Innovative Voltage-Activated Ultrasound Imaging Agent for Selective Myocardial Enhancement

用于选择性心肌增强的创新电压激活超声成像剂

• 批准号: 10256398
• 负责人: Michael Cimorelli
• 金额: $ 83.37万
• 依托单位: SONNEST, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256398
• 关键词: Accident and Emergency department; Acoustics; Affect; American; Animals; Blood; Blood Circulation; Capital; Cardiac; Cause of Death; Cessation of life; Charge; Chest Pain; Clinic; Clinical Research; Contracts; Coronary Angiography; Coronary heart disease; Data; Development; Diagnosis; Diagnostic; Dose; Echocardiography; Equipment; Exposure to; Family suidae; Fluorocarbons; Formulation; Funding; Gases; Goals; Grant; Heart; Heart Diseases; Image; Imaging Techniques; Investigational Drugs; Investigational New Drug Application; Ionizing radiation; Ions; Liposomes; Liquid substance; Magnetic Resonance Imaging; Monitor; Myocardial; Myocardial Infarction; Myocardial perfusion; Myocardial tissue; Myocardium; Nuclear; Office Visits; Outcome; Particle Size; Patient Care; Patient Monitoring; Patients; Perfusion; Persons; Phase; Phase Transition; Phospholipids; Privatization; Production; Rattus; Risk; Rodent; Running; S Phase; Secure; Shortness of Breath; Signal Transduction; Small Business Innovation Research Grant; Sonication; Specific qualifier value; Sterility; Stream; Structure; Technology; Testing; Time; Toxic effect; Triage; Ultrasonography; United States; Validation; Venous; Water; Work; aqueous; base; blind; clinical investigation; clinically relevant; cost; design; electric field; experience; heart electrical activity; imaging agent; imaging modality; imaging study; improved; innovation; intravenous administration; manufacturing facility; point of care; pre-clinical; preclinical safety; preclinical toxicity; scale up; soft drink; standard of care; success; time use; verification and validation; voltage

ABSTRACT Significance: Heart disease is the leading cause of death in the United States and coronary heart disease (CHD), which impacts approximately 18M Americans, is the most common form of heart disease. CHD can cause chest pain and shortness of breath, increases the likelihood a person will experience a myocardial infarction and accounts for 1 of every 7 deaths in the United States. The Problem: It is challenging to visualize myocardial perfusion without expensive centralized equipment, exposure to ionizing radiation and/or invasive coronary angiography. The Solution: A voltage- activated ultrasound imaging agent call Electrast™ that can transform the way cardiologists diagnose and monitor CHD. Unlike other ultrasound enhancement agents, Electrast™ is in an inactive state as it circulates through the bloodstream and is selectively activated in viable, perfused myocardium by the electrical depolarization wave that makes the heart beat, allowing clinicians to assess the microperfusion of the heart at the bedside in real time without the need for ionizing radiation. Preliminary Data: Proof-of-principle validation data demonstrating that Electrast™ can selectively enhance myocardial tissue has been generated in small (rodent) and large (swine) animal studies. Specific Aims: This project will support the scale-up and cGMP manufacturing work necessary to produce sterile Electrast™ for the preclinical safety, toxicity and verification and validation testing required to secure approval of a Phase I Investigational New Drug (IND) application for Electrast™ from the FDA. In Specific Aim 1 the team will validate in swine that Electrast™ provides selective enhancement of viable, perfused myocardium using core perfluorocarbon droplets synthesized by microfluidization in place of sonication and comprised in part or in full of C4F10 in place of pure C5F12. In Specific Aim 2 will support transfer of manufacturing to a current good manufacturing practices (cGMP)-certified contract organization for scale-up and production of a 10 L lot of sterile Electrast™ that meets specified product release criteria for particle size, concentration, and stability. Finally, in Specific Aim 3 Sonnest will confirm, via internal and third-party testing, that Electrast™ meets the company’s product specification and release criteria and FDA pre-clinical safety and toxicity requirements for approval of a Phase I IND application. Expected Outcomes: At the end of this Direct to Phase II SBIR Grant, Sonnest will have validated cGMP manufacturing to make Electrast™ at scale, robust preclinical safety and toxicity data, and an approved IND for the Phase I clinical investigation of Electrast™. .

摘要 意义：心脏病是美国人的主要死因，冠心病 心脏病(CHD)是最常见的心脏疾病，影响着大约1800万美国人 疾病。冠心病会导致胸痛和呼吸急促，增加患者患上心脏病的可能性。 经历过心肌梗塞，在美国每7人中就有1人死于心肌梗塞。这个 问题：在没有昂贵的中央设备的情况下，可视化心肌灌注是具有挑战性的， 暴露于电离辐射和/或有创冠状动脉造影术。解决方案：一种电压- 激活的超声成像剂Call Electrast™可以改变心脏病医生的诊断方式 并监测冠心病。与其他超声增强剂不同，Electrast™处于非活性状态，因为 它在血液中循环，并在存活的、灌流的心肌中被选择性地激活 使心脏跳动的电除极波，使临床医生能够评估 在床边实时进行心脏微灌流，无需电离辐射。 初步数据：原则验证数据表明ELECTAST™可以有选择地 在小型(啮齿动物)和大型(猪)动物研究中已经产生了增强的心肌组织。 具体目标：该项目将支持必要的扩大和cGMP制造工作 生产用于临床前安全性、毒性和验证验证测试的无菌ELESTEST™ 需要确保ELESTEST™的第一阶段研究新药(IND)申请获得批准 来自食品和药物管理局。在特定的目标1中，研究小组将在猪身上验证Electrast™提供的选择性 用合成的核心全氟碳微滴增强存活的灌流心肌 代替超声波的微流态化，由部分或全部取代纯C5F12的C4F10组成。 在具体目标2中，将支持将制造转移到当前良好的制造实践 L无菌电工™10批次规模化生产合同组织 符合规定的产品释放标准的颗粒大小、浓度和稳定性。最后，在 Sonnest将通过内部和第三方测试确认Electrast™符合 公司的产品规格和发布标准以及FDA临床前的安全性和毒性 批准第一阶段IND申请的要求。预期结果：在此结束时 直接到第二阶段SBIR拨款，桑内斯特将验证cGMP制造，以制造电子™ 在规模上，强大的临床前安全性和毒性数据，以及I期临床批准的IND 电铸™的研究。 。