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

美国的黑色素瘤发病率正在迅速增长。手术结合放射治疗可治愈 但是，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 结果有所改善，但低应答率、获得性耐药性和不良事件限制了这些患者的生活质量 患者(5岁存活率为25%)。在谓词研发下，视点(VMT)证明了多肽受体- 靶向α(A)粒子([212Pb]VMT01)治疗(PRRT)，靶向黑素皮质素亚型1受体(MC1R)； 单独或与FDA批准的药物联合使用。VMT01的创新包括我们的双正交“点击” 环化作用；增强~(203)Pb/~(212)Pb放射性金属偶联的铅专一性螯合剂(PSC)；以及连接化学 改善VMT01对受体结合的内化作用。PRRT的商业潜力从最近的 FDA批准β(B)粒子PRRT治疗神经内分泌肿瘤(Lutathera‘)。而客观的回答是 在第三阶段试验中，Lutathera Developer(AAA)只在18%的患者中出现，被诺华公司以39亿美元收购。 阿尔法(A)-粒子疗法是一种令人兴奋的新兴PRRT形式，它产生了目标(甚至是完全的) 临床反应。观点获得融资以支持第一阶段[203Pb]VMT01人体成像/剂量学 在[212Pb]VMT01的治疗试验之前，根据FDA的指导进行试验(从2020年5月开始；梅奥诊所)。这 直接进行第二阶段研究意义重大，因为VMT的a-疗法有可能改善结果 对于成千上万的转移性黑色素瘤，神经内分泌肿瘤患者，所有治疗方法都不适用。 预测里程碑：获得65万美元的投资；第二阶段SBIR(CA203430)，以实施 [203Pb]VMT01成像/剂量学试验(梅奥诊所)；与爱荷华大学合作的NIH R01(CA243014； 观点CSO Schultz is Co-PI)进行神经内分泌肿瘤的1期a治疗试验(VMT-a-Net)； 自动放射性药物生产(GMP成套设备)；独家许可的IP；与 兰修斯；建立了放射性制药业务；完成了212铅生产装置(VMT-)的工作原型 A-Gen)和成熟的制造设施。以下具体目标为VMT治疗试验做好准备。 目的1.GMP VMT01多肽的制备和验证及其在非人类体内的药理学/毒理学研究 灵长类动物与资助的第一阶段成像试验平行进行。 目的2.临床试验用224Ra/212Pb生产装置(VMT-a-Gen)的规模化和验证制造。 影响：如果成功，我们预计将获得经过验证的GMP级VMT01多肽和 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 预计已扩展VMT-a-Gen制造规模，以满足我们资助的VMT每周1台发电机的需求- 神经内分泌肿瘤试验和VMT01转移性黑色素瘤治疗试验。因此， 观点将形成控制治疗按需供应的竞争优势 放射性核素212Pb用于VMT-a-Net和VMT01的扩大试验和商业化。

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.