Elution of a Small Molecule from a Bio Ceramic Collagen Bone Graft Device Heals Bone while InhibitingBreast Cancer Bone Metastases

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Project Summary: Bone growth is critical to a favorable prognosis in the 70% of de novo metastatic breast cancer patients that have skeletal metastases, or approximately 115,000 new patients per year in the US. Lytic lesions, or void-defects in the bone, result from local bone destruction caused by tumor cell-directed osteoclastic bone re- absorption and lead to pathologic fractures and increased patient morbidity. Surgical intervention is necessary to prevent initial fracture or other skeletal related events and involves stabilizing the defect created by the tumor. Unfortunately, a growing population of patients are at risk for implant failure due to the inability of hardware or bone cement to promote bone formation. Because of high failure rates and increased patient survival, lytic lesions account for approximately $2-billion in US healthcare expenditures per year. Patients with breast cancer bone metastases (i.e. a skeletal related event) require surgical intervention to stabilize the tumor-directed defect using intra-medullar nails, total joint prostheses, and/or bone cement. However, hardware and bone cement don’t promote bone formation. The underlying unfilled bone defects can result in implant loosening and loss of mechanical stability. Growth factors have become a popular option to increase bone healing. However, these therapies, such as BMP-2 (Infuse®) and PTH (Forteo®), have safety risks for cancer patients and some have been contraindicated for use or given a black-box warning by the FDA for patients with active tumor or patients with history of tumor. In particular, BMP-2 has been associated with increased tumor risk in patients who are undergoing X-radiation therapy or possess nascent undetected tumor. In response to this unmet need, Zetagen Therapeutics, Inc., a New York regenerative medicine startup is commercializing the Nalovent™ Bone Graft, a new combination product with a demonstrated ability to treat lytic lesions by inducing osteogenesis while inhibiting local growth of cancer cells. Based on the discovery of a novel molecular pathway for bone growth, Nalovent induces osteogenesis via the local implantation of a calcium phosphate bioceramic / bovine collagen-based bone graft that contains the opioid antagonist, naloxone. If validated, the Nalovent Bone Graft would empower clinicians with a much-needed solution to heal lytic bone defects and fight residual tumor in order to deliver significantly improved outcomes to the large and growing population of breast cancer patients with skeletal metastases. This proposal consists of three AIMs meant to drive the Nalovent Bone Graft towards FDA approval using standard safety, bioavailability, and efficacy assessments: 1) Assess the safety of Nalovent, 2) Test the bioavailability of Nalovent and 3) Validate that the Nalovent Bone Graft promotes bone growth. If successful, this proposal will demonstrate commercial validation for the Nalovent Bone Graft implant and establish the foundation for the preparation for first-in-man trials.