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

Award Number: R44DE025524
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/21/2015
PERIOD OF PERFORMANCE END DATE: 02/28/2022

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2018	BIOVINC, LLC	1421 STATE ST STE B	SANTA BARBARA	CA	93101	SANTA BARBARA	USA	Oral Diseases and Disorders Research	000	3	7/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	BIOVINC, LLC	1421 STATE ST STE B	SANTA BARBARA	CA	93101	SANTA BARBARA	USA	Oral Diseases and Disorders Research	000	3	1/20/2021	NON-COMPETING CONTINUATION	$0
2021	2018	BIOVINC, LLC	1421 STATE ST STE B	SANTA BARBARA	CA	93101	SANTA BARBARA	USA	Oral Diseases and Disorders Research	001	3	1/21/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	BIOVINC, LLC	1421 STATE ST STE B	SANTA BARBARA	CA	93101	SANTA BARBARA	USA	Oral Diseases and Disorders Research	000	3	11/13/2019	SUPPLEMENT FOR EXPANSION	$0
2020	2018	BIOVINC, LLC	1421 STATE ST STE B	SANTA BARBARA	CA	93101	SANTA BARBARA	USA	Oral Diseases and Disorders Research	001	3	2/6/2020	NON-COMPETING CONTINUATION	$0
2020	2018	BIOVINC, LLC	1421 STATE ST STE B	SANTA BARBARA	CA	93101	SANTA BARBARA	USA	Oral Diseases and Disorders Research	002	3	2/6/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $1,440,987 )
2018	2018	BIOVINC, LLC	1421 STATE ST STE B	SANTA BARBARA	CA	93101	SANTA BARBARA	USA	Oral Diseases and Disorders Research	001	3	7/31/2018	SUPPLEMENT FOR EXPANSION	$691,832
2018	2018	BIOVINC, LLC	1421 STATE ST STE B	SANTA BARBARA	CA	93101	SANTA BARBARA	USA	Oral Diseases and Disorders Research	000	3	2/13/2018	NON-COMPETING CONTINUATION	$749,155
														Subtotal = $1,440,987

Issue Date FY: 2017 ( Subtotal = $740,777 )
2017	2017	BIOVINC, LLC	1421 STATE ST STE B	SANTA BARBARA	CA	93101	SANTA BARBARA	USA	Oral Diseases and Disorders Research	000	2	3/15/2017	COMPETING CONTINUATION	$740,777
														Subtotal = $740,777

Grand Total All Awards = $2,181,764

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

Award Number: R44DE025524

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/21/2015

PERIOD OF PERFORMANCE END DATE: 02/28/2022

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