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

一种治疗感染性骨折的新型骨靶向抗生素疗法

• 批准号: 10603486
• 负责人: Frank H. Ebetino
• 金额: $ 29.68万
• 依托单位: BIOVINC, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-03 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603486
• 关键词: Acids; Affect; Affinity; Aging; Amputation; Animal Model; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Bacteria; Biological; Blood Circulation; Bone Resorption; Bone Surface; Bone remodeling; Carbamates; Caring; Cells; Chemistry; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Ensure; Environment; Excretory function; Exposure to; Femur; Fluoroquinolones; Fracture; Goals; Health system; Hour; Hydrolysis; Impaired healing; Incidence; Infection; Intervention; Investigational New Drug Application; Lead; Length of Stay; Medical; Medical Care Costs; Metabolic; Methodology; Methods; Miniature Swine; Modeling; Morbidity - disease rate; Open Fractures; Operative Surgical Procedures; Osteoclasts; Osteomyelitis; Osteoporosis; Outcome; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Polymorph; Population; Preparation; Process; Production; Public Health; Quality of life; Reaction; Regimen; Relapse; Rodent Model; Safety; Sampling; Series; Site; Small Business Innovation Research Grant; Sodium Chloride; Solvents; Surgical Models; Techniques; Testing; Therapeutic; Toxicology; Trauma; Treatment outcome; United States Food and Drug Administration; Work; analog; antimicrobial drug; appropriate dose; base; bisphosphonate; bone; bone fracture repair; chemical release; clinical development; commercialization; cost; design; efficacy study; first-in-human; healing; improved; improved outcome; in vivo; infection rate; innovation; liquid chromatography mass spectrometry; long bone; manufacture; meetings; mortality; novel; novel strategies; older patient; opioid use; patient subsets; pharmacologic; phase 2 study; pre-clinical; prevent; productivity loss; safety assessment; safety study; scale up; screening; skeletal; tibia; urinary

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.

抽象的 骨折是美国的一个大医疗问题，每年有600万次演讲，导致 费用很大。此外，由于老化，美国的骨折总负担正在增长 种群和骨质疏松症增加。这些骨折中的一些无法正确愈合，主要是由于感染 在这一子集中导致高昂的成本和发病率。另外，通常由 创伤，可能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。减轻了受影响的患者的生活质量和 美国公共卫生和卫生系统非常重要。双膦酸盐（BPS）是一类 用于治疗骨吸收性疾病的治疗化合物，并在骨骼中积聚，异常高 亲和力，这使它们成为新型骨骼靶向药物输送平台的绝佳部分。 Biovinc是一家成立于骨骼相关疾病领导者的公司，有很多 初步数据，显示使用新型骨靶向双膦酸盐共轭氟喹诺酮的可行性 化合物作为骨断裂愈合问题的治疗方法。在这个FastTrack Sbir提案中，我们将移动 Biovinc溶液用于感染的延迟/非工会骨折用于商业用途。我们的计划是确定理想 临床发展候选人并完成必要的非临床研究，以提高我们的领先地位 IND阶段使研究能够支持IND在人体安全试验中的首先应用。为了确定 偶联物的最佳剂量，并对药代动力学和 毒理学，将进行研究以确认开发途径的机会。具体来说，我们会的 进行两个目标的两个阶段：第一阶段目标。改善BP-氟喹诺酮铅的合成 化合物证明规模超过商业量将是可行的；第一阶段目标两个。执行 在迷你猪中的初步药代动力学研究，以证明该动物的骨骼暴露于 关键启用功效研究；第二阶段目标。进一步改善合成方法，使得 在50-100克量表上制备BP-Fluoroquinolone，以提供材料以支持疗效研究 迷你猪并开发工艺化学，以大规模合成可转移至kg的铅化合物 GMP产生初步盐和多晶型筛选；第二阶段目标两个。测试铅化合物的 它在裂缝手术修复的迷你猪模型中的功效。 拟议工作的成功完成将提供商业化所需的临床前数据 我们用于感染裂缝的创新产品。这将满足减少的重大未满足的医疗需求 与康复不良，多次手术，复发和延长住院相关的发病率和死亡率 由于需要长时间的康复和日常静脉注射疗法，这通常证明是不成功的。