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

Pb-212 受体靶向 α 粒子治疗神经内分泌肿瘤的临床前药理学、毒理学、生物分布和剂量测定以及放射性核素产生 CMC 验证。

• 批准号: 10264081
• 负责人: Michael King Schultz
• 金额: $ 99.86万
• 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: 2020-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264081
• 关键词: Agreement; Alpha Particles; Animals; Automation; Award; Benchmarking; Beta Particle; Binding; Biodistribution; Biological Markers; Capital; Cells; Chelating Agents; Chemicals; Clinic; Clinical; Column Chromatography; Custom; Data; Devices; Documentation; Endotoxins; Engineering; Ensure; Exposure to; FDA approved; Formulation; Funding; Guidelines; Human Resources; In Vitro; In complete remission; Incidence; Investments; Iowa; Isotopes; Kidney; Kidney Neoplasms; Legal patent; Letters; Licensing; Liquid substance; Malignant Neoplasms; Medical Imaging; Modification; Molecular; National Security; Neuroendocrine Therapy; Neuroendocrine Tumors; Organ; Outcome; Patients; Peptide Receptor; Peptides; Pharmacology and Toxicology; Phase; Process; Production; Property; Published Comment; Publishing; Radiation Dose Unit; Radiation exposure; Radioactivity; Radioisotopes; Radiolabeled; Radionuclide Generators; Radionuclide therapy; Radiopharmaceuticals; Radium-224; Research; Risk; Rivers; SSTR2 gene; Sales; Secure; Seeds; Series; Small Business Innovation Research Grant; Somatostatin; Sterility; System; Temperature; Testing; Text; Therapeutic; Therapeutic Trials; Therapy Clinical Trials; Therapy trial; Time; Toxic effect; Toxicology; United States National Institutes of Health; Universities; Validation; Work; commercialization; design; dosimetry; human subject; image guided; improved; improved outcome; in vivo; innovation; manufacturing facility; next generation; nonhuman primate; novel therapeutics; particle therapy; phase I trial; phase III trial; pre-clinical; protocol development; prototype; receptor; research and development; response; standard of care; success; tumor

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.

神经内分泌肿瘤(Net)是一种发病率上升、预后差(5年)的神秘恶性肿瘤。 存活率为30%)。最近，使用[177Lu]DOTATEβ(B)粒子进行多肽受体放射性核素治疗(PRRT) 与护理标准相比，治疗(Lutathera)提高了存活率，并获得了FDA的批准。然而，客观的肿瘤 在第三阶段试验中，应答率很低(18%)。尽管如此，Lutathera开发商AAA，Inc.随后 被诺华公司以39亿美元收购，展示了PRRT产品的商业潜力和重要性。 视点公司的下一代PRRT采用阿尔法(A)粒子疗法，这是PRRT的一种新兴形式， 产生客观的(甚至是完整的)反应。观点和爱荷华大学已经获得了一所国立卫生研究院 R01(CA243014-01；Viewpoint CSO Michael Schultz是Co-PI)，支持Viewpoint的第一阶段试验 [203/212PB]人类受试者中Net的VMT-a-net(a-治疗将于2021年10月开始)。VMT-a-Net(现已申请专利 正在申请中)是创新的，因为合理设计的分子修饰(正在申请专利) 显著改善放射性标记、体外细胞/内化结合(20倍)KD(高达6倍)和体内PK 显著改善肿瘤累积/保留并减少其他器官保留的性质(例如， 与竞争对手相比，肿瘤与肾脏的比例增加了8倍)。因此，这项研究具有重要意义，因为 新的预测生物标记物和疗效数据表明，治疗窗口可以显著改善 净患者的结果。这项研究具有进一步的意义，因为视点公司拥有专有的212PB 生产设备(VMT-a-Gen)建立了对商业化的212Pb按需供应的控制。在这 修订后的直接到第二阶段SBIR项目，视点将(I)采购GMP VMT-a-Net并进行IND启用 在治疗试验之前进行毒理学检查；以及(Ii)验证配方并使VMT-a-Gen的生产自动化。 预测里程碑：获得120万美元的种子融资；签署了首轮投资条款；经过验证 SST2R目标；[203/212Pb]VMT-a-Net第一阶段治疗试验的安全R01；用于生产的GMP试剂盒；独家 许可证；有保障的203铅供应(兰修斯)；治疗性同位素(212铅)生产装置的工作原型 (VMT-a-Gen)；VMT-a-Gen MFG设施齐全。完成两个具体目标为试验准备观点： 目的1.制备和验证GMP VMT-a-Net多肽，并进行FDA要求的非 人类灵长类动物在资助(R01)第一阶段临床治疗试验之前。 目标2.自动化、验证和记录212Pb生产装置(VMT-a-Gen)的制造。 影响：如果成功，我们预计将验证GMP VMT-a-Net并完成所需的毒理学 CMC/IND提交/批准的非人灵长类研究。我们还希望有自动化的 我们的~(212)Pb放射性同位素发生器(VMT-a-GEN)的制造。因此，视点将准备进入 资助的第一阶段试验，并具有按需控制治疗供应的竞争优势 放射性核素212Pb用于VMT-a-Net的扩大试验和商业化。