Phase II year
2021
(last award dollars: 2022)
Phase II Amount
$2,053,452
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 cancause 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 posesa 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 manychemotherapies are nephrotoxic) and peripheral artery disease, in which contrast enhanced MRI is critical forpatient management. There is no alternative imaging for these patients. Contrast enhanced computedtomography can cause acute and irreversible kidney injury and is also contraindicated. Patients are being deniedcontrast enhanced MRI exams because of the risk of Gd-associated toxicity, and physicians are forced to makekey 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 withnormal renal function, and that Gd deposition is cumulative with repeat dosing. The toxicological implications ofdeposited Gd are still unknown, but it is an active area of concern for physicians, patients, and regulatoryagencies. In 2017 the FDA announced a new class warning for all GBCAs. The European Medicines Agencysuspended the marketing authorizations for the 4 GBCAs that are associated with the highest risk of Gddeposition, and arguably may have removed all GBCAs had there been a safe, Gd-free alternative. Accumulationof 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 contrastto commercial GBCAs for detecting tumors in mice, myocardial infarction in pigs, and imaging arteries in baboonmodels on clinical MRI scanners. Mass balance and biodistribution in rats demonstrated that Mn injected asRVP-001 is more efficiently eliminated than Gd from an equal dose of Gd-DOTA, which is considered the stateof the art GBCA for safety with respect to Gd dissociation. Toxicology and safety pharmacology studiesperformed under GLP conditions in rats and cynomolgus monkeys indicate RVP-001 is safe and well toleratedup to very high doses. This project we will assess safety, tolerability, pharmacokinetics, elimination, and massbalance of RVP-001 in healthy volunteers in a single ascending dose, double blinded, placebo controlled Phase1 clinical trial, and provide the basis for subsequent Phase 2 clinical trials to demonstrate imaging efficacy.
Public Health Relevance Statement: Project Narrative
Gadolinium based contrast agents (GBCAs) are used with MRI to detect and stage cancers and other disease
and guide treatment. However there are safety concerns about the potentially toxic gadolinium metal ion. We
have invented a gadolinium-free contrast agent called RVP-001 to replace GBCAs. The goal of this proposal is
to assess the safety, tolerability, pharmacokinetics and elimination of RVP-001 in healthy volunteers. Once
initial safety is established, subsequent studies (not part of this grant) will test its utility in detecting cancer.
Project Terms: <21+ years old> 