GMP peptide manufacturing, pharmacology/toxicology, and scaled radionuclide production and validation for Pb-212 receptor targeted alpha-particle therapy clinical trials for metastatic melanoma.

GMP 肽制造、药理学/毒理学以及大规模放射性核素生产和验证，用于针对转移性黑色素瘤的 Pb-212 受体靶向 α 粒子治疗临床试验。

• 批准号: 10080429
• 负责人: Michael King Schultz
• 金额: $ 99.99万
• 依托单位: VIEWPOINT MOLECULAR TARGETING, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080429
• 关键词: Adverse event; Agreement; Alpha Particles; Automation; Beta Particle; Cancer Patient; Capital; Chelating Agents; Chemistry; Clinic; Clinical; Clinical Trials; Collaborations; Coupling; Cyclization; Data; Devices; Discipline of Nuclear Medicine; Dose; Endotoxins; FDA approved; Formulation; Funding; Guidelines; Human; Image; Immunotherapy; In complete remission; Incidence; Investments; Iowa; Laboratories; Mediation; Medical Imaging; Metastatic Melanoma; National Security; Neuroblastoma; Neuroendocrine Tumors; New Mexico; Operative Surgical Procedures; Outcome; Patients; Peptide Receptor; Peptides; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Preparation; Process; Prodrugs; Production; Published Comment; Quality of life; Radiation; Radiation therapy; Radioisotopes; Radionuclide therapy; Radiopharmaceuticals; Radium-224; Research; Resistance; Rivers; Secure; Seeds; Small Business Innovation Research Grant; Therapeutic Trials; Therapy Clinical Trials; Therapy trial; Time; Toxicology; United States; United States National Institutes of Health; Universities; Validation; acquired drug resistance; base; commercialization; dosimetry; falls; human imaging; image guided; improved; improved outcome; innovation; manufacturing facility; melanoma; meningioma; nonhuman primate; operation; particle therapy; phase III trial; prototype; receptor; receptor binding; research and development; response; side effect; success

Melanoma incidence in the United States is growing rapidly. Surgery combined with radiation can be curative at early stages but, metastatic melanoma is usually fatal. Since 2011, targeted MAPKi and immunotherapies have improved outcomes, but low response rates, acquired resistance, and adverse events limit quality of life for these patients (5-yr. survival <25%). Under predicate R&D, Viewpoint (VMT) demonstrated the potential of peptide-receptor- targeted alpha(a)-particle ([212Pb]VMT01) therapy (PRRT) targeting the melanocortin subtype 1 receptor (MC1R); alone and in combination with FDA-approved drugs. VMT01 innovations include our biorthogonal “click” cyclization; Pb-specific chelator (PSC) that enhances 203Pb/212Pb radiometal coupling; and linker-chemistry that improves VMT01 internalization on receptor binding. The commercial potential of PRRT is evidenced by the recent FDA approval of beta(b)-particle PRRT for neuroendocrine tumors (LutatheraÔ). While objective responses were seen in only 18% of patients in the Phase 3 trial, Lutathera developer (AAA) was acquired by Novartis for $3.9Bln. Alpha(a)-particle therapy is an exciting-emerging form of PRRT that is producing objective (and even complete) responses clinically. Viewpoint secured financing to support a Phase 1 [203Pb]VMT01 human imaging/dosimetry trial according to FDA guidance (begins May, 2020; Mayo Clinic) prior to therapy trials of [212Pb]VMT01. This Direct to Phase II research is significant because VMT’s a-therapies have the potential to improve outcomes for thousands of metastatic melanoma, neuroendocrine tumor patients for whom all therapies fall short. PREDICATE MILESTONES: Secured $650k investment; a Phase II SBIR (CA203430) to conduct an [203Pb]VMT01 imaging/dosimetry trial (Mayo Clinic); an NIH R01 with the University of Iowa to (CA243014; Viewpoint CSO Schultz is Co-PI) to conduct a Phase 1 a-therapy trial (VMT-a-NET) for neuroendocrine tumors; automated radiopharmaceutical production (GMP kits); exclusively licensed IP; 203Pb supply agreement with Lantheus; established radiopharmacy operations; completed working prototype of 212Pb production device (VMT- a-GEN) and established manufacturing facilities. The following Specific Aims ready VMT for therapy trials. AIM 1. Manufacture & validate GMP VMT01 peptide and conduct pharmacology/toxicology in non-human primates in parallel with funded Phase 1 imaging trial. AIM 2. Scale and validate manufacturing of 224Ra/212Pb production device (VMT-a-GEN) for clinical trials. IMPACT: With success, we expect to have obtained validated GMP grade VMT01 peptide and the pharmacology/toxicology data needed for CMC/IND submission/approval for VMT01 therapy trials. We further expect to have scaled VMT-a-GEN manufacturing to meet the need of 1 generator per week for our funded VMT- a-NET for neuroendocrine tumors trial and yet to be funded VMT01 for metastatic melanoma therapy trial. Thus, Viewpoint will have developed the competitive advantage of control of on-demand supply of therapeutic radionuclide 212Pb for expanded trials and commercialization of VMT-a-NET and VMT01.

美国的黑色素瘤发病率正在迅速增长。手术与放疗相结合，可以治愈