MICROBIOTIX, INC. — Department of Health and Human Services SBIR Phase I: NIA

Description

AbstractApproximatelymillion Americans have rheumatoid arthritisRAwhich is one of the most common chronic autoimmune disorders in the older populationThere is no cure for RAand up toof patients do not respond to current therapiesAs a resultdisease progression leads to joint destruction and severe disability in the elderlyThereforethe identification of a novel therapeutic strategy used alone or in combination with existing therapies would resolve a critical barrier in RA treatmentThe overall goal of this project is to address this unmet medical need by developing novel small molecule drugs for RA therapyOur strategy is to build upon two new discoveriesathe important role of the toll like receptorTLRin RAandba novel chemical series of small molecule TLRinhibitorsPreliminary studies revealed that TLRis highly elevated in RA myeloid cells as compared to normal myeloid cellsand its expression closely correlates with RA disease activity scoreDASFurthermoreligation of TLRto its natural ligand expressed in the joints transforms RA peripheral bloodPBmyeloid cells into proinflammatory Mmacrophages and mature osteoclastsIn micesystemic and local injection of a TLRagonist exacerbates joint swelling and bone erosionConverselyantiTLRantibodyAbtherapy attenuates collagen induced arthritisCIAjoint inflammation and bone destructionCoincident with these studiescollaborators discovered small molecule TLRinhibitors that antagonize the interaction between TLRand its agonistflagellinfrom bacterial infectious agents including Pseudomonas and BurkholderiaSeveral validated hits from the screen are effective in RA PB myeloid cellsIn particularaiminobenzimidazoleneIBZseries of compounds abrogates RA Mmacrophage differentiation and osteoclast maturation more effectively than does anti TNF Abanti ILR Ab or a TLRantagonistand several analogs reduced flagellin induced TNFILand CCLproduction by up toin RA PB myeloid cells with low cytotoxicityyielding a selectivity index of rtand responsive structure activity relationshipsSARthat will guide further chemical optimizationAll three active analogs displayed good stabilityandin the presence of mouse liver microsomesNADPHand the aqueous solubility of allanalogs was in excess ofMIn Phase I of this translational drug development projectthe IBZ series will be chemically optimized to maximize potency and selectivity as well as drug like absorptiondistributionmetabolism and excretionADMEpropertiesand the mechanism of action together with the target specificity will be determined for the IBZ seriesOther compounds from the TLRinhibition screen at MBX will serve as backup scaffolds for this projectIn Phase IIin vivo validated leads and a preclinical candidate will be identified from the IBZ series by formulating and evaluating prioritized analogs in mice to determine the maximum tolerated dosepharmacokinetics and efficacy in a murine collagen induced arthritis modelIn Phase IIIthe effectiveness of the preclinical candidate will be evaluated in comparison with other currently available therapies using acute and chronic RA preclinical modelsand Investigational New DrugINDenabling toxicology and safety pharmacology studies will be carried out