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.

美国的黑色素瘤事件正在迅速增长。手术与辐射结合可以治愈 早期阶段，但转移性黑色素瘤通常是致命的。自2011年以来，有针对性的MAPKI和免疫疗法具有 改善的结果，但反应率低，获得的抵抗和不良事件限制了生活质量 患者（5年生存<25％）。在谓词研发下，观点（VMT）证明了胡椒受体的潜力 靶向α（A） - 粒子（[212pb] VMT01）治疗（PRRT）靶向黑素皮质素亚型1受体（MC1R）； 单独并与FDA批准的药物结合使用。 VMT01创新包括我们的生物融合“点击” 环化； PB特异性螯合剂（PSC），可增强203pb/212pb辐射耦合；和接头化学 改善对受体结合的VMT01内在化。 PRRT的商业潜力得到了最近的 FDA批准神经内分泌肿瘤（Lutatheraô）的Beta（B） - 粒子PRRT。而客观的回应是 在第三阶段试验中，只有18％的患者在18％的患者中，洛塔特拉开发人员（AAA）被诺华以3.9 bln的价格收购。 Alpha（A） - 粒子疗法是一种令人兴奋的PRRT形式，正在产生目标（甚至完整） 临床反应。观点有安全融资以支持1阶段1 [203pb] VMT01人体成像/剂量测定法 根据[212pb] VMT01的治疗试验，根据FDA指南（始于2020年5月，梅奥诊所）。这 直接进入II期研究很重要，因为VMT的A-Therapies具有改善预后的潜力 对于成千上万的转移性黑色素瘤，所有疗法都缺乏的神经内分泌肿瘤患者。 谓词里程碑：获得65万美元的投资； II期SBIR（CA203430）进行 [203pb] VMT01成像/剂量学试验（Mayo Clinic）；爱荷华大学（CA243014）与爱荷华大学的NIH R01； 查看点CSO Schultz是Co-Pi）进行神经内分泌肿瘤的1阶段A-疗法试验（VMT-A-NET）； 自动放射药物生产（GMP套件）；独家许可的IP； 203pb供应协议与 兰海斯建立的放射药物运作；完成的212pb生产设备的工作原型（VMT- A-gen）并建立了制造设施。以下特定目的是用于治疗试验的VMT。 AIM 1。制造和验证GMP VMT01 Peppere并在非人类中进行药理学/毒理学 灵长类动物与资助的1阶段成像试验并行。 目标2。用于临床试验的224RA/212pb生产装置（VMT-A-GEN）的规模和验证制造。 影响：在成功的情况下，我们期望获得已验证的GMP级VMT01 Peppered和 CMC/IND提交/批准VMT01治疗试验所需的药理学/毒理学数据。我们进一步 希望规模扩大VMT-A-GEN制造业，以满足我们每周1个发电机的需求 A-NET用于神经内分泌肿瘤试验，尚未获得用于转移性黑色素瘤治疗试验的VMT01。那， 观点将发展控制按需治疗供应的竞争优势 Radiouclide 212pb用于扩展的试验和VMT-A-NET和VMT01的商业化。