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

描述(申请人提供)：Marval Treateutics的创始人发明了一种用于计算机断层扫描(CT)的新型脂质体纳米颗粒造影剂，称为NCTX。在我们的第一阶段应用中，我们寻求资金支持这类试剂的一个关键开发步骤：实现足够高的碘浓度，以便能够以合理的注射量在人体内进行CT成像。在这个第二阶段的方案中，我们通过研究NCTX使用3RO程序同时成像胸部血管系统(右心/肺、左心/主动脉和冠状动脉血管)的所有区域的能力，寻求将NCTX平台快速转化为临床使用。首先，我们将在一个大型动物模型(绵羊)中比较NCTX(相对于传统造影剂)对胸部血管成像的能力。其次，我们将获得证明NCTX在人类身上使用的合理性所需的关键药代动力学(PK)和毒性数据。虽然NCTX中使用的脂质体的器官分布是众所周知的，但我们与有兴趣为第三阶段提供资金的风险投资组织的对话表明，在他们提供第三阶段资金之前，这些是所需的两个关键信息。这一第二阶段应用的具体目的是：1.NCTX检测：比较常规增强CT和NCTX对(1)导管置入的肺血栓和(2)人工冠状动脉狭窄的检测。具体地说，将调查每种方法所需的对比剂剂量和X射线剂量。这些制剂的器官分布将通过CT成像进行测量。2.初步毒性测试：向FDA提交NCTX的IND(研究新药)申请将需要在一个小动物和一个大动物模型上进行毒性和PK测试。老鼠和狗通常被推荐进行这样的测试。在这项研究中，我们将研究其在小鼠身上的毒性。将研究NCTX的消除途径、肾毒性和肝脏毒性，并与传统造影剂进行比较。Marval Treateutics的创始人发明了一种用于计算机断层扫描(CT)的新型脂质体纳米颗粒造影剂，称为NCTX。在我们的第一阶段应用中，我们寻求资金支持这类试剂的一个关键开发步骤：实现足够高的碘浓度，以便能够以合理的注射量在人体内进行CT成像。在成功实现这一技术进步之后，我们一直致力于NCTX临床应用的开发，这是第一阶段应用的唯一具体目标。虽然确定了几个具有临床意义的应用，但我们专注于一个特别引人注目的适应症，目前的成像技术没有有效地解决这个问题：急性胸痛--仅在美国，每年就有500-800万患者出现在急诊室(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：肺血栓(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)。这三个实体的诊断(或排除)很复杂，经常需要入院和高侵入性测试；然而，最近有人提出，这三个实体可以使用最新一代超高速层析多层螺旋CT扫描仪在急诊室进行非侵入性诊断。即使使用最新的扫描仪技术，这一“三重排除”(3RO)程序目前也很难执行，因为需要在增强峰值期间准确地成像肺、冠状动脉和主动脉循环。3RO是临床医生和扫描仪制造商广泛研究的主题。在这个第二阶段的方案中，我们通过研究NCTX使用3RO程序同时成像胸部血管系统(右心/肺、左心/主动脉和冠状动脉血管)的所有区域的能力，寻求将NCTX平台快速转化为临床使用。首先，我们将在一个大型动物模型(绵羊)中比较NCTX(相对于传统造影剂)对胸部血管成像的能力。其次，我们将获得证明NCTX在人类身上使用的合理性所需的关键药代动力学(PK)和毒性数据。虽然NCTX中使用的脂质体的器官分布是众所周知的，但我们与有兴趣为第三阶段提供资金的风险投资组织的对话表明，在他们提供第三阶段资金之前，这些是所需的两个关键信息。

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.