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

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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.