Bone targeted delivery of an antimicrobial drug for osteomyelitis therapy

骨靶向递送抗菌药物治疗骨髓炎

• 批准号: 9909618
• 负责人: Frank H. Ebetino
• 金额: $ 99.93万
• 依托单位: BIOVINC, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909618
• 关键词: Adverse event; Affect; Affinity; Aging; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Back; Bone Marrow; Bone Resorption; Canis familiaris; Characteristics; Chemicals; Ciprofloxacin; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Clinical assessments; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Engineering; Enzymes; Excision; Failure; Feasibility Studies; Femoral Fractures; Foundations; Fracture; Future; Generations; Goals; Health system; Healthcare Systems; Hospitalization; Hospitals; Implant; Incidence; Industry; Infection; Infectious Bone Diseases; Joint Prosthesis; Joint Revision; Joints; Kinetics; Lead; Length; Length of Stay; Life; Medical; Modeling; Morbidity - disease rate; Mus; Musculoskeletal; Open Fractures; Operative Surgical Procedures; Organism; Osteitis; Osteomyelitis; Outcome; Outcome Study; Participant; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Plasma; Population; Process; Production; Public Health; Quality of life; Rattus; Recovery; Replacement Arthroplasty; Reporting; Research; Resolution; Rivers; Safety; Secondary to; Sepsis; Series; Site; Skin; Small Business Innovation Research Grant; Source; Staphylococcus aureus; Surface; System; Testing; Therapeutic; Therapeutic Index; Time; Toxicology; Translating; Translational Research; Translations; Trauma; Treatment Efficacy; Universities; Vancomycin; Work; antimicrobial; antimicrobial drug; base; bisphosphonate; bone; clinical candidate; clinical development; cost; diabetic; efficacy trial; experimental study; first-in-human; foot; hip replacement arthroplasty; improved; in vivo; innovation; joint infection; knee replacement arthroplasty; lead candidate; long bone; methicillin resistant Staphylococcus aureus; mortality; mouse model; novel; novel strategies; pathogen; patient population; resistant strain; safety assessment; safety study; scale up; small molecule; success; targeted delivery; translation to humans

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.

抽象的 一般来说，接受全膝关节和髋关节手术的患者骨髓炎的发生率约为1-2% 置换手术。当患者必须接受修复治疗以更换受感染的种植体时，死亡率 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，医院每年因受感染而进行翻修手术的费用预计将达到 16 亿美元 到 2020 年，减少这一对受影响患者的生活质量和患者的重大负担 美国公共卫生和卫生系统的需求非常重大。双膦酸盐 (BP) 是一类 用于治疗骨吸收障碍的治疗化合物，并在骨中积累异常 高亲和力，这使它们成为新型骨靶向药物递送平台的优秀部分。 BioVinc 是一家致力于成为骨相关疾病领域领导者的公司，最近的事实证明， 该项目的第一阶段，使用新型双膦酸盐缀合抗菌化合物作为抗菌剂的可行性 治疗骨髓炎。在此 II 期 SBIR 提案中，我们将采用 BioVinc 骨髓炎解决方案 通过创建具有适当特性的额外 BP-抗生素结合物来实现商业用途 骨髓炎作为我们当前先导化合物的改进或备份，以及在 新型人工关节感染翻修手术模型（PJI）。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，以推进我们的领先地位 IND 阶段使研究能够支持 IND 申请首次在人体安全性和有效性试验中的应用。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 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）合成新型 BP-抗生素结合物，包括扩大我们在 I期，具有最佳的骨亲和力和优化的抗菌功效；并开发化学工艺 临床候选药物的 GMP 生产量为 1 公斤； 2) 在 PJI 模型中测试化合物，包括 单阶段假体关节翻修手术； 3) 进行药代动力学 (PK) 和毒理学研究 符合 FDA 行业指南的两个模型动物系统。 成功完成拟议工作将使我们能够将我们的创新产品商业化 假体关节感染。这将满足显着的未满足的医疗需求，以降低发病率和死亡率 与多次修复手术以及由于需要长时间的住院时间而延长住院时间相关 康复和日常静脉注射治疗常常被证明是不成功的。