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.

摘要