Preclinical Development of Oxy200 for the Treatment of Osteoporosis

ABSTRACT Osteoporosis directly affectsmillion Americans and anothermillion are osteopenic and at risk for developing osteoporosisPostmenopausal osteoporosis is most commonbut osteoporosis does also frequently affect older menAt MAX BioPharmawe are developing new and improved therapies for osteoporosis that aim to rebalance both bone formation and resorption based on a dual therapy approachBisphosphonate drugsfor examplealendronic acidALNFosamaxcan improve bone density and reduce fracture risk by slowing osteoclastic bone resorptionhowevermany of the existing anti resorptive therapies are plagued with untoward side effects and limited duration of clinical benefitsComplementary to antiresorptive therapytransient activation of anabolic bone formation could become part of a new treatment paradigmPresentlythere are only two FDA approved bone anabolic agentsForteo and Tymloswhich confer significant clinical benefits in osteoporosis with daily subcutaneous administrationbut their use is severely restricted due to safety concernsSeveral years agowe discovered that specific oxysterols induce osteogenesis when applied to mesenchymal stem cellsMSCswhile inhibiting their adipogenesisThe most promising bone anabolic oxysterol to dateOXYpotently induces osteogenic differentiation in vitroincluding in primary ratrabbit and human MSCsand stimulates robust localized bone formation in vivo in rat and rabbit spine fusion and cranial and femoral defect modelsIn the context of osteoporosisour research has addressed the targeted delivery of Oxyto skeletal tissuesWe proposed that conjugation of Oxywith ALN could selectively deliver both agents to bone tissuepotentially inducing synergistic clinical benefitsSupported by the ongoing NIA sponsored Phase II SBIR grantwe have examined chemical syntheses and biological properties of numerous OxyALN conjugatesWe have identified Oxya carbamate linked OxyALN monoconjugate as a potent osteogenic compound in vitro that is highly water soluble and chemically scalable to multi gram levelsWhen administered orally to ovariectomized ratsOxysignificantly inhibited bone loss with no evidence of toxicity or ectopic calcificationIn this Phase IIB applicationwe propose detailed studies that seek to further appraise the qualities of Oxyas a therapeutic candidate for osteoporosis in IND enabling studiesAccording to a therapeutic development plan that we have devised in collaboration with regulatory advisorsthese studies will expand on our Phase II grant accomplishments in three Specific AimsAimEfficacy and pharmacokinetic studiesdosing optimization studies will be performed in rats and dogs AimGenotoxicity studiesthese will include in vitro and in vivo GLP mutagenesis assays to assess safety AimAcute toxicity and safety pharmacology studiesthese studies will be performed on Albino rats and Beagle dogs following oral administration to further assess safety and tolerability of OxyRELEVANCE TO PUBLIC HEALTH The proposed studies in this application will continue the characterization and preclinical development of a novel oxysterol compoundOxythat is a potent stimulator of bone formation and inhibitor of bone resorptionOxywhen administered orally inhibits bone loss in ovariectomized ratsa model of postmenopausal osteoporosisThe excellent safety profile of Oxyand its oral bioavailability make this compound an excellent candidate for therapeutic development for intervention in osteoporosisand therefore studies in this application are designed to prepare Oxyfor human clinical trials