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

NCTX，一种用于血池成像的新型脂质体 CT 造影剂

• 批准号: 7324954
• 负责人: RUSSELL M LEBOVITZ
• 金额: $ 35.39万
• 依托单位: MARVAL BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7324954
• 关键词: Accident and Emergency department; Acute; Address; Admission activity; Alteplase; Animal Model; Animals; Aorta; Area; Blood; Blood Circulation; Bolus Infusion; Canis familiaris; Capital; Catheters; Chest; Chest Pain; Class; Clinical; Complex; Condition; Contrast Media; Coronary; Coronary Stenosis; Data; Detection; Development; Diagnosis; Dissecting Aneurysm; Dissecting aortic aneurysm; Dose; Drug Kinetics; Embolism; Encapsulated; Exclusion; Funding; Gadolinium DTPA; Gadopentetate Dimeglumine; Generations; Heart; Hepatic; Hospitals; Human; Image; Imagery; Imaging technology; Incidence; Injection of therapeutic agent; Invasive; Investigational Drugs; Investigational New Drug Application; Iodine; Kidney; Left; Life; Liposomes; Lung; Magnetic Resonance Imaging; Manufacturer Name; Measures; Methods; Modeling; Monitor; Mus; Myocardial Infarction; Numbers; Organ; Oryctolagus cuniculus; Paper; Parents; Patients; Personal Satisfaction; Phase; Procedures; Publishing; Pulmonary Embolism; Pulmonary artery structure; Purpose; Rattus; Relative (related person); Research; Risk; Rodent; Roentgen Rays; Route; Scanning; Sheep; Signal Transduction; Slice; Spinal; Technology; Testing; Therapeutic; Tomography, Computed, Scanners; Toxic effect; Toxicity Tests; Translational Research; Translations; United States Food and Drug Administration; Venous; X-Ray Computed Tomography; base; clinical application; clinically significant; detector; heart circulation; interest; lung imaging; nanoparticle; novel; residence; success

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.

描述（由申请人提供）：Marval Therapeutics 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。在我们的一期申请中，我们寻求资金来支持此类药物的关键开发步骤：达到足够高的碘浓度，以便通过合理的注射量对人体进行 CT 成像。在此第 2 阶段提案中，我们通过研究 NCTX 使用 3RO 程序同时对胸部脉管系统所有区域（右心/肺、左心/主动脉和冠状脉管系统）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）中对胸部血管系统进行成像的能力。其次，我们将获得证明 NCTX 在人体中使用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已广为人知，但我们与有兴趣为第 3 阶段提供资金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。该第 2 阶段应用的具体目标是： 1. NCTX 测试检测：比较传统增强 CT 和 NCTX 对 (1) 导管放置的肺栓塞和 (2) 人工冠状动脉狭窄的检测。具体来说，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 成像测量药物的器官分布。 2. 初步毒性测试：向 FDA 提交 NCTX IND（研究性新药）申请需要在一种小动物和一种大型动物模型中进行毒性和 PK 测试。通常建议使用小鼠和狗进行此类测试。在这项研究中，我们将研究小鼠的毒性。将研究NCTX剂的消除途径、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。在我们的一期申请中，我们寻求资金来支持此类药物的关键开发步骤：达到足够高的碘浓度，以便通过合理的注射量对人体进行 CT 成像。在成功实现这一技术进步（第一阶段应用的唯一具体目标）之后，我们进行了转化研究，重点是开发 NCTX 的临床应用。虽然已经确定了几种具有临床意义的应用，但我们重点关注当前成像技术无法有效解决的一个特别引人注目的适应症：急性胸痛——仅在美国，每年就有 5-800 万名患者到急诊室 (ER) 就诊。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）、冠状动脉供血不足引起的心肌梗死（MI）和主动脉夹层动脉瘤（AD）。这三种疾病的诊断（或排除）很复杂，经常需要入院并进行高侵入性检测；然而，最近有人提出，可以使用最新一代超快 64 层多探测器 CT 扫描仪在急诊室中对这 3 个实体进行非侵入性诊断。即使采用最新的扫描仪技术，这种“三重排除”(3RO) 程序目前也很难执行，因为需要在峰值增强期间准确地对肺、冠状动脉和主动脉循环进行成像。 3RO 是临床医生和扫描仪制造商广泛研究的主题。在此第 2 阶段提案中，我们通过研究 NCTX 使用 3RO 程序同时对胸部脉管系统所有区域（右心/肺、左心/主动脉和冠状脉管系统）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）中对胸部血管系统进行成像的能力。其次，我们将获得证明 NCTX 在人体中使用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已广为人知，但我们与有兴趣为第 3 阶段提供资金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。