Max Biopharma, Inc. — Department of Health and Human Services SBIR Phase II: NIAMS

Description

DESCRIPTION provided by applicant Osteoporosis affects million Americans and another million are osteopenic and at risk for developing osteoporosis Since the s bisphosphonate drug therapy has produced clinical benefits such as improved bone density and reduced fracture risk by slowing osteoclastic bone resorption Many of the existing anti resorptive drugs are plagued with untoward side effects and limited duration of clinical benefits New and improved strategies for therapeutic intervention in osteoporosis are needed particularly in the area of new medicines that safely promote anabolic bone growth Presently there is only one FDA approved bone anabolic agent Forteo teriparatide that confers significant clinical benefits in osteoporosis but its use is severely restricted due to safety concerns Multipotent mesenchymal stem cells MSCs are precursors of a variety of cell types including osteoblasts and adipocytes Formation of new bone is driven by osteoblastic differentiation of MSCs a process that can be disrupted by age and various disorders including diabetes and cancer Parhami et al discovered that specific oxysterols induce osteogenesis when applied to MSCs while inhibiting their adipogenesis The most promising proprietary semi synthetic oxysterol to date OXY displays increased potency for osteogenic differentiation in vitro including in primary rat rabbit and human MSCs and it stimulates robust localized bone formation in vivo in rat and rabbit spine fusion and cranial and femoral defect models During the SBIR Phase I research we begun evaluating Oxy as a bone anabolic agent in the context of systemic administration and bone targeting We worked out practical methods for conjugation of OXY to a known bone targeting agent BTA derived from tetracycline and we developed detailed protocols for their bioanalytical assessment The resulting Oxy BTA conjugates display strong in vitro binding to bone mineral and stimulate moderate to robust Hedgehog Hh pathway signaling and osteogenesis in MSCs In a pilot study we found that one Oxy BTA conjugate Oxy is deposited in bone tissue following ip administration in mice Expanding on our successful Phase I studies we propose to perform Phase II studies as part of Specific Aims Characterization of the molecular mechanism of action of Oxy BTA conjugates which includes the study of the structural requirements for binding of Oxy BTA conjugates to the allosteric sterol binding site of Smoothened Smo protein and their examination of allosteric Hh pathway activation and induction of osteogenic differentiation Examination of the ADME PK and tissue distribution properties of Oxy BTA conjugates in mice that will help identify candidate molecules best suited for in vivo systemic administration and efficacy studies and Assessment of the efficacy of select Oxy BTA conjugates to reverse osteoporosis in ovariectomized mice in vivo Information obtained from these studies will lay the foundation for future IND enabling Phase III studies that will lead to the development of new bone anabolic agents fit for use in humans PUBLIC HEALTH RELEVANCE The proposed studies in this application will characterize a novel class of compounds that are potent stimulators of bone formation and will validate the ability of these molecules to selectively target bone when conjugated with a novel bone targeting agent and administered systemically Results from the studies during this Phase II of the SBIR grant will provide important information for further selection of a lead compound for future Phase III IND enabling studies of osteoporosis intervention through stimulation of bone formation