SBIR-STTR Award

Ischemic heart disease is the leading cause of morbidity and death in the United Statesrepresenting 1 in 3 American deaths and globally (17 million deaths annually). Contrast enhanced computedtomography (CT) and magnetic resonance imaging (MRI) play a key role in managing heart disease by enablingnon-invasive assessment of myocardial perfusion, infarction, and viability. Contrast enhanced scans areincreasingly relied upon for ischemic heart disease diagnosis and treatment planning, and for assessingtreatment efficacy. Thus, cardiac imaging is the fastest growing segment of the MRI market in Europe andincreasing in the United States with the recent randomized controlled MR-INFORM trial demonstratingequivalency between invasive catherization and contrast enhanced MRI. Unfortunately, both iodinated CTradiocontrast and gadolinium-based MRI contrast agents are contraindicated in patients suffering moderate tosevere renal impairment. Iodinated contrast media can cause acute and irreversible kidney injury in renallyimpaired patients and gadolinium-based MRI contrast agents (GBCAs) are directly linked to nephrogenicsystemic fibrosis (NSF) in renally impaired patients. Chronic kidney disease (CKD) afflicts 16% of US adults andis increasing due to the diabetes and obesity epidemics and the aging population. Cardiac and renal output areinextricably linked - renal dysfunction is present in 33% of patients with heart failure complicating their diagnosticworkup and management despite the clear benefit of non-invasive cardiac MRI over invasive percutaneouscatherization. As a result, when imaging heart disease patients with CKD, clinicians are either faced with limitedradiologic information or placing the patient at higher risk for complications by using GBCA. There is a major unmet clinical need for contrast-enhanced cardiovascular imaging using safer alternatives togadolinium-based contrast agents. Reveal Pharmaceuticals is developing a gadolinium-free contrast agentbased on technology developed at Massachusetts General Hospital. Our lead compound RVP-001 is an stablemanganese chelate with relaxivity and pharmacokinetics similar to GBCAs resulting in equivalent imagingproperties. RVP-001 is rationally designed for partial hepatobiliary elimination, which provides a compensatoryelimination mechanism for renally impaired patients. Our ultimate goal is to develop RVP-001 as a contrast agentfor use in renally impaired subjects as well as the general patient population. In this SBIR application we will demonstrate the efficacy of RVP-001 for cardiac imaging in a porcine model ofmyocardial infarction to demonstrate and validate RVP-001 equivalency to a commercially available GBCA. Wewill first identify a formulation of RVP-001 best suited for bolus delivery, and then demonstrate that RVP-001 isequivalent or better than the commercial GBCA Gd-DOTA for assessing myocardial perfusion and viability. Theproposed imaging will support the commercialization of RVP-001 as a cardiovascular contrast agent for use inthe large and growing population of renally impaired patients.

Public Health Relevance Statement:
Project Narrative. Heart imaging to detect ischemic heart disease and measure heart muscle viability after heart attack rely on contrast agents. Many patients who need heart imaging studies also have poor kidney function and these patients cannot be given contrast agents. Reveal Pharmaceuticals is developing a manganese-based MRI contrast agent (RVP-001) as safe alternative to use in patients with impaired kidney function and the objective of this study is to demonstrate that RVP-001 can be effectively used to measure heart perfusion and viability.

Project Terms:
Noise ; Patients ; Perfusion ; Drug Kinetics ; Pharmacokinetics ; Play ; Radiology Specialty ; General Radiology ; Radiology ; Salts ; Sodium ; Na element ; Stains ; Staining method ; Family suidae ; Pigs ; Suidae ; Swine ; porcine ; suid ; Technology ; Tetrazolium ; X-Ray Computed Tomography ; CAT scan ; CT X Ray ; CT Xray ; CT imaging ; CT scan ; Computed Tomography ; Tomodensitometry ; X-Ray CAT Scan ; X-Ray Computerized Tomography ; Xray CAT scan ; Xray Computed Tomography ; Xray computerized tomography ; catscan ; computed axial tomography ; computer tomography ; computerized axial tomography ; computerized tomography ; United States ; Viscosity ; Water ; Hydrogen Oxide ; Sirius Red F3B ; picrosirius red ; sirius red F 3B ; Measures ; Osmolalities ; Myocardial Ischemia ; Ischemic Heart ; Ischemic Heart Disease ; Ischemic myocardium ; cardiac ischemia ; coronary ischemia ; heart ischemia ; myocardial ischemia/hypoxia ; myocardium ischemia ; Injury to Kidney ; kidney injury ; renal injury ; base ; density ; Acute ; Clinical ; Link ; Ensure ; Renal function ; kidney function ; Deposit ; Deposition ; Diagnostic ; Myocardial perfusion ; Scanning ; extracellular ; American ; cardiac imaging ; cardiac scanning ; heart scanning ; heart imaging ; treatment planning ; Adverse Experience ; Adverse event ; cardiovascular imaging ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Dose ; Defect ; Bolus ; Bolus Infusion ; randomisation ; randomization ; randomly assigned ; Randomized ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Myocardial ; Cardiac ; Image ; imaging ; Output ; design ; designing ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; manufacturing process ; Population ; Hepatobiliary ; Impairment ; commercialization ; aging population ; aged population ; population aging ; high risk ; patient population ; disease diagnosis ; in vivo imaging ; imaging in vivo ; contrast enhanced ; Formulation ; Tissue imaging ; experimental study ; experiment ; experimental research ; imaging study ; perfusion imaging ; imaging properties ; Injections ; Nephrogenic Systemic Fibrosis ; Obesity Epidemic ; kidney dysfunction ; renal dysfunction ; porcine model ; pig model ; piglet model ; swine model ; Adult ; 21+ years old ; Adult Human ; adulthood ; Blood ; Blood Reticuloendothelial System ; bone ; Brain ; Brain Nervous System ; Encephalon ; Cardiovascular Agents ; Cardiovascular Drugs ; Cardiovascular system ; Cardiovascular ; Cardiovascular Body System ; Cardiovascular Organ System ; Heart Vascular ; circulatory system ; Chelating Agents ; Chelators ; Complexons ; Chlorides ; Cicatrix ; Scars ; comorbidity ; co-morbid ; co-morbidity ; Contrast Media ; Contrast Agent ; Contrast Drugs ; Radiopaque Media ; Cessation of life ; Death ; Diabetes Mellitus ; diabetes ; Europe ; Gadolinium ; Gd element ; Goals ; Heart ; Heart Diseases ; Cardiac Diseases ; Cardiac Disorders ; heart disorder ; Heart failure ; cardiac failure ; Histology ; General Hospitals ; Image Enhancement ; Infarction ; infarct ; Kidney ; Kidney Urinary System ; renal ; Chronic Kidney Failure ; Chronic Renal Disease ; Chronic Renal Failure ; chronic kidney disease ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Magnetic Resonance Imaging ; MR Imaging ; MR Tomography ; MRI ; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance ; NMR Imaging ; NMR Tomography ; Nuclear Magnetic Resonance Imaging ; Zeugmatography ; Manganese ; Mn element ; Massachusetts ; Meglumine ; Methylglucamine ; Microspheres ; Microbeads ; Morbidity - disease rate ; Morbidity ; Myocardial Infarction ; Cardiac infarction ; Myocardial Infarct ; cardiac infarct ; coronary attack ; coronary infarct ; coronary infarction ; heart attack ; heart infarct ; heart infarction ; Myocardium ; cardiac muscle ; heart muscle ;

Cardiovascular disease is the leading cause of morbidity and death, representing 1 in 3 deaths in the UnitedStates, and 18.6 million deaths globally annually. Contrast enhanced magnetic resonance imaging (MRI) andcomputed tomography (CT) play a key role in managing heart disease by enabling non-invasive assessment ofmyocardial perfusion, infarction, and viability. Cardiac imaging is the fastest growing segment of the MRI market,with recent landmark trials such as MR-INFORM demonstrating equivalence of contrast enhanced MRI to lifesaving invasive catheterization procedures, and SCD-HeFT demonstrating prognostic value in predictingcardiovascular adverse events. Unfortunately, both iodinated CT radiocontrast and gadolinium-based MRIcontrast agents pose safety risks to patients with renal impairment. Iodinated contrast media can cause acuteand irreversible kidney injury to renally impaired patients. Gadolinium-based contrast agents (GBCAs) can triggernephrogenic systemic fibrosis (NSF) in renally impaired patients and all deposit Gd in brain and bone. Cardiacand renal output are inextricably linked and chronic kidney disease (CKD) patients suffer cardiovascular co-morbidities at a rate disproportionately high compared to the general population (~25% of ischemic heart diseasepopulation). When imaging heart disease patients with CKD, clinicians must choose between limited radiologicinformation or placing the patient at higher risk for complications by using a GBCA. Reveal Pharmaceuticals is addressing this challenge by developing RVP-001, a gadolinium-free extracellularfluid MRI contrast agent. RVP-001 is a stable manganese chelate with relaxivity and pharmacokinetics similar toGBCAs resulting in equivalent imaging properties. RVP-001 recently completed the in clinic portion of an NIH-funded Phase 1 clinical trial (NCT05413668). Our ultimate goal is to develop RVP-001 for multiple indications(CNS, cardiac, angiography, breast) for both renally impaired subjects and the general patient population. The objective of this Phase II SBIR proposal is to perform non-clinical imaging and late phase enablingtoxicology experiments in support of a cardiac indication. This work builds upon our recently completed NHLBI-funded Phase I project (R43HL156713), which demonstrated that RVP-001 is diagnostically equivalent to GBCAto characterize acute myocardial infarction (MI) in pigs. Here, we will evaluate RVP-001 in the contexts of chronicmyocardial infarction and diffuse myocardial fibrosis that recapitulate human heart failure with reduced ejectionfraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), respectively. We posit that an equaldose of RVP-001 will perform similarly to GBCA given at the indicated dose, that superior cardiac imaging canbe achieved through a larger dose of RVP-001, and that regulatory bodies would be receptive to a RVP-001dose indication that is larger than GBCAs. The late phase enabling component comprises cGLP repeat dosetoxicology and toxicokinetics in rats.

Public Health Relevance Statement:
PROJECT NARRATIVE Given the well-documented risks of administering iodinated CT radiocontrast and gadolinium-based MRI contrast agents to renally impaired patients and the prevalence of heart disease renally impaired population, there is a major unmet need for new contrast media that is safe for renally impaired patients. Reveal Pharmaceuticals is developing a manganese-based MRI contrast agent (RVP-001) as safe gadolinium-free alternative (NCT05413668). The objectives of this proposal are to demonstrate that RVP-001 is functionally equivalent to Gd-based contrast agents in pig models of chronic ischemic and non-ischemic heart disease and to perform late phase clinical trial enabling toxicology studies in rats.

Project Terms:
<21+ years old>