Development and Commercialization of a New Molecularly Targeted Imaging Agent for Multiple Myeloma

项目总结 Sarya LLC(Sarya)是一家核医学技术公司，成立目的是将放射性药物商业化。 这种快速跟踪STTR的目标是开发一种新的特定显像剂，用于诊断、分期和 治疗血液病、多发性骨髓瘤(MM)。多发性骨髓瘤是第二种最常见的血癌 据估计，每年新增病例3.2万例，死亡1.3万人。准确的检测对于提高 多发性骨髓瘤患者的生存率。传统的骨骼测量和骨扫描对溶骨症的敏感性有局限性 用正电子发射断层扫描(PET)放射性药物进行的MM正电子发射断层扫描(PET)中的病变 (显像剂)是一种敏感、定量和非侵入性的临床成像技术，可以准确地检测到， MM细胞在全身的定位和表型。18F-氟代脱氧葡萄糖(FDG)是唯一的FDA- 批准用于MM的PET显像剂不幸的是，MM细胞表达低水平的GLUT-1转运体和 己糖激酶，这是FDG摄取和保留所必需的。此外，MM骨髓中含有FDG- 嗜热性炎症细胞。对分子靶向、灵敏和特异的多发性骨髓瘤成像的需求尚未得到满足 能够准确分期和重新分期MM，识别高危MM患者，指导个性化MM的代理 治疗，并评估治疗的临床反应。这个STTR的产品将是一个特定的和 用于MM的灵敏的PET显像剂(64Cu-LLP2A)已公布的数据和正在进行的首例人体试验结果 对这项提议的第一阶段和第二阶段目标有很大的了解。第一阶段分段由两个部分组成 具体目的：(1)进行小鼠剂量递增和单剂量毒性试验。(2)为新项目编制数据 给药并向FDA提交EIND修正案。第一阶段将达到三个里程碑：(1)将有新的质量 根据未观察到的不良反应水平(NOAEL)选择，即器官毒性的临床体征(载体与 实验性的)。(2)基于新确定的质量和体内临床前图像质量数据，新的 将确定比活度(Ci/摩尔)。(3)获得FDA批准SARYA赞助的修订后的EIND 申请。第二阶段涉及一项临床试验，并有一个特定的目标：量化 64铜-LLP2A-PET显像检测活动性多发性骨髓瘤的前瞻性成像试验第二阶段 里程碑是：(1)显示高检测率(对局灶性病变呈阳性的扫描的百分比，p&lt；0.05) MM患者64Cu-LLP2A与FDG的比较。(2)对64Cu-LLP2A诊断活动性MM的准确性进行评估 以常规骨髓活检和血清生物标记物M-蛋白水平为标准 参考资料。相关系数为0.7将被视为相当强。总之，第一阶段将证明 64Cu-LLP2A对NOAEL耐受的可行性导致新的EIND。二期将提供64Cu- LLP2A-PET初步性能数据支持64Cu-LLP2A作为新药的新药应用 FDA批准的第二阶段临床试验的分子实体(NME)。

PROJECT SUMMARY Sarya LLC (Sarya) is a nuclear medicine technology company formed to commercialize radiopharmaceuticals. The goal of this Fast-Track STTR is to develop a new specific imaging agent for diagnosis, staging, and treatment of the hematological cancer, multiple myeloma (MM). MM is the 2nd most common blood cancer with an estimated 32,000 new cases and 13,000 deaths per year. Accurate detection is critical for enhancing survival in MM patients. Traditional skeletal survey and bone scans have sensitivity limitations for osteolytic lesions manifested in MM. Positron Emission Tomography (PET) performed with a PET radiopharmaceutical (imaging agent) is a sensitive, quantitative and non-invasive clinical imaging technology to accurately detect, localize and phenotype MM cells throughout the body. 18F-fluorodeoxyglucose (FDG) is the only FDA- approved PET imaging agent for MM. Unfortunately, MM cells express low levels of GLUT-1 transporter and hexokinase, which are required for FDG uptake and retention. Additionally, MM bone marrow harbors FDG- avid inflammatory cells. There is an unmet need for molecularly targeted, sensitive and specific MM imaging agents that can accurately stage and restage MM, identify high-risk MM patients, guide personalized MM treatment, and evaluate clinical response to treatment. The product of this STTR will be a specific and sensitive PET imaging agent (64Cu-LLP2A) for MM. Published data and ongoing first-in-human trial results have significantly informed the Phase I and II aims of this proposal. The Phase I Segment consists of two specific aims: (1) Perform dose escalation and single dose toxicity testing in mice. (2) Compile data for new dose and submit amendment of eIND to FDA. Three milestones will be met in Phase I: (1) A new mass will be selected based on no-observed-adverse-effect level (NOAEL), i.e. clinical signs of organ toxicity (vehicle vs experimental). (2) Based on the new determined mass, and in vivo preclinical image quality data, a new specific activity (Ci/mol) will be established. (3) Obtain FDA approval of Sarya sponsored amended eIND application. The Phase II segment involves a clinical trial and has one specific aim: Quantify the efficacy of 64Cu-LLP2A-PET imaging for detecting active MM in humans in a prospective imaging trial. Phase II milestones are: (1) Demonstrate high detection rates (% of scans that are positive for a focal lesion, p<0.05) for 64Cu-LLP2A versus FDG in MM patients. (2) Accuracy of 64Cu-LLP2A for active MM will be assessed using standard-of-care bone marrow (BM) biopsies and serum biomarker M-protein levels as the standards of reference. A correlation coefficient of 0.7 will be considered reasonably strong. In summary, Phase I will prove feasibility that 64Cu-LLP2A is tolerable with NOAEL resulting in a new eIND. Phase II will provide 64Cu- LLP2A-PET preliminary performance data to support a New Drug Application for 64Cu-LLP2A as a New Molecular Entity (NME) for FDA approval of Phase 2 clinical trials.