Bone targeted delivery of an antimicrobial drug for osteomyelitis therapy

摘要 一般来说，在接受全膝关节和全髋关节手术的患者中，骨髓炎的发生率约为1-2%。 替代手术。当患者不得不接受翻修治疗以更换感染的植入物时，死亡率 是18%。由于美国人口老龄化和关节成形术总数的增加 在这一人群中，医院每年接受感染翻修手术的费用预计将达到16亿美元 到2020年。减轻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化合物，并在骨骼中积聚，具有特殊的 高亲和力，使其成为新型骨靶向给药平台的极佳部分。 BioVinc是一家成立于骨骼相关疾病领域的领先公司，最近展示了 这个项目的第一阶段，使用一种新的双膦酸酯偶联抗菌化合物作为 治疗骨髓炎。在这个第二阶段的SBIR提案中，我们将把BioVinc型骨髓炎解决方案 通过创造额外的具有适当特性的BP-抗生素结合物用于 骨髓炎作为我们目前的引线的改进或备份，以及在 人工关节感染翻修手术新模型。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支持研究阶段，以支持IND在人体安全性和有效性试验中的首次应用。为了 确定结合物的最佳剂量，并对药物动力学进行初步的安全性评估 和毒理学，将进行研究，以确认开发途径的机会。具体来说， 我们将：1)合成新的BP-抗生素结合物，包括放大我们在 第一阶段，具有最佳的骨骼亲和力和最佳的抗菌效果；并开发化学工艺 用于生产1公斤临床候选的GMP；2)在PJI模型中测试化合物，包括 单期假体关节翻修手术；3)进行药物动力学和毒理学研究 两个符合FDA行业指南的动物模型系统。 拟议工作的成功完成将使我们的创新产品能够商业化 假体关节感染。这将满足一个重大的未得到满足的医疗需求，以降低发病率和死亡率 与多次翻修手术相关，以及由于需要长时间住院而延长住院时间 康复和每日静脉注射治疗经常被证明是不成功的。

ABSTRACT In general, the incidence of osteomyelitis is around 1-2% in patients undergoing total knee and hip replacement surgeries. When patients have to undergo revision therapy to replace infected implants, mortality is 18%. Due to the aging of the population in the US, and the increase in the number of total joint arthroplasties in this population, the annual cost of infected revision surgeries to hospitals is projected to reach $1.6 billion dollars by 2020. 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 recently demonstrated, as Phase I of this project, the feasibility of using a novel bisphosphonate conjugated antimicrobial compound as a treatment for osteomyelitis. In this Phase II SBIR proposal, we will move the BioVinc osteomyelitis solution toward commercial use by creating additional BP-antibiotic conjugates with the proper characteristics for use in osteomyelitis as improvement or back-ups to our current leads, as well as testing the lead compounds in a novel revision surgery model of prosthetic joint infection (PJI). 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 and efficacy 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: 1) synthesize novel BP-antibiotic conjugates, including the scale-up of our initial leads identified in Phase I, with optimal bone affinity and optimized antimicrobial efficacy; and develop the chemical processes for a GMP production of 1kg of the clinical candidate; 2) test the compounds in a model of PJI including a single stage prosthetic joint revision surgery; and 3) perform pharmacokinetic (PK) and toxicology studies in two model animal systems in accordance with FDA guidance for industry. Successful completion of the proposed work will allow us to commercialize our innovative product for prosthetic joint infections. This will meet a significant unmet medical need to reduce the morbidity and mortality associated with multiple revision surgeries as well as extended hospital stays due to the need for lengthy recoveries and daily IV therapy that often proves unsuccessful.