Preclinical pharmacology, toxicology, biodistribution and dosimetry, and radionuclide production CMC validation for Pb-212 receptor targeted alpha-particle therapy for neuroendocrine tumors.

神经内分泌肿瘤（NET）是一种神秘的恶性肿瘤，发病率不断增加，预后不良（5年 存活率<30%）。最近，使用[177 Lu]DOTATATE β（B）-粒子的肽受体放射性核素疗法（PRRT 与标准治疗相比，治疗（LutatheraTM）改善了生存率，并获得FDA批准。然而，客观肿瘤 在3期试验中，应答率较低（18%）。尽管如此，Lutathera开发商AAA，Inc.随后 诺华以39亿美元收购了该公司，证明了PRRT产品的商业潜力和重要性。 Viewpoint的下一代PRRT采用α（a）粒子治疗，这是一种新兴的PRRT形式， 产生客观的（甚至是完整的）反应。观点和爱荷华州大学已经获得了一个国家卫生研究院 R 01（CA 243014 -01; Viewpoint CSO Michael Schultz是Co-PI），支持Viewpoint的1期试验 [203/212 Pb]VMT-a-NET用于人类受试者的NET（a-治疗至10月开始，2021年）。VMT-a-NET（现已获得专利 申请中）是创新的，因为合理设计的分子修饰（专利正在申请中） 显着改善放射性标记、体外细胞/内化结合（20倍）Kd（高达6倍）和体内PK 显著改善肿瘤积聚/滞留并减少其它器官滞留的性质（例如， 肿瘤：肾比率增加8倍）。因此，这项研究意义重大，因为 新的实质等同生物标志物和疗效数据表明，治疗窗口可以显著改善 NET患者的结果。这项研究具有进一步的意义，因为Viewpoint的专有212 Pb 生产装置（VMT-a-GEN）建立了对用于商业化的212 Pb的按需供应的控制。在这 修订后的直接进入第二阶段SBIR项目，Viewpoint将（i）采购GMP VMT-a-NET并进行IND启用 （ii）验证VMT-a-GEN的制剂和自动化制造。 预测里程碑：获得120万美元种子融资;签署A轮投资条款;验证 SST 2 R目标;[203/212 Pb]VMT-a-NET 1期治疗试验的安全R 01;用于生产的GMP试剂盒;独家 许可证;有保障的203 Pb供应（Lantheus）;治疗性同位素（212 Pb）生产设备的工作原型 （VMT-a-GEN）; VMT-a-GEN设施建立。完成两个特定目标为Viewpoint的试验做好准备： AIM 1.生产和验证GMP VMT-a-NET肽，并在非药物环境中进行FDA要求的毒理学检查。 在资助的（R 01）1期临床治疗试验之前， AIM 2.自动化、验证和记录212 Pb生产设备（VMT-a-GEN）的制造。 影响：随着成功，我们预计将验证GMP VMT-a-NET并完成所需的毒理学 用于CMC/IND提交/批准的非人灵长类动物研究。我们还预计， 我们的212 Pb放射性同位素发生器（VMT-a-GEN）的制造。因此，观点将准备进入 受资助的1期试验，并具有按需控制治疗药物供应的竞争优势 放射性核素212 Pb用于VMT-a-NET的扩大试验和商业化。

Neuroendocrine tumors (NET) are enigmatic malignancies, with an increasing incidence and poor outcomes (5-yr survival <30%). Recently, peptide-receptor radionuclide therapy (PRRT) using [177Lu]DOTATATE beta(b)-particle treatment (LutatheraÔ) improved survival vs standard of care and was FDA approved. However, objective tumor responses were low (18%) in the Phase 3 trial. Nonetheless, Lutathera developer AAA, Inc. was subsequently acquired by Novartis for $3.9 Bln demonstrating the commercial potential and significance of PRRT products. Viewpoint’s next-generation PRRT employs alpha(a)-particle therapy, an emergent form of PRRT that is producing objective (and even complete) responses. Viewpoint and the University of Iowa have secured an NIH R01 (CA243014-01; Viewpoint CSO Michael Schultz is Co-PI) that supports a Phase 1 trial of Viewpoint’s [203/212Pb]VMT-a-NET for NET in human subjects (a-therapy to begin Oct., 2021). VMT-a-NET (patent now pending) is innovative because rationally-designed molecular modifications (patents now pending) significantly improve radiolabeling, in vitro cell/internalization binding (20-fold) Kd (up to 6-fold) and in vivo PK properties that significantly improve tumor accumulation/retention and reduce other organ retention (e.g., tumor:kidney ratio increased 8-fold) compared to competing agents. Thus, this research is significant because new predicate biomarker and efficacy data demonstrate a therapeutic window that can significantly improve outcomes for NET patients. This research is further significant because Viewpoint’s proprietary 212Pb production device (VMT-a-GEN) establishes control of on-demand supply of 212Pb for commercialization. In this revised Direct to Phase II SBIR project, Viewpoint will (i) procure GMP VMT-a-NET and conduct IND-enabling toxicology prior to the therapy trial; and (ii) validate formulations and automate manufacturing of VMT-a-GEN. PREDICATE MILESTONES: Secured $1.2Mln seed financing; signed terms for Series A investment; validated SST2R target; secured R01 for [203/212Pb]VMT-a-NET Phase 1 therapy trial; GMP kits for production; exclusive licenses; secured 203Pb supply (Lantheus); working prototype of therapeutic isotope (212Pb) production device (VMT-a-GEN); VMT-a-GEN mfg. facilities established. Completing two Specific Aims readies Viewpoint for trials: AIM 1. Manufacture and validate GMP VMT-a-NET peptide and conduct FDA-required toxicology in non- human primates prior to a funded (R01) Phase 1 clinical therapy trial. AIM 2. Automate, validate, and document manufacturing of 212Pb production device (VMT-a-GEN). IMPACT: With success, we expect to have validated GMP VMT-a-NET and completed required toxicology studies in non-human primates for CMC/IND submission/approval. We further expect to have automated manufacturing of our 212Pb radioisotope generator (VMT-a-GEN). Thus, Viewpoint will be prepared to enter the funded Phase 1 trial and have the competitive advantage of on-demand control of the supply of therapeutic radionuclide 212Pb for expanded trials and commercialization of VMT-a-NET.