SBIR-STTR Award

Significance: The failure of bone fractures to adequately repair in elderly patients causes significant morbidity and mortality each year in the United States. This problem will continue to be exacerbated by an aging population, with a 160% increase in hip fractures alone expected by 2040 and significant costs in lost work, quality of life, physical therapy, extended care facility stays, and surgeries. Conventional therapy includes mechanically stabilizing the fracture, but thus far, no systemic bone anabolic therapies exist to target and accelerate fracture repair. Preliminary Data: Novosteo Inc. has developed a fracture targeted therapeutic that has demonstrated a dramatic acceleration in healing time and callus formation and remarkable specificity to bone fracture sites. Administered systemically through subcutaneous injection, the drug selectively accumulates on hydroxyapatite, the inorganic portion of bone exposed in a fracture, providing a site-specific dose of anabolic agent. The targeted specificity to the fracture callus limits accumulation of the drug in off-target tissues, reducing the potential for side effects. Also, the systemic delivery route allows for multiple doses of anabolic agent to be administered rather than a single bolus possible via surgery. While bypassing the invasiveness of surgery, the drug mimics a locally- administered anabolic in that drug accumulation is limited to the fracture site and sufficient dose can be administered for accelerated healing. Thus far, Novosteo's biodistribution studies have demonstrated no detectable toxicities at doses that dramatically accelerate fracture repair. Proposal: The overall goal of this Fast-Track SBIR proposal will be to prepare the proposed fracture-targeted therapy for clinical trials. The first step will be to optimize the chemistry of Novosteo's lead candidate. This will be accomplished in Phase I by performing the following: (1) optimization of the fracture targeting ligand composition and (2) conducting a thorough analysis of the fracture targeted drug's toxicity. Phase II will focus on preparing the fracture targeted drug for IND. This will be accomplished by: (1) validating Phase I results in a non-rodent model, (2) conducting MTD, GLP pharmacokinetics, and GLP toxicity studies, and (3) conducting genotoxicity analysis to evaluate any morphogenic dangers. Conclusion: The ability to accelerate bone fracture repair is a fundamental need that has not been addressed by conventional methods. If granted, the completion of the proposed studies would enable the optimization and pre-clinical evaluation of an indispensable therapy for bone fracture repair. Its safety and efficacy could then be explored and evaluated in other settings where accelerated bone regeneration is desired, such as hairline vertebral fractures in osteoporosis patients or craniofacial reconstruction and repair.

Public Health Relevance Statement:
Project Narrative Accelerating fracture healing is an important economic and ethical problem that needs to be addressed. Novosteo Inc. will meet this need by developing the first targeted bone anabolic agent that will concentrate on a bone fracture surface following systemic administration. This bone fracture therapy will help to save lives, limit fracture associated morbidities, and reduce costs.

Project Terms:
Acceleration; Address; Adverse effects; Age; aging population; Anabolic Agents; Animal Model; Animals; autocrine; Biodistribution; Bolus Infusion; bone; Bone callus; Bone Growth; bone quality; Bone Regeneration; Bypass; Canis familiaris; Cessation of life; Charge; Chemistry; Clinic; Clinical Trials; conventional therapy; cost; craniofacial; Data; design; Development; Dose; Drug Kinetics; drug synthesis; Drug Targeting; Drug toxicity; Economic Burden; Economics; Elderly; Ethics; Extravasation; Failure; Femoral Fractures; Formulation; Fracture; Fracture Healing; Frequencies; genotoxicity; Goals; Grant; healing; Hip Fractures; Human; Hydroxyapatites; improved; Lead; lead candidate; Life; Ligands; Mechanics; Methods; Minerals; Modification; Monitor; Morbidity - disease rate; mortality; Non-Rodent Model; older patient; Oligopeptides; Operative Surgical Procedures; Osteoporosis; Osteoporotic; Paracrine Communication; parathyroid hormone-related protein; Patients; Pharmaceutical Preparations; Phase; Physical therapy; preclinical evaluation; Productivity; Quality of life; reconstruction; Recovery; repaired; Role; Route; Safety; scale up; Site; Skilled Nursing Facilities; Small Business Innovation Research Grant; Specificity; Spinal Fractures; Subcutaneous Injections; Surface; targeted treatment; Technology; Therapeutic; Therapy Clinical Trials; Time; Tissues; Toxic effect; Translations; Trauma; Treatment Efficacy; Treatment-related toxicity; United States; Work

Significance: The failure of bone fractures to adequately repair in elderly patients causes significant morbidity and mortality each year in the United States. This problem will continue to be exacerbated by an aging population, with a 160% increase in hip fractures alone expected by 2040 and significant costs in lost work, quality of life, physical therapy, extended care facility stays, and surgeries. Conventional therapy includes mechanically stabilizing the fracture, but thus far, no systemic bone anabolic therapies exist to target and accelerate fracture repair. Preliminary Data: Novosteo Inc. has developed a fracture targeted therapeutic that has demonstrated a dramatic acceleration in healing time and callus formation and remarkable specificity to bone fracture sites. Administered systemically through subcutaneous injection, the drug selectively accumulates on hydroxyapatite, the inorganic portion of bone exposed in a fracture, providing a site-specific dose of anabolic agent. The targeted specificity to the fracture callus limits accumulation of the drug in off-target tissues, reducing the potential for side effects. Also, the systemic delivery route allows for multiple doses of anabolic agent to be administered rather than a single bolus possible via surgery. While bypassing the invasiveness of surgery, the drug mimics a locally- administered anabolic in that drug accumulation is limited to the fracture site and sufficient dose can be administered for accelerated healing. Thus far, Novosteo's biodistribution studies have demonstrated no detectable toxicities at doses that dramatically accelerate fracture repair. Proposal: The overall goal of this Fast-Track SBIR proposal will be to prepare the proposed fracture-targeted therapy for clinical trials. The first step will be to optimize the chemistry of Novosteo's lead candidate. This will be accomplished in Phase I by performing the following: (1) optimization of the fracture targeting ligand composition and (2) conducting a thorough analysis of the fracture targeted drug's toxicity. Phase II will focus on preparing the fracture targeted drug for IND. This will be accomplished by: (1) validating Phase I results in a non-rodent model, (2) conducting MTD, GLP pharmacokinetics, and GLP toxicity studies, and (3) conducting genotoxicity analysis to evaluate any morphogenic dangers. Conclusion: The ability to accelerate bone fracture repair is a fundamental need that has not been addressed by conventional methods. If granted, the completion of the proposed studies would enable the optimization and pre-clinical evaluation of an indispensable therapy for bone fracture repair. Its safety and efficacy could then be explored and evaluated in other settings where accelerated bone regeneration is desired, such as hairline vertebral fractures in osteoporosis patients or craniofacial reconstruction and repair.

Public Health Relevance Statement:
Project Narrative Accelerating fracture healing is an important economic and ethical problem that needs to be addressed. Novosteo Inc. will meet this need by developing the first targeted bone anabolic agent that will concentrate on a bone fracture surface following systemic administration. This bone fracture therapy will help to save lives, limit fracture associated morbidities, and reduce costs.

NIH Spending Category:
Aging; Dental/Oral and Craniofacial Disease; Injury (total) Accidents/Adverse Effects; Osteoporosis; Women's Health

Project Terms:
Acceleration; Address; Age; aging population; Anabolic Agents; Animal Model; Animals; autocrine; Biodistribution; Bolus Infusion; bone; Bone callus; Bone Growth; bone quality; Bone Regeneration; Bypass; Canis familiaris; Cessation of life; Charge; Chemistry; Clinic; Clinical Trials; conventional therapy; cost; craniofacial; Data; design; Development; Dose; Drug Kinetics; drug synthesis; Drug Targeting; Drug toxicity; Economic Burden; Economics; Elderly; Ethics; Extravasation; Failure; Femoral Fractures; Formulation; Fracture; Fracture Healing; Frequencies; genotoxicity; Goals; Grant; healing; Hip Fractures; Human; Hydroxyapatites; improved; Lead; lead candidate; Life; Ligands; Mechanics; Methods; Minerals; Modification; Monitor; Morbidity - disease rate; mortality; Non-Rodent Model; older patient; Oligopeptides; Operative Surgical Procedures; Osteoporosis; Osteoporotic; Paracrine Communication; parathyroid hormone-related protein; Patients; Pharmaceutical Preparations; Phase; Physical therapy; preclinical evaluation; Productivity; Quality of life; reconstruction; Recovery; repaired; Role; Route; Safety; scale up; side effect; Site; Skilled Nursing Facilities; Small Business Innovation Research Grant; Specificity; Spinal Fractures; Structure; Subcutaneous Injections; Surface; targeted treatment; Technology; Therapeutic; Therapy Clinical Trials; Time; Tissues; Toxic effect; Translations; Trauma; Treatment Efficacy; Treatment-related toxicity; United States; Work