Development of a novel small molecule-based approach for accelerated fracture repair in the aging skeleton

项目摘要/摘要 美国每年约有630万人发生骨折，占所有骨折总数的16% 肌肉骨骼损伤，并导致1000多万医院和医生办公室就诊。高达10%的 骨折是顽固性骨折，需要手术治疗才能正常愈合。关节中虚弱的骨骼 不断增长的老年人口是这种骨科问题病例数量增加的原因之一，而且 预计将刺激对新的创新解决方案的需求。根据经济和社会部的数据 联合国人口司，2013年60岁以上人口数量为8.41亿， 预计到2050年将达到20亿。因此，预计未来市场将出现巨大的需求。 几十年。开曼化学公司寻求通过开发和开发 用于高危老年人的一种新的小分子局部给药基质组合的商业化 骨折患者延迟骨折或骨不连(DNFS)。开曼群岛发现并申请了一系列 设计、合成和筛选EP4受体激动剂的靶向效力和选择性、细胞活性和 代谢和理化性质易于迅速全身清除，适合局部给药。 在该项目的第一阶段，开曼选择了具有成骨作用的先导化合物KMN-159 在体外的能力，并将作为活性药物成分(原料药)组合产品。一个 用不同剂量的KMN-159对骨传导矿化胶原基质(MCM)进行功能化处理。 在一种公认的幼年大鼠股骨临界大小的骨不连骨折模型中对联合治疗进行了评估， 表现出剂量依赖的疗效。在第二阶段，开曼群岛将展示剂量依赖的疗效 在一个类似于先导研究中使用的模型中的组合中，使用来自NIA的幼鼠和老年鼠 啮齿动物聚居地。开曼群岛还将启动原料药制造流程的cGMP开发，并将 生产将用于符合GLP标准的关键兔研究的释放原料药批次。开曼群岛将合并 发布的原料药带有商业510(K)批准的MCM，并在GLP中证明了有效性和安全性 兔子研究。

PROJECT SUMMARY/ABSTRACT Approximately 6.3 million fractures occur in the United States each year, accounting for 16% of all musculoskeletal injuries and leading to well over 10 million hospital and physician offices visits. Up to 10% of fractures are recalcitrant and require surgical intervention for proper healing. The weakened bones in the growing geriatric population are contributing to the rising number of cases of this orthopedic problem and are projected to fuel demand for new, innovative solutions. According to the Department of Economic and Social Affairs, United Nations, Population Division, the number of people aged over 60 was 841 million in 2013 and is expected to reach 2 billion in 2050. Thus, the market is anticipated to witness a significant demand in coming decades. Cayman Chemical Company, Inc. seeks to address the unmet need by developing and commercializing a new small molecule based locally-administered drug-matrix combination for at-risk elderly fracture patients with delayed or nonunion fractures (DNFs). Cayman had discovered and patented a series of EP4 receptor agonists designed, synthesized, and screened for target potency and selectivity, cell activity, and metabolic and physicochemical properties amenable to rapid systemic clearance suitable for local administration. During Phase I of this project, Cayman selected the lead compound, KMN-159, that demonstrated osteogenic capacity in vitro and will serve as the active pharmaceutical ingredient (API) in the combination product. An osteoconductive mineralized collagen matrix (MCM) was functionalized with multiple doses of KMN-159, and the combination was evaluated in an accepted young rat femoral critical size defect model of nonunion fracture, demonstrating dose-dependent efficacy. During Phase II, Cayman will demonstrate dose-dependent efficacy of the combination in a model comparable to that used in the pilot study using young and old rats from the NIA rodent colony. Cayman will also initiate cGMP development of the API manufacture process, with which it will produce the release API batch that will be used for a GLP-compliant pivotal rabbit study. Cayman will combine the released API with a commercial 510(k)-approved MCM and demonstrate efficacy and safety in the GLP rabbit study.