Competitive Equilibrium-based Displacement of Bisphosphonates as Novel Therapeutic Approach for BRONJ

Period of Performance: 03/15/2017 - 02/28/2018

$741K

Phase 2 SBIR

Recipient Firm

Biovinc, LLC
Santa Barbara, CA 93101
Principal Investigator

Abstract

ABSTRACT Since 1995, several nitrogen-containing bisphosphonate (NBP) drugs have been approved for the treatment of Paget's disease, metastatic disease of the bone, and osteoporosis. The later indication has led to the prescription of these drugs to millions of patients in the last 20 years. Patients who have bone metastasis receive very large doses of these drugs, in some cases receiving the amount in one month that osteoporosis patients receive in a year. The NBPs are effective and safe drugs which have reduced morbidity and mortality for a large number of patients with osteoporosis and bone metastatic disease. A side effect now notoriously associated with NBP use is BRONJ (bisphosphonate associated osteonecrosis of the jaw). While the overall risk of developing this side effect is small, it is associated with significant morbidity. Some have advocated for drug holidays prior to dental work (a risk factor for the development of BRONJ), however, this is not an option for the patients with cancer and bone metastases who are at high risk for fracture. In our Phase I study, we developed a novel strategy for preventing or treating BRONJ based on the removal of anti-resorptive NBPs by local application of a secondary fluorescent bisphosphonate (FL-BP) that does not have effects on bone metabolism. In our Phase II study we will build on the feasibility demonstrated in Phase I using three specific aims with the goal of generating data to demonstrate clinical utility and safety of this concept: Aim 1. Synthesize the novel indocyanine green (ICG)-based near infrared (NIR) FL-BP conjugates (ICG-BPs) based on the antiresorptive inactive para-pyridyl ethanebisphosphonate (p-PyrEBP); Aim 2. Test the effectiveness of the ICG-BP from Aim 1 in a murine model to prevent ONJ via local delivery; and Aim 3. Develop a method for compound analysis in plasma and other tissues and carryout initial PK and toxicology studies. The product ultimately developed in this project will be delivered locally to the oral cavity without significant systemic effects and will have a near infrared fluorescent moiety that allows visualization of the loading of this new drug and therefore the displacement of the active NBP, thus serving as an indicator for safely initiating a dental procedure. If successful, this product would find great use to help remove the fear of this debilitating side effect of NBP use for these patient populations.