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置换术的患者中，骨髓炎的发生率约为1- 2 替代手术当患者必须接受翻修治疗以更换感染的植入物时， 是18%。由于美国人口老龄化，以及全关节置换术数量的增加， 在这一人群中，医院每年用于感染翻修手术的费用预计将达到16亿美元 到2020年，美元。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 用于治疗骨吸收疾病的治疗化合物，并在骨骼中异常累积 高亲和力，这使得它们成为用于新型骨靶向药物递送平台的优异部分。 BioVinc是一家致力于成为骨相关疾病领域领导者的公司， 该项目的第一阶段，使用新型双膦酸盐缀合的抗微生物化合物作为抗微生物化合物的可行性。 治疗骨髓炎。在此II期SBIR提案中，我们将把BioVinc骨髓炎溶液 通过产生具有适当特性的另外的BP-抗生素缀合物用于商业用途， 骨髓炎作为改善或备份，我们目前的铅，以及测试铅化合物在一个 人工关节感染（PJI）的新型翻修手术模型。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和有效性试验。为了 确定偶联物的最佳剂量并获得药代动力学的初步安全性评估 和毒理学，将进行研究，以确认开发途径的机会。具体地说， 我们将：1）合成新的BP-抗生素缀合物，包括扩大我们在 第一阶段，具有最佳的骨亲和力和最佳的抗菌功效;并开发化学工艺 对于1 kg临床候选物的GMP生产; 2）在PJI模型中测试化合物，包括 单阶段人工关节翻修手术;和3）进行药代动力学（PK）和毒理学研究， 两个模型动物系统符合FDA行业指南。 成功完成拟议的工作将使我们能够将我们的创新产品商业化， 人工关节感染这将满足一个显著的未满足的医疗需求，即降低发病率和死亡率。 与多次翻修手术以及由于需要长时间 恢复和日常静脉治疗，往往证明不成功。

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.