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

开发一种基于小分子的新型方法，用于加速老化骨骼的骨折修复

• 批准号: 9909263
• 负责人: Stephen Douglas Barrett
• 金额: $ 72.83万
• 依托单位: CAYMAN CHEMICAL COMPANY, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909263
• 关键词: Accounting; Address; Aging; Agonist; Body Weight; Bone Regeneration; Caymans; Cells; Chemicals; Clinical Pathology; Clinical Research; Collagen; Cyclic GMP; Defect; Development; Devices; Dose; EP4 receptor; Economic Burden; Economics; Elderly; Evaluation; Fracture; Fracture Healing; Funding; Grant; Growth; Histology; Hospitals; In Vitro; Intervention; Lead; Legal patent; Measures; Metabolic; Minerals; Modeling; Office Visits; Operative Surgical Procedures; Organ; Orthopedics; Oryctolagus cuniculus; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiologic Ossification; Pilot Projects; Population; Process; Property; Radial; Rattus; Risk; Rodent; Safety; Series; Skeleton; Techniques; Tissues; United Nations; United States; aged; aging population; base; bone; design; efficacy study; first-in-human; healing; improved; innovation; manufacturing process; meetings; musculoskeletal injury; novel; novel therapeutics; off-patent; older patient; osteogenic; phase 2 study; physical conditioning; programs; repaired; small molecule; social; soft tissue

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.

项目总结/文摘