Development of New Improved Perflutren Ultrasound Contrast Agent

新型改良Perflutren超声造影剂的研制

基本信息

批准号：
9409654
负责人：
THOMAS R PORTER
金额：
$ 122.94万
依托单位：
MICROVASCULAR THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-17 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9409654
关键词：
Acids Adverse effects Adverse event Animals Back Pain Blinded Bolus Infusion Charge Clinical Complement Complement Activation Cone Contrast Media Definity Development Dose Echocardiography Electrostatics Etiology Excipients FDA approved Family suidae Formulation Generic Drugs Goals Hydrolysis Image Imagery Inflammation Infusion procedures Intravenous infusion procedures Ionizing radiation Kidney Label Lead Legal patent Life Lipids Mediating Membrane Microbubbles Modeling Myocardial perfusion Optison Outcomes Research Palmitic Acids Pathway interactions Patients Phospholipids Preparation Production Program Development Research Personnel Resistance Safety Sickle Cell Anemia Sterilization Temperature Therapeutic Time Translating Ultrasonography clinical development cost imaging study improved meetings molecular imaging perfusion imaging portability programs research and development targeted imaging theranostics volunteer

项目摘要

Three ultrasound contrast agents (Definity®, Optison® and Lumason®) are FDA approved for echocardiography in the U.S. Definity currently has over 75% market share. Definity’s dominance in the market is due to its ease of administration via IV infusion and robust ultrasound contrast. Definity® has shelf-life of 2 years and must be stored under refrigerated conditions. Definity has an unpleasant side effect of back pain in about 2% of patients. In some groups, e.g. patients with sickle cell disease, the rate of side effects is much higher, e.g. about 20%. The most likely etiology of the back pain is complement activation. Definity is stabilized by three phospholipids one of which is dipalmitoylphosphatidic acid (DPPA). The investigators in this proposal have shown that DPPA shortens the storage life of Definity and likely causes the side effect of the back pain. Microvascular Therapeutics (MVT) has discovered that not only is DPPA the most rapidly hydrolyzed lipid in the Definity formulation but that DPPA also accelerates the hydrolysis of the other lipids. When DPPA hydrolyzes it forms lyso-PA - a potent stimulating molecule causing inflammation likely responsible for the adverse side effects. MVT has invented a stable, neutral MB (MVT-100). Compared to Definity, MVT-100 is four times more resistant to hydrolysis. In a model of complement-mediated renal retention MVT-100 had fewer bioeffects than Definity – which should translate into significantly less adverse events. Echocardiography in pigs shows that MVT-100 is comparable, if not superior to Definity, in providing LV opacification and myocardial perfusion contrast. MVT has received guidance from the FDA that MVT-100 can be developed via the 505(b)(2) pathway, no additional animal studies are required;; an accelerated clinical program can be used to lead to approval. MVT-100 will serve as a platform for development of theranostics. Specific Aims: 1. GMP manufacture MVT-100, file IND. 2. Dose ranging study in 32 volunteers (bolus and infusion, Definity vs MVT-100)3. Pivotal study in 61 patients with suboptimal echocardiograms;; significant improvement in LV border delineation in > 85% of subjects. 4. File NDA Rationale: MVT-100 is an improved product. Perfluoropropane is the API and the lipids are excipients in the product. The 505(b)(2) pathway allows for an accelerated approval pathway for such products. Upon NDA submission, typical 11-month review period by the FDA before approval. The development pathway will yield identical label claims as those for Definity. Additional label claims can be pursued later or in parallel. Expected outcomes of research: Development of an FDA approved improved perflutren product, MVT-100 with longer shelf-life (potential for room temperature storage and terminal sterilization – increasing safety of the product) and decreased adverse side effects. Since the product is electrostatically neutral, MVT-100 will also serve as a robust platform for development of molecular imaging targeted ultrasound contrast agents and theranostic agents.

三种超声造影剂（Definity®、Optison® 和 Lumason®）经 FDA 批准用于 Definity 目前在美国超声心动图市场占有超过 75% 的市场份额。这是因为它易于通过静脉输注给药，并且 Definity® 的保质期为 2。且必须在冷藏条件下保存，Definity 会产生令人不快的副作用，如背痛。在某些群体中，例如患有镰状细胞病的患者，大约有 2% 的患者出现副作用。较高，例如，背痛最可能的病因是补体激活。由三种磷脂组成，其中之一是二棕榈酰磷脂酸（DPPA）。研究表明，DPPA 会缩短 Definity 的保存期限，并可能导致背痛的副作用。微血管治疗 (MVT) 发现 DPPA 不仅是体内水解速度最快的脂质 Definity 配方，但 DPPA 也会加速其他脂质的水解。水解形成 lyso-PA - 一种强效刺激分子，引起炎症，可能是导致 MVT发明了一种稳定、中性的MB（MVT-100），与Definity相比，MVT-100是一种稳定的、中性的MB。在补体介导的肾潴留模型中，MVT-100 的水解抵抗力要高出四倍。与 Definity 相比，其生物效应应转化为显着更少的不良事件。猪表明 MVT-100 在提供 LV 混浊度和 MVT已获得FDA指导可以开发MVT-100。通过 505(b)(2) 途径，无需进行额外的动物研究；；加速临床计划。 MVT-100 将作为治疗诊断学的开发平台。具体目标： 1. GMP 生产 MVT-100，文件 IND. 2. 32 名志愿者的剂量范围研究（推注和注射）输注，Definity 与 MVT-100）3. 对 61 名超声心动图不佳的患者进行的关键研究； > 85% 的受试者左室边界轮廓得到改善 4. 提交 NDA。理由： MVT-100 是一种改进产品，API 为全氟丙烷，脂质为赋形剂。 505(b)(2) 途径允许加速此类产品的批准途径。提交，FDA 批准前通常需要 11 个月的审查期。标签声明与 Definity 的标签声明相同。可以稍后或同时提出其他标签声明。研究预期成果：开发 FDA 批准的改良 perflutren 产品 MVT-100 具有更长的保质期（室温储存和最终灭菌的潜力 - 提高产品的安全性产品）并减少不良副作用。由于该产品是静电中性的，MVT-100 还将作为开发分子成像靶向超声造影剂的强大平台和治疗诊断剂。