SBIR-STTR Award

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.

Thesaurus Terms:

A kit based PET agent: edotreotide Ga 68 for clinical imaging of somatostatin receptor expressing tissue. 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 (MIP) and the company is moving forward with phase 3 clinical testing of in somatostatin refractory patients. GMP manufacturing of the API peptide and therapeutic freeze dried kits have been performed by MIP. An approved diagnostic agent, to image SSTR expressing tumors, Indium-111 Octreoscan is already commercial available, although the photon emitting isotope produces low quality images and is not quantitative. Numerous academic centers outside the US have been performing PET imaging with edotreotide Ga-68 and two commercial gallium-68 generators have become available. Clinical studies have demonstrated PET imaging with edotreotide Ga 68 in thyroid disease, neuroendocrine tumors, gastrinomas, carcinoid, meningiomas, prostate cancer, thymoma, non- small cell lung carcinoma and as a potential in vivo monitor of therapeutic drug development and genomic medicine research. The goal of this proposal is to make sterile, GMP quality imaging formulation kits of edotreotide available for generation of the PET agent to image somatostatin receptor expressing tissue. Specifically, the GMP campaign for imaging edotreotide kits will be initiated and a physician sponsored safety assessment IND will be conducted for edotreotide Ga-68 (with our collaborators at Mass General Hospital). The Chemistry, manufacturing and controls for the final drug product solution along with a normal human image data base and human safety reports will be generated. Pre-clinical biological comparability studies and preclinical toxicity data on the API and precursor, will be combined with the human phase 1 data and made available to the SNM Clinical trial Network and be made available to widely dispersed clinical sites as amended INDs for research and efficacy testing. 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 research, therapeutic treatment monitoring and new drug development.

Public Health Relevance:
A kit based PET agent: edotreotide Ga 68 for clinical imaging of somatostatin receptor expressing tissue. The challenge for diagnostic drugs is their occasional use does not provide a financial incentive to develop new agents. Providing a consistent high quality agent for testing various potential indications at multiple clinical sites s paramount to obtaining innovative new products. We plan to make sterile high quality kits for production of edotreotide Ga 68 to facilitate community access to this investigational molecular imaging biomarker.