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:
    10384872
  • 负责人:
  • 金额:
    $ 114.99万
  • 依托单位:
  • 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 2023-08-31
  • 项目状态:
    已结题

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.
项目摘要 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,在2006年发现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,重度肾损害患者禁用GBCA。这种禁忌症 这是一个巨大的医学挑战,因为16%的美国成年人患有中度或重度慢性肾脏疾病 (CKD),并且该患者人群不成比例地患有癌症等合并症(其中许多 化疗是肾毒性的)和外周动脉疾病,其中对比增强MRI对于 病人管理对于这些患者,没有替代成像。对比增强计算机 断层扫描可引起急性和不可逆的肾损伤,也是禁忌的。病人被拒绝 对比增强MRI检查,因为Gd相关毒性的风险,医生被迫使 关键的患者管理决策与有限的放射学信息。 自2014年以来,已经表明所有GBCA都在大脑和骨骼中存款一些Gd,即使在患有 肾功能正常,并且Gd沉积随着重复给药而累积。的毒理学意义 沉积的Gd仍然是未知的,但它是医生,患者和监管机构关注的一个活跃领域。 社. 2017年,FDA宣布对所有GBCA发出新的警告。欧洲药品管理局 暂停了与Gd风险最高相关的4种GBCA的上市许可 沉积,并且可以说,如果存在安全的无Gd替代品,则可以去除所有GBCA。积累 对于癌症幸存者和癌症高危人群,例如BRCA阳性女性, 他们需要定期进行GBCA增强型MRI进行监测,并且一生中可能会接受数十次MRI。 Reveal制药公司正在开发一种基于锰的无钆MRI造影剂RVP-001, 基于马萨诸塞州总医院发明的技术。RVP-001提供了等效的图像对比度 用于检测小鼠肿瘤、猪心肌梗死和狒狒动脉成像的商业GBCA 用于临床MRI扫描仪。大鼠中的质量平衡和生物分布表明, 从相同剂量的Gd-DOTA中,RVP-001比Gd更有效地消除,这被认为是 在Gd解离方面的安全性的现有技术GBCA。毒理学和安全药理学研究 在GLP条件下在大鼠和食蟹猴中进行的研究表明,RVP-001安全且耐受性良好 达到非常高的剂量。本项目将评估安全性、耐受性、药代动力学、消除和质量 在单次给药剂量递增、双盲、安慰剂对照阶段中,健康志愿者中RVP-001的平衡 1项临床试验,并为后续II期临床试验提供基础,以证明成像疗效。

项目成果

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Vera Hoffman其他文献

Vera Hoffman的其他文献

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{{ truncateString('Vera Hoffman', 18)}}的其他基金

Manganese Based MRI Contrast Agent
锰基 MRI 造影剂
  • 批准号:
    10678476
  • 财政年份:
    2023
  • 资助金额:
    $ 114.99万
  • 项目类别:
Fibrogenesis Targeted Manganese Based MRI Contrast Agent
纤维发生靶向锰基 MRI 造影剂
  • 批准号:
    10726638
  • 财政年份:
    2022
  • 资助金额:
    $ 114.99万
  • 项目类别:
Fibrogenesis Targeted Manganese Based MRI Contrast Agent
纤维发生靶向锰基 MRI 造影剂
  • 批准号:
    10547505
  • 财政年份:
    2022
  • 资助金额:
    $ 114.99万
  • 项目类别:
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
  • 批准号:
    10495256
  • 财政年份:
    2021
  • 资助金额:
    $ 114.99万
  • 项目类别:
Manganese-based Contrast Agent for Cardiovascular MRI
用于心血管 MRI 的锰基造影剂
  • 批准号:
    10699412
  • 财政年份:
    2020
  • 资助金额:
    $ 114.99万
  • 项目类别:
Manganese-based Contrast Agent for Cardiovascular MRI
用于心血管 MRI 的锰基造影剂
  • 批准号:
    10157538
  • 财政年份:
    2020
  • 资助金额:
    $ 114.99万
  • 项目类别:
Liver Specific Manganese Based MRI Contrast Agent
肝脏专用锰基 MRI 造影剂
  • 批准号:
    10247834
  • 财政年份:
    2019
  • 资助金额:
    $ 114.99万
  • 项目类别:
Liver Specific Manganese Based MRI Contrast Agent
肝脏专用锰基 MRI 造影剂
  • 批准号:
    10226496
  • 财政年份:
    2019
  • 资助金额:
    $ 114.99万
  • 项目类别:
Manganese based MRI contrast agent
锰基MRI造影剂
  • 批准号:
    10010976
  • 财政年份:
    2017
  • 资助金额:
    $ 114.99万
  • 项目类别:

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