Bone targeted delivery of an antimicrobial drug for osteomyelitis therapy

ABSTRACTIn 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.