Manganese Based MRI Contrast Agent

基于Gd的磁共振造影剂(GBCA)在临床磁共振成像(MRI)中的应用 用于癌症检测和分期，特别是原发和转移性脑癌。然而，有一些 对GBCA潜在的长期毒性的担忧。GBCA会导致肾源性系统性纤维化(NSF)， 这是一种破坏性的疾病，会影响肾病患者。FDA对美国食品和药物管理局发布了黑匣子警告 GBCA在这一人群中的使用。这对医学有重大影响：16%的美国成年人患有中度或 严重的慢性肾脏疾病(CKD)，这一患者群体不成比例地患有合并症 比如癌症(许多化疗药物都是肾毒性的)。对于这些患者来说，没有其他的成像方法。 CT增强扫描可导致急性不可逆性肾损伤，也是禁忌症。所有GBCA 导致Gd在大脑和骨骼中积聚，即使在肾功能正常的患者中也是如此。GD是剧毒的 以其自由形式存在，人们对沉积的Gd的毒理学影响知之甚少： 医生、患者和监管机构。2017年，FDA宣布了针对所有GBCA的新类别警告。 欧洲药品管理局暂停了对相关4种GBCA的营销授权 具有最高的Gd沉积风险，而且可以说已经移除了所有GBCA，如果有一个保险箱，Gd- 免费选择。对于癌症幸存者和癌症高危人群来说，Gd的积累尤其令人担忧 癌症，例如BRCA阳性的女性。他们需要常规的GBCA增强磁共振成像来进行监测或筛查， 一生中可能有几十次核磁共振检查。避免GBCA迫使医生对关键患者进行管理 在影像信息有限的情况下做出决定，而继续使用可能会将这些脆弱的患者置于危险之中。 Display PharmPharmticals正在开发不含Gd的磁共振造影剂RVP-001，发明于 麻省总医院。RVP-001在不同的环境中提供与商用GBCA相同的图像对比度 动物模型。注射为RVP-001的锰(Mn)比同等剂量的Gd更有效地清除 Gd-DOTA，在稳定性方面的安全性被认为是同类GBCA中最好的。非临床研究 为RVP-001建立了非常高的安全裕度。评估安全性、耐受性和 RVP-001在健康受试者中的药代动力学研究表明，RVP-001在较高剂量时是安全和耐受性良好的 超过了预期的临床剂量。这笔赠款将支持人类磁共振成像研究的第一个项目。我们将表演一场 GBCA增强型中枢神经系统损害患者的剂量范围发现研究，例如脑癌， 以评估成像效果、药效学和安全性。我们将评估RVP-001损害的程度 与平扫MRI进行比较，并与患者GBCA增强MRI进行比较。的目标是 这项研究旨在为进一步的临床开发和批准建立一个有效的剂量。 此拨款申请基于快速通道NIH拨款奖励R44 DK113906-03，是 重新提交拨款申请9 R44 CA261240-04

Gadolinium (Gd)-based MRI contrast agents (GBCAs) are used in clinical magnetic resonance imaging (MRI) for cancer detection and staging, particularly of primary and metastatic brain cancers. However, there are concerns about the potential long-term toxicity of GBCAs. GBCAs cause nephrogenic systemic fibrosis (NSF), a devastating disorder that affects patients with kidney disease. FDA imposed a “black box” warning against GBCA use in this population. This has a significant medical impact: 16% of US adults suffer from moderate or severe chronic kidney disease (CKD), and this patient population is disproportionately afflicted with comorbidities like cancer (where many chemotherapies are nephrotoxic). There is no alternative imaging for these patients. Contrast enhanced CT can cause acute and irreversible kidney injury and is also contraindicated. All GBCAs cause accumulation of Gd in the brain and bone, even in patients with normal kidney function. Gd is highly toxic in its free form, and little is known about the toxicological implications of deposited Gd: concern is rising among physicians, patients, and regulatory agencies. In 2017 the FDA announced a new class warning for all GBCAs. The European Medicines Agency suspended the marketing authorizations for the 4 GBCAs that are associated with the highest risk of Gd deposition, and arguably may have removed all GBCAs had there been a safe, Gd- free alternative. Accumulation of Gd is particularly worrisome for cancer survivors and those at high risk for cancer, e.g. BRCA positive women. They require regular GBCA-enhanced MRIs for surveillance or screening, and may have dozens of MRIs through life. Avoiding GBCAs forces physicians to make key patient management decisions with limited imaging information, while continued use may put these vulnerable patients at risk. Reveal Pharmaceuticals is developing the gadolinium-free MRI contrast agent, RVP-001, invented at Massachusetts General Hospital. RVP-001 provides equivalent image contrast to commercial GBCAs in different animal models. Manganese (Mn) injected as RVP-001 is more efficiently eliminated than Gd from an equal dose of Gd-DOTA, which is considered the best in class GBCA for safety with respect to stability. Nonclinical studies established a very high safety margin for RVP-001. A Phase 1 study to assess safety, tolerability, and pharmacokinetics in healthy subjects demonstrated that RVP-001 is safe and well tolerated up to doses higher than the anticipated clinical dose. This grant will support first in human MR imaging studies. We will perform a dose range finding study in patients with GBCA-enhancing central nervous system lesions, e.g. brain cancers, to assess imaging efficacy, pharmacodynamics, and safety. We will assess the degree of RVP-001 lesion enhancement compared to unenhanced MRI and compared to the patient’s GBCA enhanced MRI. The goal of the study is to establish an effective dose for further clinical development and approval. This grant application is predicated on the Fast Track NIH grant award R44 DK113906-03 and is a resubmission of the grant application 9 R44 CA261240-04