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

描述（由申请人提供）：诺华公司在近30年前开发了靶向生长抑素受体（SSTR）的合成肽，以抑制内源性生长因子对恶性组织的影响。放射治疗版本已被授权给分子洞察，该公司正在推进生长抑素难治性患者的临床试验。API肽的GMP生产和新GMP冻干试剂盒的生产已转移至专业制药生产设施。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，并且无法定量。美国以外的许多学术中心一直在使用Edotreotide Ga-68进行PET成像，最近已经出现了高质量的Ga-68发生器。临床研究已经证明了在甲状腺疾病、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使用依多曲肽Ga 68的PET成像。该提案的目标是开发一种用于产生PET显像剂的依多曲肽制剂，以定位生长抑素阳性肿瘤。具体而言，将对治疗性依多曲肽试剂盒进行稀释，并使用Ga-68发生器进行标记测试，以获得最佳标记性能并使最终产品的比活性最大化。将进行生物可比性研究，以联系公司申办的IND中目前使用的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，以确定稀释试剂盒制剂的冻干循环。将在MGH为医生申办的IND编辑这些数据，并将其扩展到SNM临床试验网络，以获得许可，并提供给广泛分布的临床研究中心。NCI，FDA，CMS，行业和临床医生之间的创新合作，以加速和扩大PET成像生物标志物的可用性，将对医学和制药领域产生重大影响。 公共卫生相关性：靶向生长抑素受体的合成肽已被用于减少与神经内分泌肿瘤相关的症状超过20年。放射治疗版本：edotreotide Y 90正在由Molecular Insight在难治性类癌患者的3期临床试验中进行测试。用正电子发射同位素Ga-68代替治疗性放射性核素，可以产生监测生长抑素阳性肿瘤的上级显像剂。生产这种PET药物的高比活性试剂盒制剂将使这种68分钟半衰期的成像剂在临床设施中可用，而不需要回旋加速器。本项目中生成的数据将桥接治疗试剂盒之前的临床前安全性试验，以支持通过SNM临床试验网络进行的多中心医生申办的IND。通过多中心IND获得PET成像生物标志物将加速测试，帮助标准化成像协议，扩大可用性，并对医学和制药领域产生重大影响。

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.