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

摘要 骨折在美国是一个很大的医疗问题，每年有600万例骨折， 非常大的成本负担。此外，由于年龄的增长，美国骨折的总负担正在增加。 人口和骨质疏松症的增加。这些骨折中的一些不能正常愈合，主要是由于感染 导致这部分患者的高附加费用和发病率。另外，开放性骨折，通常是由 创伤，可导致非常高的感染率（20-30%），这可能导致骨不连或截肢， 最好的照顾。减轻这种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，并以异常高的浓度在骨中积累， 亲和性，这使它们成为一种新型骨靶向药物递送平台的优良部分。 BioVinc是一家致力于成为骨相关疾病领域领导者的公司， 显示使用新型骨靶向双膦酸盐缀合氟喹诺酮的可行性的初步数据 化合物作为骨折愈合问题的治疗。在此FastTrack SBIR提案中，我们将 BioVinc解决方案用于商业用途的感染延迟/不愈合骨折。我们的计划是找出理想的 临床开发候选人，并完成必要的非临床研究，以推进我们的领先地位， IND阶段，使研究能够支持IND申请首次用于人体安全性试验。为了确定 缀合物的最佳剂量，并获得药代动力学的初步安全性评估， 毒理学，将进行研究，以确认开发途径的机会。具体来说，我们将 实施两个阶段，四个目标：第一阶段目标一。BP-氟喹诺酮先导化合物的合成工艺改进 化合物，以证明规模扩大到商业数量将是可行的;第一阶段目标二。开展 在小型猪中进行的初步药代动力学研究，以证明动物的骨骼暴露量， 关键性IND有效性研究; II期目标一。进一步改进合成方法， 制备50-100克规模的BP-氟喹诺酮，以提供支持以下有效性研究的材料： 小型猪和开发工艺化学大规模合成的铅化合物转移到公斤 GMP生产与初步盐和多晶型筛选;第二阶段目标二。测试铅化合物 其在小型猪骨折手术修复模型中的功效。 成功完成拟议工作将提供商业化所需的临床前数据 我们用于感染性骨折的创新产品。这将满足一个重大的未满足的医疗需求， 与愈合不良、多次手术、复发和住院时间延长相关的发病率和死亡率 因为需要长时间的恢复和每天的静脉注射治疗，这通常被证明是不成功的。

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.