# Manganese Based MRI Contrast Agent - First In Human Clinical Trial

> **NIH NIH R44** · REVEAL PHARMA · 2022 · $903,512

## Abstract

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 Phas...

## Key facts

- **NIH application ID:** 10495256
- **Project number:** 5R44CA268392-02
- **Recipient organization:** REVEAL PHARMA
- **Principal Investigator:** Vera Hoffman
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $903,512
- **Award type:** 5
- **Project period:** 2021-09-24 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495256

## Citation

> US National Institutes of Health, RePORTER application 10495256, Manganese Based MRI Contrast Agent - First In Human Clinical Trial (5R44CA268392-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10495256. Licensed CC0.

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