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: 10084796
• 负责人: Frank H. Ebetino
• 金额: $ 97.56万
• 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/10084796
• 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.

摘要