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

黑色素瘤在美国的发病率正在迅速增长。手术结合放射治疗可以治愈， 早期阶段，但转移性黑素瘤通常是致命的。自2011年以来，靶向MAPKi和免疫疗法 改善的结果，但低反应率，获得性耐药，和不良事件限制了这些生活质量 患者（5年）存活率<25%）。在同品种研发中，Viewpoint（VMT）证明了肽-受体- 靶向黑皮质素亚型1受体（MC 1 R）的靶向α（a）粒子（[212 Pb] VMT 01）治疗（PRRT）; 单独使用和与FDA批准的药物联合使用。VMT 01创新包括我们的双正交“点击” 环化;增强203 Pb/212 Pb放射性金属偶联的Pb特异性螯合剂（PSC）;和 改善VMT 01对受体结合的内化。PRRT的商业潜力由最近的 FDA批准β（B）-粒子PRRT用于神经内分泌肿瘤（Lutatheraplastoma）。虽然客观的反应是 在3期试验中，只有18%的患者出现这种情况，Lutathera developer（AAA）被诺华公司以39亿美元收购。 阿尔法（a）粒子治疗是一种令人兴奋的新兴形式的PRRT，是生产客观（甚至完全） 临床反应。Viewpoint获得融资以支持第1阶段[203 Pb] VMT 01人体成像/剂量测定 在[212 Pb] VMT 01治疗试验之前，根据FDA指南进行试验（2020年5月开始;马约诊所）。这 直接进入II期研究是重要的，因为VMT的a-疗法有可能改善结果 治疗数以千计的转移性黑色素瘤和神经内分泌肿瘤患者，这些患者的所有治疗都达不到要求。 可预测的里程碑：获得65万美元的投资;第二阶段SBIR（CA 203430）， [203 Pb] VMT 01成像/剂量测定试验（马约诊所）;爱荷华州大学的NIH R 01（CA 243014; Viewpoint CSO Schultz是Co-PI）进行神经内分泌肿瘤的1期a-治疗试验（VMT-a-NET）; 自动化放射性药物生产（GMP试剂盒）;独家许可的IP; 203 Pb供应协议， Lantheus;建立了放射性药物业务;完成了212 Pb生产设备（VMT-212）的工作原型。 a-GEN）和已建立的生产设施。以下具体目标准备VMT治疗试验。 AIM 1.生产和验证GMP VMT 01肽，并在非人类中进行药理学/毒理学研究 灵长类动物与受资助的1期成像试验平行。 AIM 2.用于临床试验的224 Ra/212 Pb生产器械（VMT-a-GEN）的规模化和验证制造。 影响：随着成功，我们预计将获得经过验证的GMP级VMT 01肽， VMT 01治疗试验CMC/IND提交/批准所需的药理学/毒理学数据。我们进一步 预计将扩大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- a-NET用于神经内分泌肿瘤试验，VMT 01用于转移性黑色素瘤治疗试验尚未获得资助。因此，在本发明中， 观点将开发控制治疗药物按需供应的竞争优势 用于VMT-a-NET和VMT 01的扩大试验和商业化的放射性核素212 Pb。

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.