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: 10318568
• 负责人: Frank H. Ebetino
• 金额: $ 98.86万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318568
• 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 通常，在膝盖和臀部的患者中，骨髓炎的发生率约为1-2％ 替换手术。当患者必须接受修订治疗以替代感染植入物时，死亡率 是18％。由于美国人口的老化，以及总关节塑料的总数增加 在这个人群中，预计受感染的修订手术的年度修订手术预计将达到16亿美元 到2020年的美元。将这种重大负担减少到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 高亲和力，这使它们成为新型骨骼靶向药物递送平台的绝佳部分。 Biovinc是一家成立于骨骼相关疾病领导者的公司，最近已证明 该项目的第一阶段，使用新型的双膦酸盐共轭抗菌化合物作为一种 治疗骨髓炎。在此II阶段SBIR提案中，我们将移动生物植物骨髓炎溶液 通过创建额外的BP抗生素结合物，具有适当的特征供商业使用 骨髓炎作为我们当前潜在客户的改进或备份，并测试A中的铅化合物 假体关节感染（PJI）的新修订手术模型。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，以提高我们的领导 IND阶段使研究能够支持IND在人体安全和功效试验中的首先应用。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）合成新型的BP抗生素结合物，包括我们在 第一阶段，具有最佳的骨骼亲和力和优化的抗菌功效；并开发化学过程 GMP生产1公斤的临床候选者； 2）测试PJI模型中的化合物，包括A 单阶段假肢修订手术； 3）在 根据FDA行业指南，两个模型动物系统。 成功完成拟议的工作将使我们能够将创新产品商业化 假体关节感染。这将满足降低发病率和死亡率的重大未满足的医疗需求 与多次修订手术以及由于需要冗长而延长的住院 经常证明没有成功的恢复和每日静脉疗法。

项目成果

Bisphosphonates in dentistry: Historical perspectives, adverse effects, and novel applications.

• DOI: 10.1016/j.bone.2021.115933
• 发表时间: 2021-06
• 期刊: Bone
• 影响因子: 4.1
• 作者: Sedghizadeh PP;Sun S;Jones AC;Sodagar E;Cherian P;Chen C;Junka AF;Neighbors JD;McKenna CE;Russell RGG;Ebetino FH
• 通讯作者: Ebetino FH