Manganese-based Contrast Agent for Cardiovascular MRI

摘要 心血管疾病是疾病和死亡的主要原因，占美国死亡人数的1/3。 全球每年有1,860万人死亡。对比增强磁共振成像(MRI)和 计算机断层扫描(CT)通过实现对心脏疾病的非侵入性评估，在管理心脏病方面发挥着关键作用 心肌灌注、梗死和存活情况。心脏成像是MRI市场中增长最快的细分市场， 最近的里程碑式的试验，如MR-INFORM，证明了对比增强的MRI与LIFE的等效性 节省有创的导尿术，SCD-HeFT在预测预后中的价值 心血管不良事件。不幸的是，无论是碘化CT放射造影剂还是基于Gd的MRI 造影剂对肾损害患者构成安全风险。加碘的造影剂会引起急性 对肾功能受损的患者造成不可逆转的肾损伤。基于Gd的造影剂(GBCA)可以触发 肾损害患者的肾源性系统性纤维化(NSF)，均可在脑和骨中沉积Gd。心脏 和肾输出量有着千丝万缕的联系，慢性肾脏疾病(CKD)患者患有心血管疾病。 与一般人群(约25%的缺血性心脏病)相比，发病率高得不成比例 人口)。当对患有慢性肾脏病的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中做出选择。 或通过使用GBCA将患者置于更高的并发症风险中。 Display PharmPharmticals正在通过开发RVP-001来应对这一挑战，RVP-001是一种无Gd的细胞外物质 液体磁共振造影剂。RVP-001是一种稳定的锰络合物，其弛豫度和药代动力学类似于 具有相同成像特性的GBCA。RVP-001最近完成了NIH的临床部分- 资助的1期临床试验(NCT05413668)。我们的最终目标是开发适用于多种适应症的RVP-001 (中枢神经系统、心脏、血管造影术、乳房)适用于肾功能受损受试者和普通患者群体。 此第二阶段SBIR提案的目标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- 资助的第一阶段项目(R43HL156713)，该项目证明RVP-001在诊断上相当于GBCA 目的：探讨猪急性心肌梗死(MI)的特点。在这里，我们将评估RVP-001在慢性 心肌梗死和弥漫性心肌纤维化重现射血减少的人类心力衰竭 射血分数(HFrEF)和心力衰竭保留射血分数(HFpEF)。我们假设一个相等的 RVP-001的剂量将与在指示剂量下给予GBCA的效果相似，这是优越的心脏成像可以 通过更大剂量的RVP-001来实现，监管机构将接受RVP-001 大于GBCAs的剂量指示。后期使能组分包括cGLP重复剂量 大鼠的毒理学和毒代动力学。

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.