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

DESCRIPTION provided by applicant Osteonecrosis of the jaw ONJ is a rare but severe oral complication which is characterized by symptoms consisting painful bone exposure or fistulation that do not resolve over several months to years It was initially described in patient treated with nitrogen containing bisphosphonates BPs and was also found later in some patients taking other antiresorptive or antiangiogenic medications In some cases ablation surgery of necrotic oral and maxillofacial bones has been required significantly affecting patientsandapos life quality Clinical reports have indicated that dental procedures markedly increase the risk of developing ONJ thus causing uncertainty and apprehension among dental healthcare professionals and patients in recent years andquot Drug holidayandquot has been recommended by American Association of Oral and Maxillofacial Surgeons AAOMS as a possible preventive measure for the patients However the FDA determined that there was no substantial data available to guide decisions regarding the initiation or duration of a drug holiday which may partially be due to BPsandapos prolonged half life in the skeletal system In addition because BPs have been marketed for nearly years a large number of patients have been treated with BPs and those patients who had received BPs but discontinued the therapy may retain the legacy BPs in their skeletal system for an extended period Therefore it may be essential to actively remove adsorbed BP from jawbone prior to dentoalveolar procedures in order to achieve more effective prevention C E McKenna University of Southern California USC and I Nishimura University of California Los Angeles UCLA recently demonstrated using fluorescently labeled BPs that one BP can displace another from hydroxyapatite modeling bone mineral This suggests that a previously adsorbed pharmacologically active BP in bone could be displaced by a newly administered pharmacologically inactive BP In this application we propose this andquot competitive equilibriumandquot based displacement of BPs as a novel preventive modality of bisphosphonate related ONJ BRONJ We will test the hypothesis that a pre adsorbed functional BP such as risedronate may be effectively displaced by a non functional BP administered by intraoral injection to the jaw As such application of a non functional BP to the site of dentoalveolar procedures such as tooth extraction should displace the functional BP locally and thus significantly reduce or abate the risk of developing BRONJ while preserving the benefit of skeletally adsorbed drug In this Phase I STTR project we will perform a proof of concept study in a mouse model and establish the drug distribution profile with local intraoral injection Our program combines complementary strengths in ONJ mechanism Nishimura UCLA with BP drug chemistry and biology F H Ebetino BioVinc LLC C E McKenna USC PUBLIC HEALTH RELEVANCE The proposed research addresses a health need that particularly challenges cancer patients requiring dental procedures namely to prevent and treat bisphosphonate related osteonecrosis of the jaw BRONJ In a partnership involving BioVinc LLC and the School of Dentistry at the University of California Los Angeles the proposed STTR Phase I project will utilize fluorescent bisphosphonate imaging probes to demonstrate proof of concept for an innovative andquot competitive equilibriumandquot based local displacement of jaw bone adsorbed BP drug by an inactive BP The outcome will be the prerequisite data model for Phase II preclinical development