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（净）是神秘的恶性肿瘤，发生率越来越差（5年 生存<30％）。最近，使用[177LU] Dotatate beta（B） - 粒子的肽受体辐射疗法（PRRT） 治疗（Lutatheraô）提高了生存与护理标准，并获得了FDA批准。但是，客观肿瘤 在第三阶段试验中，反应较低（18％）。尽管如此，Lutathera开发人员AAA，Inc。随后是 由诺华以$ 3.9的BLN收购，证明了PRRT产品的商业潜力和意义。 Viewpoint的下一代PRRT员工Alpha（A） - 粒子疗法，一种新兴的PRRT形式 产生目标（甚至是完整）的响应。观点和爱荷华大学获得了NIH R01（CA243014-01; Viewpoint CSO Michael Schultz是Co-Pi），支持观点的第一阶段试验 [203/212pb]人类受试者的网络vmt-a-net（2021年10月开始的A疗法）.VMT-A-NET（立即专利） 待处理）是创新的，因为合理设计的分子修饰（现在的专利正在待处理） 显着改善了放射性标记，体外细胞/内在化结合（20倍）KD（最多6倍）和体内PK 显着改善肿瘤积累/保留并减少其他器官保留的特性（例如， 肿瘤：与竞争剂相比，肾脏比率增加了8倍）。那是重要的，因为 新的谓词生物标志物和有效数据展示了一个可以显着改善的治疗窗口 净患者的结果。这项研究更加重要，因为观点的专有212pb 生产装置（VMT-A-GEN）建立了对212pb的按需供应进行商业化的控制。在这个 转到第二阶段SBIR项目，观点将（i）采购GMP VMT-A-NET并进行指控 治疗试验之前的毒理学； （ii）验证VMT-A-Gen的公式和自动化制造。 谓词里程碑：获得1200万美元的种子融资； A系列投资的签名条款；经过验证 SST2R目标；为[203/212pb] VMT-A-NET 1阶段治疗试验确保R01； GMP生产套件；独家的 许可证；获得203pb供应（Lantheus）；热同位素（212pb）生产装置的工作原型 （vmt-a-gen）; VMT-A-Gen Mfg。建立的设施。完成两个特定的目标，重新观察试验的观点： AIM 1。制造和验证GMP VMT-A-NET胡椒，并在非 - 在经过资助（R01）1期临床治疗试验之前的人类初级试验。 目标2。自动化，验证和文档生产设备（VMT-A-GEN）的生产。 影响：在成功之后，我们希望已经验证了GMP VMT-A-NET并完成了所需的毒理学 针对CMC/IND提交/批准的非人类隐私研究。我们进一步期望自动化 我们的212PB放射性同位素发生器（VMT-A-GEN）的制造。那就是，将准备进入 资助的第一阶段试验，具有按需控制治疗供应的竞争优势 Radioionuclide 212pb，用于扩大试验和VMT-A-NET的商业化。