Chronic kidney disease (CKD) afflicts 14% of US adults and represents a foremost challenge facing public health. CKD patients have a higher prevalence of co-morbidities and represent a population that often requires medical intervention. However patient management is confounded because contrast media routinely used with computed tomography (CT) and magnetic resonance (MR) imaging is contra-indicated in patients with moderate to severe CKD. CT contrast media can cause acute and irreversible kidney injury to renally impaired patients. Gadolinium-based contrast agents (GBCAs) used as MR contrast media are directly linked to nephrogenic systemic fibrosis (NSF) in renally impaired patients. The prevalence of co-morbidities and the risk associated with contrast media both increase with decreased renal function. Thus as patients grow increasingly vulnerable physicians are forced to make key decisions with limited radiologic information or to use contrast media and place the patient at high risk for renal failure or for NSF. There is a major unmet medical need for a safer contrast media alternative. GBCAs have also recently been shown to deposit small amounts of gadolinium in the brain and other organs, even in patients with normal renal function, and that Gd deposition increases with increasing exposure. While the medical implications of these deposits are still unknown, this is an area of active concern for the FDA. Reveal Pharmaceuticals is developing a gadolinium-free contrast agent based on technology developed at Massachusetts General Hospital. Our lead compound, RVP-001, is a very stable manganese chelate with equivalent imaging properties to GBCAs but without using the toxic gadolinium ion. RVP-001 is 100,000 times more stable than Teslascan, another manganese-based compound previously used in clinical imaging. RVP- 001 is functionally equivalent to GBCAs having similar relaxivity and biodistribution, and is excreted from the body intact. RVP-001 enhanced MRI is equivalent to GBCA enhanced MRI in the same animal model. Our ultimate goal is to develop RVP-001 for use in renally impaired subjects and as a general purpose MR contrast agent. It is critical that RVP-001 does not lead to Mn accumulation in the body and result in a toxicological effect. In this FastTrack application we will use the positron emitting Mn-52 isotope (t1/2 = 5.2d) to study the retention and excretion of Mn under acute and subacute dosing with comparison to unchelated Mn and to GBCA. We will also perform preclinical safety evaluations of RVP-001. For clinical development and ultimately to compete with GBCAs we will need a very cost effective synthesis that does not involve HPLC purification. We have identified different synthetic routes to RVP-001 and these will be systematically evaluated and a chemical process with analytical controls will be developed.

Public Health Relevance

Patients with chronic kidney disease or acute kidney injury are often denied needed imaging exams because the contrast media used can produce serious side effects such as kidney failure and death in these patients. The goal of this proposal is to develop a new contrast agent for magnetic resonance imaging that would be safe for use with these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
1R44DK113906-01
Application #
9347632
Study Section
Special Emphasis Panel (ZRG1-SBIB-T (10)B)
Program Officer
Gossett, Daniel Robert
Project Start
2017-05-11
Project End
2020-04-30
Budget Start
2017-05-11
Budget End
2018-04-30
Support Year
1
Fiscal Year
2017
Total Cost
$233,423
Indirect Cost
Name
Reveal Pharma
Department
Type
Domestic for-Profits
DUNS #
080345910
City
Cambridge
State
MA
Country
United States
Zip Code
02140