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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在美国，骨折是一个大的医疗问题，每年有 600 万例就诊，导致骨折非常大的成本负担。此外，由于老年人的老龄化，美国骨折的总负担正在增加。人口和骨质疏松症的增加。其中一些骨折无法正常愈合，主要是由于感染导致这部分患者的额外费用和发病率较高。此外，开放性骨折通常是由以下原因引起的：外伤，可导致非常高的感染率（20-30%），甚至可能导致骨不连或截肢以最好的照顾。减轻受影响患者的生活质量和美国公共卫生和卫生系统有非常重大的需求。双膦酸盐 (BP) 是一类用于治疗骨吸收障碍的治疗化合物，并以极高的浓度在骨中积累亲和力，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，拥有大量的初步数据显示使用新型骨靶向双膦酸盐缀合氟喹诺酮的可行性化合物作为骨折愈合问题的治疗方法。在此 FastTrack SBIR 提案中，我们将移动 BioVinc 解决方案用于治疗感染性迟发/不愈合骨折，并用于商业用途。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首次人体安全试验的 IND 申请。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方面，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。改进 BP-氟喹诺酮先导化合物的合成化合物以证明扩大到商业数量是可行的；第一阶段目标二。执行在小型猪中进行的初步药代动力学研究，以证明用于治疗的动物的骨骼暴露关键的 IND 促进功效研究；第二阶段目标一。进一步改进合成方法，使制备 50-100 克规模的 BP-氟喹诺酮，为支持功效研究提供材料迷你猪并开发用于大规模合成可转移至千克的先导化合物的工艺化学进行 GMP 生产并进行初步盐和晶型筛选；第二阶段目标二。测试先导化合物其在小型猪骨折手术修复模型中的疗效。成功完成拟议工作将提供商业化所需的临床前数据我们的创新产品用于治疗感染性骨折。这将满足未满足的重大医疗需求，以减少与愈合不良、多次手术、复发和延长住院时间相关的发病率和死亡率由于需要漫长的恢复时间和每日静脉注射治疗，而这种治疗常常被证明是不成功的。