Manganese Based MRI Contrast Agent

钆（Gd）基MRI造影剂（gbca）用于临床磁共振成像（MRI）。

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