Manganese-based Contrast Agent for Cardiovascular MRI

用于心血管 MRI 的锰基造影剂

• 批准号: 10699412
• 负责人: Vera Hoffman
• 金额: $ 102.66万
• 依托单位: REVEAL PHARMA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699412
• 关键词: Acute; Acute myocardial infarction; Address; Adult; Adverse event; Angiography; Animal Model; Animals; Brain; Breast; Cardiac; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Catheterization; Cessation of life; Cholesterol; Chronic; Chronic Kidney Failure; Cicatrix; Clinic; Clinical Protocols; Clinical Trials; Contrast Media; Deposition; Detection; Diabetes Mellitus; Diagnostic; Diet; Diffuse; Dose; Drug Kinetics; EFRAC; Europe; Extracellular Fluid; FDA approved; Face; Family suidae; Farm; Fatty acid glycerol esters; Fibrosis; Fructose; Funding; Gadolinium; General Population; Goals; Heart Diseases; Heart failure; Hepatobiliary; Human; Image; Impairment; Infarction; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Left; Life; Link; MRI Scans; Magnetic Resonance Imaging; Manganese; Marketing; Measures; Mineralocorticoids; Miniature Swine; Modeling; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; National Heart, Lung, and Blood Institute; Nephrogenic Systemic Fibrosis; Obesity; Output; Patients; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Placebos; Play; Population; Prevalence; Procedures; Radiology Specialty; Rattus; Reperfusion Therapy; Risk; Rodent; Safety; Scanning; Small Business Innovation Research Grant; Sodium Chloride; Toxicokinetics; Toxicology; Treatment Efficacy; United States; United States National Institutes of Health; Ventricular; Work; X-Ray Computed Tomography; aging population; bone; cardiac magnetic resonance imaging; chelation; comorbidity; contrast enhanced; coronary artery occlusion; coronary fibrosis; design; disease diagnosis; experimental study; extracellular; heart imaging; high risk; imaging properties; imaging study; improved; insight; kidney dysfunction; manufacture; patient population; porcine model; preservation; prognostic value; rational design; treatment planning

ABSTRACT Cardiovascular disease is the leading cause of morbidity and death, representing 1 in 3 deaths in the United States, and 18.6 million deaths globally annually. Contrast enhanced magnetic resonance imaging (MRI) and computed tomography (CT) play a key role in managing heart disease by enabling non-invasive assessment of myocardial perfusion, infarction, and viability. Cardiac imaging is the fastest growing segment of the MRI market, with recent landmark trials such as MR-INFORM demonstrating equivalence of contrast enhanced MRI to life saving invasive catheterization procedures, and SCD-HeFT demonstrating prognostic value in predicting cardiovascular adverse events. Unfortunately, both iodinated CT radiocontrast and gadolinium-based MRI contrast agents pose safety risks to patients with renal impairment. Iodinated contrast media can cause acute and irreversible kidney injury to renally impaired patients. Gadolinium-based contrast agents (GBCAs) can trigger nephrogenic systemic fibrosis (NSF) in renally impaired patients and all deposit Gd in brain and bone. Cardiac and renal output are inextricably linked and chronic kidney disease (CKD) patients suffer cardiovascular co- morbidities at a rate disproportionately high compared to the general population (~25% of ischemic heart disease population). When imaging heart disease patients with CKD, clinicians must choose between limited radiologic information or placing the patient at higher risk for complications by using a GBCA. Reveal Pharmaceuticals is addressing this challenge by developing RVP-001, a gadolinium-free extracellular fluid MRI contrast agent. RVP-001 is a stable manganese chelate with relaxivity and pharmacokinetics similar to GBCAs resulting in equivalent imaging properties. RVP-001 recently completed the in clinic portion of an NIH- funded Phase 1 clinical trial (NCT05413668). Our ultimate goal is to develop RVP-001 for multiple indications (CNS, cardiac, angiography, breast) for both renally impaired subjects and the general patient population. The objective of this Phase II SBIR proposal is to perform non-clinical imaging and late phase enabling toxicology experiments in support of a cardiac indication. This work builds upon our recently completed NHLBI- funded Phase I project (R43HL156713), which demonstrated that RVP-001 is diagnostically equivalent to GBCA to characterize acute myocardial infarction (MI) in pigs. Here, we will evaluate RVP-001 in the contexts of chronic myocardial infarction and diffuse myocardial fibrosis that recapitulate human heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), respectively. We posit that an equal dose of RVP-001 will perform similarly to GBCA given at the indicated dose, that superior cardiac imaging can be achieved through a larger dose of RVP-001, and that regulatory bodies would be receptive to a RVP-001 dose indication that is larger than GBCAs. The late phase enabling component comprises cGLP repeat dose toxicology and toxicokinetics in rats.

抽象的 心血管疾病是发病率和死亡的主要原因，统一死亡分为三分之一 各州，每年有1,860万人死亡。对比增强的磁共振成像（MRI）和 计算机断层扫描（CT）通过非侵入性评估来控制心脏病 心肌灌注，梗塞和生存能力。心脏成像是MRI市场增长最快的部分， 随着MR-inform等最近的具有里程碑意义的试验，表明对比度的等效性增强了MRI对寿命 保存侵入性导管程序，SCD-HEFT在预测中证明了预后价值 心血管不良事件。不幸的是，碘化的CT放射性对比和基于Gadolinium的MRI 对比剂对肾脏损伤患者构成安全风险。碘化对比介质会引起急性 以及对肾脏受损患者的不可逆肾脏损伤。基于Gadolinium的对比剂（GBCA）可以触发 肾脏受损的患者和脑部和骨骼中的所有沉积物中的肾病全身性纤维化（NSF）。心脏 肾脏产量是密不可分的，慢性肾脏疾病（CKD）患者患有心血管共同 与普通人群相比，率不成比例的病情（占缺血性心脏病的25％） 人口）。当成像心脏病患者患有CKD时，临床医生必须在有限的放射学之间进行选择 通过使用GBCA，信息或使患者处于较高的并发症风险。 揭示药品正在通过开发无gadolinium细胞外RVP-001来应对这一挑战 流体MRI对比剂。 RVP-001是一种稳定的锰螯合，具有放松性和药代动力学类似 GBCA导致等效成像特性。 RVP-001最近完成了NIH-的诊所部分 资助的1期临床试验（NCT05413668）。我们的最终目标是开发用于多个指示的RVP-001 （中枢神经系统，心脏，血管造影，乳房），用于肾脏受损的受试者和普通患者人群。 该阶段II SBIR提案的目的是执行非临床成像和后期启用 支持心脏指示的毒理学实验。这项工作建立在我们最近完成的NHLBI-上 资助的I期项目（R43HL156713），证明RVP-001在诊断上等同于GBCA 为了表征猪中的急性心肌梗塞（MI）。在这里，我们将在慢性的情况下评估RVP-001 心肌梗死和弥漫性心肌纤维化，以减少的射血症概括人心力衰竭 分数（HFREF）和心力衰竭分别具有保留的射血分数（HFPEF）。我们认为这是一个平等的 RVP-001的剂量将类似于指定剂量给出的GBCA，高级心脏成像可以 可以通过较大剂量的RVP-001实现，并且该调节物体可以接受RVP-001 剂量指示大于GBCA。后期启用组件包括CGLP重复剂量 大鼠的毒理学和毒理学。