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

Description

DESCRIPTION provided by applicant Osteoporosis directly affects million Americans and another million are osteopenic and at risk for developing osteoporosis Bisphosphonate drugs for example alendronic acid ALN Fosamax can improve bone density and reduce fracture risk by slowing osteoclastic bone resorption however many of the existing anti resorptive therapies are plagued with untoward side effects and limited duration of clinical benefits New and improved strategies for therapeutic intervention in osteoporosis are needed particularly with new treatments that safely promote anabolic bone growth A dual therapy approach addressing both resorption and formation of bone could also be helpful 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 thrown off balance by age lifestyle factors and hormonal changes that occur with menopause 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 crania and femoral defect models During SBIR Phase I research we have begun evaluating drug conjugates of osteo anabolic Oxy and Alendronate ALN a well established anti resorptive drug that also serves as a bone targeting agent We have worked out methods for chemical conjugation and characterized biophysical and biological properties of the resulting conjugates Oxy ALN conjugates display strong in vitro binding to bone mineral and stimulate Hedgehog Hh pathway signaling and osteogenesis in MSCs In this application we propose to further develop Oxy ALN conjugates as potential dual therapy agents for osteoporosis stimulating bone formation by osteoblasts function of Oxy and inhibiting bone resorption by osteoclasts function of ALN Expanding on our successful Phase I studies we propose to perform Phase II studies as part of Specific Aims Aim Development of scalable methods for the synthesis of Oxy ALN conjugates Aim Evaluation of the inhibition of osteoclastic bone resorption by Oxy ALN conjugates and the possibility of a dual therapy Aim Determination of Oxy ALN conjugate tissue distribution properties and evaluation of select Oxy ALN conjugates for efficacy in an OVX mouse model PUBLIC HEALTH RELEVANCE The proposed studies in this application will continue the characterization of 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 bisphosphonate drug such as Alendronate and administered systemically Results will also examine if these novel compounds can inhibit osteoporosis in mice and will provide important information for selection of a lead compound for future Phase III studies of osteoporosis intervention through stimulation of bone formation