Targeting Therapeutics for Accelerated Bone Fracture Repair

加速骨折修复的靶向治疗

• 批准号: 9981850
• 负责人: Stewart Andrew Low
• 金额: $ 54.69万
• 依托单位: NOVOSTEO, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981850
• 关键词: Acceleration; Address; Age; Anabolic Agents; Animal Model; Animals; Biodistribution; Bolus Infusion; Bone Growth; Bone Regeneration; Bone callus; Bypass; Canis familiaris; Cessation of life; Charge; Chemistry; Clinic; Clinical Trials; Data; Development; Dose; Drug Kinetics; Drug Targeting; Drug toxicity; Economic Burden; Economics; Elderly; Ethics; Extravasation; Failure; Femoral Fractures; Formulation; Fracture; Fracture Healing; Frequencies; Goals; Grant; Hip Fractures; Human; Hydroxyapatites; Lead; Life; Ligands; Mechanics; Methods; Minerals; Modification; Monitor; Morbidity - disease rate; Non-Rodent Model; Oligopeptides; Operative Surgical Procedures; Osteoporosis; Osteoporotic; Paracrine Communication; Patients; Pharmaceutical Preparations; Phase; Physical therapy; Productivity; Quality of life; Recovery; Role; Route; Safety; Site; Skilled Nursing Facilities; Small Business Innovation Research Grant; Specificity; Spinal Fractures; Structure; Subcutaneous Injections; Surface; Technology; Therapeutic; Therapy Clinical Trials; Time; Tissues; Toxic effect; Translations; Trauma; Treatment Efficacy; Treatment-related toxicity; United States; Work; aging population; autocrine; bone; bone quality; conventional therapy; cost; craniofacial; design; drug synthesis; genotoxicity; healing; improved; lead candidate; mortality; older patient; parathyroid hormone-related protein; preclinical evaluation; reconstruction; repaired; scale up; side effect; targeted treatment

Project Summary/Abstract Significance: The failure of bone fractures to adequately repair in elderly patients causes significant morbidity and mortality each year in the United States. This problem will continue to be exacerbated by an aging population, with a 160% increase in hip fractures alone expected by 2040 and significant costs in lost work, quality of life, physical therapy, extended care facility stays, and surgeries. Conventional therapy includes mechanically stabilizing the fracture, but thus far, no systemic bone anabolic therapies exist to target and accelerate fracture repair. Preliminary Data: Novosteo Inc. has developed a fracture targeted therapeutic that has demonstrated a dramatic acceleration in healing time and callus formation and remarkable specificity to bone fracture sites. Administered systemically through subcutaneous injection, the drug selectively accumulates on hydroxyapatite, the inorganic portion of bone exposed in a fracture, providing a site-specific dose of anabolic agent. The targeted specificity to the fracture callus limits accumulation of the drug in off-target tissues, reducing the potential for side effects. Also, the systemic delivery route allows for multiple doses of anabolic agent to be administered rather than a single bolus possible via surgery. While bypassing the invasiveness of surgery, the drug mimics a locally- administered anabolic in that drug accumulation is limited to the fracture site and sufficient dose can be administered for accelerated healing. Thus far, Novosteo's biodistribution studies have demonstrated no detectable toxicities at doses that dramatically accelerate fracture repair. Proposal: The overall goal of this Fast-Track SBIR proposal will be to prepare the proposed fracture-targeted therapy for clinical trials. The first step will be to optimize the chemistry of Novosteo's lead candidate. This will be accomplished in Phase I by performing the following: (1) optimization of the fracture targeting ligand composition and (2) conducting a thorough analysis of the fracture targeted drug's toxicity. Phase II will focus on preparing the fracture targeted drug for IND. This will be accomplished by: (1) validating Phase I results in a non-rodent model, (2) conducting MTD, GLP pharmacokinetics, and GLP toxicity studies, and (3) conducting genotoxicity analysis to evaluate any morphogenic dangers. Conclusion: The ability to accelerate bone fracture repair is a fundamental need that has not been addressed by conventional methods. If granted, the completion of the proposed studies would enable the optimization and pre-clinical evaluation of an indispensable therapy for bone fracture repair. Its safety and efficacy could then be explored and evaluated in other settings where accelerated bone regeneration is desired, such as hairline vertebral fractures in osteoporosis patients or craniofacial reconstruction and repair.

项目总结/摘要 意义：老年患者骨折未能充分修复会导致严重发病率 和死亡率。这一问题将继续因老龄化而加剧。 人口，预计到2040年，仅髋部骨折就将增加160%，失业成本巨大， 生活质量、物理治疗、长期护理设施停留和手术。常规治疗包括 机械稳定骨折，但到目前为止，还没有系统的骨合成代谢治疗存在的目标， 加速骨折修复。 初步数据：Novosteo Inc.开发了一种骨折靶向治疗方法， 愈合时间和骨痂形成的显著加速以及对骨折部位的显著特异性。 通过皮下注射全身给药，药物选择性地积聚在羟基磷灰石上， 骨折处暴露的骨的无机部分，提供特定部位剂量的合成代谢剂。目标 对骨折骨痂的特异性限制了药物在非靶组织中的积累，降低了副作用的可能性。 方面的影响.此外，全身递送途径允许施用多剂量的合成代谢剂，而不是 比通过手术单次推注更有效。在绕过手术的侵入性的同时，这种药物模拟了局部- 施用合成代谢药物的原因在于药物积聚限于骨折部位，并且可以 用于加速愈合到目前为止，Novosteo的生物分布研究表明， 可检测到的毒性，大大加速骨折修复的剂量。 提案：本快速通道SBIR提案的总体目标是准备针对 临床试验的治疗。第一步将是优化Novosteo主要候选药物的化学成分。这将 在阶段I中通过进行以下操作来完成：（1）优化压裂靶向配体 （2）对骨折靶向药物的毒性进行彻底分析。第二阶段将重点关注 为IND准备骨折靶向药物。这将通过以下方式实现：（1）验证I期结果， 非啮齿动物模型，（2）进行MTD、GLP药代动力学和GLP毒性研究，和（3）进行 遗传毒性分析，以评估任何形态发生危险。 结论：加速骨折修复的能力是尚未得到解决的基本需求 通过常规方法。如果获得批准，完成拟议的研究将能够优化和 骨折修复不可或缺的治疗方法的临床前评价。它的安全性和有效性可以 在需要加速骨再生的其他环境中进行了探索和评价，例如发际线 骨质疏松症患者的脊椎骨折或颅面重建和修复。