Manganese Based MRI Contrast Agent - First In Human Clinical Trial

项目摘要 基于Gd的磁共振造影剂(GBCA)在临床磁共振成像中得到了广泛的应用 核磁共振(MRI)，尤指用于癌症的检测和分期。然而，在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疾病。 因此，GBCA在有严重肾损害的患者中是禁忌的。这一禁忌症表明 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严重的慢性肾脏疾病 (CKD)，这一患者群体不成比例地患有癌症等并存疾病(其中许多 化疗是肾毒性的)和外周动脉疾病，在这些疾病中，增强MRI对 病人管理。对于这些患者来说，没有其他的成像方法。对比度增强计算 断层扫描可导致急性和不可逆转的肾脏损伤，也是禁忌。病人被拒绝了 由于Gd相关毒性的风险，增强磁共振成像检查，医生被迫进行 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，所有的GBCA都在大脑和骨骼中沉积了一些Gd，即使是在患有脑血管疾病的患者中也是如此。 肾功能正常，Gd沉积随着重复剂量的增加而累积。它的毒理学意义 沉积的Gd仍然未知，但它是医生、患者和监管机构积极关注的领域 经纪公司。2017年，FDA宣布了针对所有GBCA的新类别警告。欧洲药品管理局 暂停与Gd风险最高相关的4个GBCA的营销授权 如果有一种安全的、不含Gd的替代品，可以说已经消除了所有的GBCA。积累 对于癌症幸存者和癌症高危人群，例如BRCA阳性女性，Gd的发病率尤其令人担忧。 他们需要定期接受GBCA增强核磁共振检查进行监测，并可能在一生中接受数十次核磁共振检查。 Display PharmPharmticals正在开发一种基于锰基、无Gd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、猪心肌梗死和恒河猴动脉成像 临床核磁共振扫描仪的型号。大鼠体内的质量平衡和生物分布表明，作为 从等剂量的Gd-DOTA中消除RVP-001比从Gd-DOTA中去除Gd更有效，这被认为是状态 关于Gd解离的安全性。毒理学和安全性药理学研究 在大鼠和食蟹猴的GLP条件下进行的研究表明，RVP-001是安全和耐受性良好的 高达非常高的剂量。这个项目我们将评估安全性、耐受性、药代动力学、消除和质量 单剂量递增、双盲、安慰剂对照的RVP-001在健康志愿者体内的平衡 1次临床试验，为后续2期临床试验验证影像效果奠定基础。

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.