Development of a kit based PET molecular imaging agent: edotreotide Ga 68 for so

开发基于试剂盒的 PET 分子显像剂：edotreotide Ga 68

• 批准号: 8059064
• 负责人: JAMES F KRONAUGE
• 金额: $ 26.3万
• 依托单位: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2011-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059064
• 关键词: Development; kit; based; PET; molecular

DESCRIPTION (provided by applicant): Synthetic peptides targeted to Somatostatin receptors (SSTR) were developed almost 30 years ago by Novartis to inhibit the effects of endogenous growth factors on malignant tissues. The radio-therapeutic version has been licensed to Molecular Insight and the company is moving forward with clinical testing of in somatostatin refractory patients. GMP manufacturing of the API peptide and production of new GMP freeze dried kits have been transferred to specialty pharmaceutical manufacturing facilities. The commercial imaging agent, to diagnose SSTR expressing tumors, Indium-111 Octreoscan, produces very low quality images and is not quantitative. Numerous academic centers outside the US have been performing PET imaging with edotreotide Ga-68 and recently a high-quality gallium-68 generator has become available. Clinical studies have demonstrated PET imaging with edotreotide Ga 68 in thyroid disease, neuroendocrine tumors, gastrinomas, carcinoid, meningiomas, prostate cancer, thymoma, and non-small cell lung carcinoma. The goal of this proposal is to develop a formulation of edotreotide for generation of the PET imaging agent to localize somatostatin positive tumors. Specifically, dilution of the therapeutic edotreotide kits will be performed, and labeling tested with Ga-68 generator eluate, to obtain optimal labeling performance and maximize the specific activity of the final product. Biological comparability studies will be performed to link to previous chemical and preclinical toxicity data on the API and precursor formulation currently used in the company sponsored IND. Development studies will also be performed to identify a lyophilization cycle of the dilute kit formulation. This data will be compiled for a physician sponsored IND at MGH and extended to the SNM Clinical trial Network for licensing to be made available to widely dispersed clinical sites. An innovative collaboration between NCI, FDA, CMS, industry and clinicians to accelerate and expand the availability of PET imaging biomarkers would have a significant impact on the fields of medicine and pharmaceuticals. PUBLIC HEALTH RELEVANCE: Synthetic peptides targeted to Somatostatin receptors have been used to reduce the symptoms associated with neuroendocrine tumors for over 20 years. The radio-therapeutic version: edotreotide Y 90 is being tested by Molecular Insight in phase 3 clinical trials in refractory carcinoid patients. Substituting the therapeutic radionuclide with the positron-emitting isotope Ga-68, can produce a superior imaging agent to monitor somatostatin positive tumors. A high specific activity kit formulation to produce this PET pharmaceutical will make this 68 min half-life imaging agent available at clinical facilities without the need of a cyclotron. The data generated in this project will bridge previous pre-clinical safety testing for the therapeutic kit to support a multi-center physician sponsored IND through the SNM Clinical trial Network. The access to PET imaging biomarkers, through a multi-centered IND, would accelerate testing, help standardize imaging protocols, expand availability and have a significant impact on the fields of medicine and pharmaceuticals.

描述（由申请人提供）：诺华公司在大约 30 年前开发了针对生长抑素受体（SSTR）的合成肽，用于抑制内源性生长因子对恶性组织的影响。放射治疗版本已获得 Molecular Insight 的许可，该公司正在推进对生长抑素难治性患者的临床测试。 API 肽的 GMP 生产和新的 GMP 冻干试剂盒的生产已转移到专业药品生产设施。用于诊断表达 SSTR 的肿瘤的商业成像剂 Indium-111 Octreoscan 产生的图像质量非常低，并且不能定量。美国以外的许多学术中心一直在使用 edotreotide Ga-68 进行 PET 成像，并且最近推出了高质量的镓 68 发生器。临床研究已证明，使用 edotreotide Ga 68 可以在甲状腺疾病、神经内分泌肿瘤、胃泌素瘤、类癌、脑膜瘤、前列腺癌、胸腺瘤和非小细胞肺癌中进行 PET 成像。该提案的目标是开发一种 edotreotide 制剂，用于生成 PET 显像剂以定位生长抑素阳性肿瘤。具体而言，将对治疗性艾曲肽试剂盒进行稀释，并用 Ga-68 发生器洗脱液进行标记测试，以获得最佳标记性能并最大化最终产品的比活性。将进行生物可比性研究，以链接到公司赞助的 IND 目前使用的 API 和前体制剂的先前化学和临床前毒性数据。还将进行开发研究以确定稀释试剂盒配方的冻干周期。这些数据将针对 MGH 的医生赞助的 IND 进行编译，并扩展到 SNM 临床试验网络，以获得许可，以供广泛分布的临床站点使用。 NCI、FDA、CMS、行业和临床医生之间的创新合作旨在加速和扩大 PET 成像生物标志物的可用性，这将对医学和制药领域产生重大影响。 公共健康相关性：20 多年来，针对生长抑素受体的合成肽一直被用来减轻与神经内分泌肿瘤相关的症状。放射治疗版本：edotreotide Y 90 正在难治性类癌患者中进行 3 期临床试验，由 Molecular Insight 进行测试。用正电子发射同位素 Ga-68 替代治疗性放射性核素，可以产生一种优异的显像剂来监测生长抑素阳性肿瘤。用于生产这种 PET 药物的高比活性试剂盒配方将使这种半衰期为 68 分钟的显像剂可在临床设施中使用，而无需回旋加速器。该项目生成的数据将连接之前治疗套件的临床前安全性测试，以支持通过 SNM 临床试验网络进行的多中心医生赞助的 IND。通过多中心 IND 获得 PET 成像生物标志物将加速测试、帮助标准化成像方案、扩大可用性并对医学和制药领域产生重大影响。