Manganese Based MRI Contrast Agent

锰基 MRI 造影剂

• 批准号: 10678476
• 负责人: Vera Hoffman
• 金额: $ 202.5万
• 依托单位: REVEAL PHARMA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678476
• 关键词: 3-Dimensional; Abdomen; Acute; Address; Adult; Affect; Angiography; Animal Model; Applications Grants; Area; Arteries; Authorization documentation; Award; Biodistribution; Blood; Brain; Brain Diseases; Cancer Detection; Cancer Survivor; Central Nervous System; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Trials; Compensation; Contrast Media; Cyclic GMP; Deposition; Devices; Diagnostic Neoplasm Staging; Disease; Dissociation; Dose; Drug Kinetics; Electrocardiogram; End stage renal failure; Enhancing Lesion; Enrollment; Equilibrium; European; Excretory function; Family suidae; Future; Gadolinium; General Hospitals; Goals; Grant; Hepatobiliary; High-Risk Cancer; Image; Injections; Injury to Kidney; Ions; Kidney; Kidney Diseases; Kidney Failure; Lesion; Life; Macaca fascicularis; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Manganese; Marketing; Massachusetts; Medical; Medicine; Metals; Modeling; Monkeys; Mus; Myocardial Infarction; Nephrogenic Systemic Fibrosis; New Agents; Papio; Patient Monitoring; Patient imaging; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology Study; Phase; Physicians; Population; Rattus; Renal function; Resolution; Risk; Rodent; Safety; Signal Transduction; Site; Suspending Agents; Technology; Time; Toxic effect; Toxicology; United States National Institutes of Health; Venous blood sampling; Vial device; Woman; adverse event monitoring; authority; bone; chemotherapy; clinical development; comorbidity; contrast enhanced; contrast enhanced computed tomography; contrast imaging; first-in-human; follow-up; glomerular filtration; high risk; imaging study; improved; invention; manufacture; nephrotoxicity; patient population; phase 1 study; safety assessment; safety testing; screening; tumor; uptake

Gadolinium (Gd)-based MRI contrast agents (GBCAs) are used in clinical magnetic resonance imaging (MRI) for cancer detection and staging, particularly of primary and metastatic brain cancers. However, there are concerns about the potential long-term toxicity of GBCAs. GBCAs cause nephrogenic systemic fibrosis (NSF), a devastating disorder that affects patients with kidney disease. FDA imposed a “black box” warning against GBCA use in this population. This has a significant medical impact: 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). There is no alternative imaging for these patients. Contrast enhanced CT can cause acute and irreversible kidney injury and is also contraindicated. All GBCAs cause accumulation of Gd in the brain and bone, even in patients with normal kidney function. Gd is highly toxic in its free form, and little is known about the toxicological implications of deposited Gd: concern is rising among 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. They require regular GBCA-enhanced MRIs for surveillance or screening, and may have dozens of MRIs through life. Avoiding GBCAs forces physicians to make key patient management decisions with limited imaging information, while continued use may put these vulnerable patients at risk. Reveal Pharmaceuticals is developing the gadolinium-free MRI contrast agent, RVP-001, invented at Massachusetts General Hospital. RVP-001 provides equivalent image contrast to commercial GBCAs in different animal models. Manganese (Mn) injected as RVP-001 is more efficiently eliminated than Gd from an equal dose of Gd-DOTA, which is considered the best in class GBCA for safety with respect to stability. Nonclinical studies established a very high safety margin for RVP-001. A Phase 1 study to assess safety, tolerability, and pharmacokinetics in healthy subjects demonstrated that RVP-001 is safe and well tolerated up to doses higher than the anticipated clinical dose. This grant will support first in human MR imaging studies. We will perform a dose range finding study in patients with GBCA-enhancing central nervous system lesions, e.g. brain cancers, to assess imaging efficacy, pharmacodynamics, and safety. We will assess the degree of RVP-001 lesion enhancement compared to unenhanced MRI and compared to the patient’s GBCA enhanced MRI. The goal of the study is to establish an effective dose for further clinical development and approval. This grant application is predicated on the Fast Track NIH grant award R44 DK113906-03 and is a resubmission of the grant application 9 R44 CA261240-04

钆 (Gd) 基 MRI 造影剂 (GBCA) 用于临床磁共振成像 (MRI) 用于癌症检测和分期，特别是原发性和转移性脑癌。然而，有 人们担心 GBCA 的潜在长期毒性。 GBCA 会导致肾源性系统性纤维化 (NSF)， 一种影响肾病患者的破坏性疾病。 FDA 对此类产品施加“黑匣子”警告 GBCA 在该人群中的使用。这具有重大的医疗影响：16% 的美国成年人患有中度或 严重的慢性肾脏病 (CKD)，并且该患者群体不成比例地患有合并症 例如癌症（许多化疗具有肾毒性）。这些患者没有其他影像学检查方法。 增强CT可导致急性且不可逆的肾损伤，也是禁忌的。所有 GBCA 导致 Gd 在大脑和骨骼中积聚，即使在肾功能正常的患者中也是如此。钆有剧毒 其游离形式，但人们对沉积的 Gd 的毒理学影响知之甚少：人们越来越担心 医生、患者和监管机构。 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 4 个相关 GBCA 的上市许可 具有最高的 Gd 沉积风险，并且如果存在安全的 Gd- 的话，可以说可能已经去除了所有 GBCA。 免费替代品。 Gd 的积累对于癌症幸存者和癌症高危人群尤其令人担忧 癌症，例如BRCA 阳性女性。他们需要定期进行 GBCA 增强 MRI 进行监测或筛查， 一生中可能会接受数十次核磁共振检查。避免 GBCA 迫使医生进行关键患者管理 在影像信息有限的情况下做出决定，而继续使用可能会使这些脆弱的患者面临风险。 Reveal Pharmaceuticals 正在开发不含钆的 MRI 造影剂 RVP-001，发明于 马萨诸塞州总医院。 RVP-001 在不同的环境下提供与商用 GBCA 相当的图像对比度 动物模型。以 RVP-001 形式注射的锰 (Mn) 比同等剂量的 Gd 更能有效消除 Gd-DOTA，被认为是同类 GBCA 中安全性和稳定性最好的。非临床研究 为 RVP-001 建立了非常高的安全裕度。评估安全性、耐受性和耐受性的第一阶段研究 健康受试者的药代动力学表明，RVP-001 在最高剂量下是安全的且耐受性良好 超过预期的临床剂量。这笔赠款将首先支持人类磁共振成像研究。我们将执行一个 GBCA 增强中枢神经系统病变患者的剂量范围探索研究，例如脑癌， 评估影像学疗效、药效学和安全性。我们将评估RVP-001病变程度 与未增强 MRI 以及与患者 GBCA 增强 MRI 相比的增强。目标是 该研究旨在确定有效剂量，以供进一步的临床开发和批准。 该补助金申请基于快速通道 NIH 补助金 R44 DK113906-03，并且是 重新提交拨款申请 9 R44 CA261240-04