Manganese-based Contrast Agent for Cardiovascular MRI

点击翻译按钮获取中文摘要

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.