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)。MM是第二种最常见的血癌， 据估计，每年有32,000个新病例和13,000人死亡。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-脱氧葡萄糖(FDG)是FDA批准的唯一 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， 它们是FDG摄取和保留所必需的。此外，MM骨髓含有FDG-Avid 炎性细胞。对分子靶向、敏感和特定的多发性骨髓瘤显像剂的需求尚未得到满足 能够准确地对多发性骨髓瘤进行分期和再分期，识别高危多发性骨髓瘤患者，指导个性化多发性骨髓瘤治疗， 并评估临床疗效。这个STTR的产品将是一种特异和灵敏的PET 用于MM的显像剂(64Cu-LLP2A)已公布的数据和正在进行的首例人体试验结果显著 告知了该提案的第一阶段和第二阶段目标。第一阶段包括两个具体目标：(1) 在小鼠身上进行剂量递增和单次剂量毒性试验。(2)编制新剂量数据并上报 Eind对fda的修正。第一阶段将达到三个里程碑：(1)将根据以下条件选择新质量 在未观察到的不良反应水平(NOAEL)上，即器官毒性的临床体征(载体与实验)。(2) 基于新确定的质量和体内临床前图像质量数据，新的比活度(Ci/Mol) 将会建立起来。(3)获得FDA对SARIA发起的修改后的EIND申请的批准。第二阶段 该部分涉及一项临床试验，并有一个特定的目标：量化64Cu-LLP2A-PET成像的疗效 在一项前瞻性成像试验中检测人类活动性多发性骨髓瘤。第二阶段的里程碑是：(1)展示高 MM中64Cu-LLP2A与FDG的检出率(局灶性病变阳性扫描的百分比，p&lt；0.05) 病人。(2)64Cu-LLP2A诊断活动性多发性骨髓瘤的准确性将使用标准护理骨髓进行评估 以(BM)活检和血清生物标记物M-蛋白水平为参考标准。相关系数为 0.7将被视为相当强劲。总之，第一阶段将证明64Cu-LLP2A是可容忍的可行性 与NOAEL产生了一个新的EIND。第二阶段将提供64Cu-LLP2A-PET初步性能数据 支持64Cu-LLP2A作为新分子实体(NME)的新药申请获得FDA第二阶段的批准 临床试验。

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.