Manganese Based MRI Contrast Agent

钆（Gd）基MRI造影剂（GBCA）用于临床磁共振成像（MRI） 用于癌症检测和分期，特别是原发性和转移性脑癌。但有 对GBCA潜在的长期毒性的担忧。GBCA引起肾源性系统性纤维化（NSF）， 一种影响肾病患者的毁灭性疾病。美国食品和药物管理局（FDA）对 GBCA在该人群中的使用。这对医学产生了重大影响：16%的美国成年人患有中度或重度抑郁症。 严重慢性肾病（CKD），并且该患者群体不成比例地患有合并症 比如癌症（许多化疗药物都有肾毒性）。对于这些患者，没有替代成像。 对比增强CT可引起急性和不可逆的肾损伤，也是禁忌症。所有GBCA 导致Gd在大脑和骨骼中积累，即使在肾功能正常的患者中也是如此。Gd有剧毒 在其游离形式，并鲜为人知的是，沉积Gd的毒理学影响：关注正在上升， 医生、患者和监管机构。2017年，FDA宣布对所有GBCA发出新的警告。 欧洲药品管理局暂停了4种相关GBCA的上市许可， 具有最高的Gd沉积风险，并且可以说，如果存在安全的Gd- 自由选择。Gd的积累对于癌症幸存者和那些处于高风险的人来说尤其令人担忧。 癌症，例如BRCA阳性女性。他们需要定期的GBCA增强MRI进行监测或筛查， 一生中可能要做几十次核磁共振避免GBCA迫使医生进行关键患者管理 然而，继续使用可能会使这些脆弱的患者处于危险之中。 Reveal Pharmaceuticals正在开发无钆MRI造影剂RVP-001，该造影剂发明于 马萨诸塞州综合医院。RVP-001在不同环境下提供与市售GBCA相当的图像对比度 动物模型以RVP-001注入的锰（Mn）比相同剂量的Gd更有效地消除 的Gd-DOTA，其被认为是GBCA类中关于稳定性的安全性最好的。非临床研究 为RVP-001建立了非常高的安全裕度。一项评估安全性、耐受性和 在健康受试者中的药代动力学证明，RVP-001在高达更高剂量下安全且耐受性良好 超过预期临床剂量。该拨款将首先支持人类MR成像研究。我们将执行一个 GBCA增强中枢神经系统病变（如脑癌）患者的剂量范围探索研究， 评估成像功效、药效学和安全性。我们将评估RVP-001病变的程度 与未增强的MRI相比以及与患者的GBCA增强的MRI相比的增强。的目标 该研究旨在为进一步的临床开发和批准建立有效剂量。 该资助申请基于快速通道NIH资助奖R44 DK 113906 -03， 重新提交资助申请9 R44 CA 261240 -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