Manganese-based Contrast Agent for Cardiovascular MRI

摘要 心血管疾病是发病和死亡的主要原因，在美国， 全球每年有1860万人死亡。对比增强磁共振成像（MRI）和 计算机断层扫描（CT）在管理心脏病中发挥着关键作用， 心肌灌注、梗死和存活率。心脏成像是MRI市场增长最快的部分， 最近的标志性试验，如MR-INFORM，证明了对比增强MRI与生命的等效性 节省了侵入性导管插入术，SCD-HeFT显示了预测 心血管不良事件。不幸的是，碘化CT放射造影和钆基MRI 造影剂对肾损害患者造成安全风险。碘造影剂可引起急性 和不可逆的肾损伤。钆基造影剂（GBCA）可触发 肾损害患者中的肾源性系统性纤维化（NSF），并且所有存款Gd都沉积在脑和骨中。心脏 和肾输出量是密不可分的，慢性肾病（CKD）患者患有心血管疾病， 与一般人群相比，发病率不成比例地高（约25%的缺血性心脏病 人口）。当对CKD心脏病患者进行成像时，临床医生必须在有限的放射学检查 信息或通过使用GBCA将患者置于更高的并发症风险中。 Reveal Pharmaceuticals正在通过开发RVP-001来应对这一挑战，RVP-001是一种不含钆的细胞外药物， 液体MRI造影剂。RVP-001是一种稳定的锰螯合物，其弛豫率和药代动力学与 GBCA导致等效成像特性。RVP-001最近完成了NIH的临床部分- 1期临床试验（NCT 05413668）。我们的最终目标是为多种适应症开发RVP-001 (CNS心脏、血管造影术、乳腺）。 本阶段II SBIR提案的目的是执行非临床成像和后期启用 支持心脏适应症的毒理学实验。这项工作建立在我们最近完成的NHLBI- 资助的I期项目（R43 HL 156713），证明RVP-001在诊断上等同于GBCA 描述猪急性心肌梗死（MI）的特征。在这里，我们将在慢性疾病背景下评价RVP-001 心肌梗死和弥漫性心肌纤维化与射血减少的心力衰竭相似 射血分数（HFrEF）和射血分数保留的心力衰竭（HFpEF）。我们认为一个平等的 RVP-001剂量的表现与指定剂量的GBCA相似，上级心脏成像可 通过更大剂量的RVP-001实现，并且监管机构将接受RVP-001 剂量指示大于GBCA。晚期使能组分包括cGLP重复给药 毒理学和大鼠毒理学。

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.