Manganese Based MRI Contrast Agent - First In Human Clinical Trial

锰基 MRI 造影剂 - 首次进行人体临床试验

基本信息

批准号：
10495256
负责人：
Vera Hoffman
金额：
$ 90.35万
依托单位：
REVEAL PHARMA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10495256
关键词：
Acute Adult Adverse event Affect Area Arteries Authorization documentation Biodistribution Blood Brain Cancer Detection Cancer Survivor Chronic Kidney Failure Clinical Clinical Research Clinical Trials Contrast Media Cyclic GMP Deposition Detection Development Plans Diagnostic Neoplasm Staging Disease Dissociation Dose Double-Blind Method Drug Kinetics Electrocardiogram End stage renal failure Equilibrium European Evaluation Excretory function Family suidae Feces Future Gadolinium General Hospitals Goals Grant Hepatobiliary High-Risk Cancer Human Image Impairment Inductively Coupled Plasma Mass Spectrometry Injections Injury to Kidney Ions Kidney Kidney Failure Laboratories Life Macaca fascicularis Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of brain Manganese Marketing Massachusetts Measures Medical Medical History Medicine Metabolism Metals Methods Modeling Monitor Monkeys Mus Myocardial Infarction Nephrogenic Systemic Fibrosis Papio Patient imaging Patients Peripheral arterial disease Pharmaceutical Preparations Pharmacologic Substance Pharmacology Study Phase I Clinical Trials Phase II Clinical Trials Physical Examination Physicians Placebo Control Placebos Plasma Process Radiology Specialty Rattus Renal function Risk Rodent Safety Site Technology Telephone Testing Toxic effect Toxicology Urine Woman analytical method base bone chemotherapy clinical development comorbidity contrast enhanced contrast enhanced computed tomography contrast imaging double-blind placebo controlled trial falls first-in-human follow-up glomerular filtration healthy volunteer high risk imaging study meetings nephrotoxicity patient population placebo controlled study preclinical safety safety study screening statistics surveillance imaging tumor

项目摘要

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.

项目概要钆（Gd）基MRI造影剂（GBCA）广泛应用于临床磁共振成像（MRI），特别是用于癌症的检测和分期。然而，2006 年人们发现 GBCA 可以导致肾源性系统性纤维化（NSF），这是一种影响肾功能不全患者的衰弱性疾病。因此，严重肾功能不全的患者禁用 GBCA。这个禁忌症引起了这是一项重大的医学挑战，因为 16% 的美国成年人患有中度或重度慢性肾病（CKD），而且这个患者群体不成比例地患有癌症等合并症（其中许多人化疗具有肾毒性）和外周动脉疾病，其中对比增强 MRI 对于以下疾病至关重要患者管理。这些患者没有其他影像学检查方法。对比度增强计算断层扫描可能导致急性和不可逆的肾损伤，也是禁忌的。患者被拒绝由于 Gd 相关毒性的风险，对比增强 MRI 检查，医生被迫做出放射学信息有限的关键患者管理决策。自 2014 年以来，研究表明所有 GBCA 都会在大脑和骨骼中沉积一些 Gd，甚至在患有以下疾病的患者中也是如此：肾功能正常，重复给药后 Gd 沉积会累积。毒理学影响沉积的 Gd 仍然未知，但它是医生、患者和监管机构关注的一个活跃领域机构。 2017 年，FDA 宣布对所有 GBCA 发出新的类别警告。欧洲药品管理局暂停了与 Gd 风险最高的 4 个 GBCA 的营销许可如果有安全、无 Gd 的替代品，可以说可能已经去除了所有 GBCA。积累 Gd 对于癌症幸存者和癌症高危人群（例如癌症患者）尤其令人担忧。 BRCA 阳性女性，需要定期进行 GBCA 增强 MRI 监测的人，并且一生中可能会接受数十次 MRI 检查。 Reveal Pharmaceuticals 正在开发一种基于锰、不含钆的 MRI 造影剂 RVP-001，基于马萨诸塞州总医院发明的技术。 RVP-001 提供同等的图像对比度商业 GBCA 用于检测小鼠肿瘤、猪心肌梗塞以及狒狒动脉成像临床 MRI 扫描仪模型。大鼠体内的质量平衡和生物分布表明，注射锰 RVP-001 在等剂量的 Gd-DOTA 中比 Gd 更有效地消除，这被认为是状态 GBCA 技术的 Gd 解离安全性。毒理学和安全药理学研究在 GLP 条件下对大鼠和食蟹猴进行的试验表明 RVP-001 是安全的且耐受性良好高达非常高的剂量。该项目我们将评估安全性、耐受性、药代动力学、消除和质量单次递增剂量、双盲、安慰剂对照阶段的健康志愿者中 RVP-001 的平衡 1期临床试验，并为后续2期临床试验证明影像疗效提供基础。