Manganese Based MRI Contrast Agent - First In Human Clinical Trial

Project Summary Gadolinium (Gd)-based MRI contrast agents (GBCAs) are widely used in clinical magnetic resonance imaging (MRI), especially for the detection and staging of cancers. However, in 2006 it was discovered that GBCAs can cause nephrogenic systemic fibrosis (NSF), a debilitating disorder that affects patients with renal insufficiency. GBCAs are consequently contraindicated in patients with severe renal impairment. This contraindication poses a substantial medical challenge, since 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) and peripheral artery disease, in which contrast enhanced MRI is critical for patient management. There is no alternative imaging for these patients. Contrast enhanced computed tomography can cause acute and irreversible kidney injury and is also contraindicated. Patients are being denied contrast enhanced MRI exams because of the risk of Gd-associated toxicity, and physicians are forced to make key patient management decisions with limited radiologic information.Since 2014 it has been shown that all GBCAs deposit some Gd in the brain and bone, even in patients with normal renal function, and that Gd deposition is cumulative with repeat dosing. The toxicological implications of deposited Gd are still unknown, but it is an active area of concern for 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, who require regular GBCA enhanced MRIs for surveillance, and may receive dozens of MRIs through life.Reveal Pharmaceuticals is developing a manganese-based, gadolinium-free MRI contrast agent, RVP-001, based on technology invented at Massachusetts General Hospital. RVP-001 provides equivalent image contrast to commercial GBCAs for detecting tumors in mice, myocardial infarction in pigs, and imaging arteries in baboon models on clinical MRI scanners. Mass balance and biodistribution in rats demonstrated that Mn injected as RVP-001 is more efficiently eliminated than Gd from an equal dose of Gd-DOTA, which is considered the state of the art GBCA for safety with respect to Gd dissociation. Toxicology and safety pharmacology studies performed under GLP conditions in rats and cynomolgus monkeys indicate RVP-001 is safe and well tolerated up to very high doses. This project we will assess safety, tolerability, pharmacokinetics, elimination, and mass balance of RVP-001 in healthy volunteers in a single ascending dose, double blinded, placebo controlled Phase 1 clinical trial, and provide the basis for subsequent Phase 2 clinical trials to demonstrate imaging efficacy.