的原因：肺栓塞（PE）、冠状动脉功能不全（MI）引起的心肌梗死和夹层主动脉瘤（AD）。这三种实体的诊断（或排除）是复杂的，并且经常需要入院和高侵入性测试;然而，最近已经提出，可以使用最新一代的超快、64层多探测器CT扫描仪在ER中非侵入性地诊断这三种实体。即使使用最新的扫描仪技术，由于需要在峰值增强期间准确地对肺循环、冠状动脉循环和主动脉循环成像，这种"三重排除"（3RO）程序目前也很难执行。3RO是临床医生和扫描仪制造商广泛研究的主题。在本II期提案中，我们通过研究NCTX使用3RO程序同时对胸部血管系统（右心/肺、左心/主动脉和冠状动脉血管系统）的所有区域进行成像的能力，寻求将NCTX平台快速转化为临床使用。首先，我们将比较NCTX（相对于传统造影剂）在大型动物模型（绵羊）中对胸部血管系统成像的能力。其次，我们将获得证明NCTX在人体中使用的关键药代动力学（PK）和毒性数据。虽然NCTX中使用的脂质体的器官分布已经很好地理解，但我们与有兴趣资助第3阶段的风险投资组织的对话表明，这些是他们提供第3阶段资金之前所需的2个关键信息。

DESCRIPTION (provided by applicant): The founders of Marval Therapeutics have invented a new class of liposomal nanoparticle contrast agents for Computed Tomography (CT), referred to as NCTX. In our Phase 1 application, we sought funding to support a key development step for this class of agents: to achieve a sufficiently high iodine concentration for the purpose of enabling CT imaging in humans with reasonable injection volumes. In this Phase 2 proposal, we seek rapid translation to clinical use of the NCTX platform by studying the ability of NCTX to simultaneously image all regions of the thoracic vasculature (right heart/pulmonary, left heart/aorta and coronary vasculature) using the 3RO procedure. First, we will compare the ability of NCTX (relative to conventional contrast agents) to image thoracic vasculature in a large animal model (sheep). Second, we will acquire key pharmacokinetics (PK) and toxicity data required to justify the use of NCTX in humans. While the organ distribution of the liposomes used in NCTX is well understood, our conversations with Venture Capital organizations interested in funding Phase 3 have indicated that these are the 2 key pieces of information required before they would provide Phase 3 funding. The Specific Aims of this Phase 2 application are: 1. Test Detection by NCTX: To compare the detection of (1) catheter-placed pulmonary emboli and (2) artificial coronary artery stenoses by conventional contrast-enhanced CT and NCTX. Specifically, the number of contrast doses and the X-ray dose required for each method will be investigated. Organ distribution of the agents will be measured by CT imaging. 2. Preliminary Toxicity Testing: The filing of an IND (Investigational New Drug) application with the FDA for NCTX will require toxicity and PK testing in one small animal and one large animal model. Mice and Dogs are usually recommended for such testing. In this study, we will study the toxicity in mice. The elimination route, renal toxicity, and hepatic toxicity of the NCTX agent will be studied, and compared to that of conventional contrast agent. The founders of Marval Therapeutics have invented a new class of liposomal nanoparticle contrast agents for Computed Tomography (CT), referred to as NCTX. In our Phase 1 application, we sought funding to support a key development step for this class of agents: to achieve a sufficiently high iodine concentration for the purpose of enabling CT imaging in humans with reasonable injection volumes. Subsequent to successful realization of this technical advance, the sole Specific Aim of the Phase 1 application, we have pursued translational research focused on development of clinical applications for the use of NCTX. While several clinically significant applications were identified, we focused on one particularly compelling indication that is not effectively addressed by current imaging technology: acute chest pain -- a condition that causes 5-8 million patients to present to Emergency Rooms (ER's) every year in the US alone. From a clinical perspective, there are three distinct, life-threatening causes of acute chest pain: pulmonary embolus (PE), myocardial infarction due to coronary insufficiency (MI) and dissecting aortic aneurysm (AD). The diagnosis (or exclusion) of these three entities is complex and frequently requires admission to the hospital and highly invasive testing; however, it has recently been proposed that these 3 entities can be diagnosed non-invasively in the ER using the latest generation of ultrafast, 64-slice multi- detector CT scanners. Even with the latest scanner technology, this "triple rule-out" (3RO) procedure is currently very difficult to perform due to the need to accurately image the pulmonary, coronary and aortic circulations, during peak enhancement. The 3RO is the subject of extensive research by both clinicians and scanner manufacturers. In this Phase 2 proposal, we seek rapid translation to clinical use of the NCTX platform by studying the ability of NCTX to simultaneously image all regions of the thoracic vasculature (right heart/pulmonary, left heart/aorta and coronary vasculature) using the 3RO procedure. First, we will compare the ability of NCTX (relative to conventional contrast agents) to image thoracic vasculature in a large animal model (sheep). Second, we will acquire key pharmacokinetics (PK) and toxicity data required to justify the use of NCTX in humans. While the organ distribution of the liposomes used in NCTX is well understood, our conversations with Venture Capital organizations interested in funding Phase 3 have indicated that these are the 2 key pieces of information required before they would provide Phase 3 funding.