A Novel Bone Targeted Antibiotic Therapy for the Treatment of Infected Fractures

摘要 在美国，骨折是一个很大的医疗问题，每年有600万次演讲，导致 成本负担非常大。此外，由于骨折的老龄化，美国骨折的总负担正在增加 人口和骨质疏松症的增加。其中一些骨折不能正常愈合，主要是由于感染。 导致这部分患者的高额外费用和发病率。此外，开放性骨折，通常是由 创伤，可导致很高的感染率(20%-30%)，甚至可能导致骨不连或截肢 以最周到的照顾。减轻这一重大负担对受影响患者的生活质量和 美国的公共卫生和卫生系统是一个非常重要的需求。双膦酸盐(BPS)是一类 用于治疗骨吸收障碍的治疗性化合物，并在骨骼中积聚异常高 亲和力，这使它们成为新型骨靶向给药平台的极佳部分。 BioVinc.是一家在骨骼相关疾病领域处于领先地位的公司，拥有广泛的 新型骨靶向双膦酸偶联氟喹诺酮的可行性初步研究 作为治疗骨折愈合问题的化合物。在此FastTrack SBIR提案中，我们将 BIOVINC解决方案，用于商业用途的感染性延迟/不愈合骨折。我们的计划是确定理想的 临床开发候选人并完成必要的非临床研究，以推动我们的领先地位 IND阶段，使研究能够支持IND在人类安全试验中的第一次应用。为了确定 结合物的最佳剂量并获得药物动力学和药物动力学的初步安全性评估 毒理学方面，将进行研究，以确认开发途径的机会。具体来说，我们将 分两个阶段，有四个目标：第一阶段，目标一。BP-氟喹诺酮先导化合物合成工艺的改进 为了证明扩大到商业数量将是可行的；第一阶段的目标是第二阶段。执行 在小型猪体内的初步药代动力学研究，以证明动物的骨骼暴露用于 Pivotal Ind Enabling功效研究；第二阶段目标一。进一步改进综合方法论，使 制备50-100克的BP-氟喹诺酮类药物，为药物疗效研究提供材料 小型猪和开发可转移到公斤的铅化合物大规模合成的过程化学 GMP生产，初步筛选食盐和多晶型；第二阶段，目标二。测试先导化合物是否 其在小型猪骨折修复手术模型中的疗效。 拟议工作的成功完成将提供商业化所需的临床前数据 我们用于感染骨折的创新产品。这将满足一个重大的未得到满足的医疗需求，以减少 与愈合不良、多次手术、复发和住院时间延长有关的发病率和死亡率 由于需要长时间的康复和每天静脉注射治疗，这往往被证明是不成功的。

ABSTRACT Bone fracture is a large medical problem in the US, with 6 million presentations each year, resulting in very large cost burdens. In addition, the total burden of fractures in the US is growing due to the aging of the population and increases in osteoporosis. Some of these fractures do not heal properly, largely due to infections resulting in high additional costs and morbidity in this subset of patients. Also, open fractures, often caused by trauma, can lead to a very high rate of infection (20-30%), which might result in nonunion or amputation even with the best of care. Reducing this significant burden to both the quality of life of the patients affected and to the US public health and health systems is a very significant need. Bisphosphonates (BPs) are a class of therapeutic compounds used to treat bone resorptive disorders, and accumulate in bone with exceptionally high affinity, which makes them an excellent moiety for a novel bone targeted drug delivery platform. BioVinc is a company founded to be a leader in bone related diseases and has an extensive amount of preliminary data showing the feasibility of using novel bone targeted bisphosphonate conjugated fluoroquinolone compounds as a treatment for bone fracture healing problems. In this FastTrack SBIR proposal we will move the BioVinc solution for infected delayed/non-union fracture toward commercial use. Our plan is to identify the ideal clinical development candidate and complete the necessary nonclinical studies in order to advance our lead to the stage of IND enabling studies to support IND application for first in human safety trials. In order to determine the optimal doses of the conjugates and to get an initial safety assessment of the pharmacokinetics and toxicology, studies will be conducted to confirm the opportunity for a development pathway. Specifically, we will carry out two phases with four aims: Phase I Aim One. Improve synthesis of the BP-fluoroquinolone lead compound to demonstrate that scale up to commercial quantities will be feasible; Phase I Aim Two. Carry out initial pharmacokinetic studies in the mini pig to demonstrate skeletal exposure in the animal to be used for pivotal IND enabling efficacy studies; Phase II Aim One. Further improve synthetic methodology to allow the preparation of the BP-fluoroquinolone at the 50-100 gram scale to provide material to support efficacy studies in mini pig and develop the process chemistry for large scale synthesis of the lead compound transferable to kg GMP production with preliminary salt and polymorph screening; Phase II Aim Two. Test the lead compound for its efficacy in the mini pig model of surgical repair of fractures. Successful completion of the proposed work will provide the preclinical data necessary to commercialize our innovative product for use in infected fractures. This will meet a significant unmet medical need to reduce the morbidity and mortality associated with poor healing, multiple surgeries, relapse, and extended hospital stays due to the need for lengthy recoveries and daily IV therapy that often proves unsuccessful.