Biotherapeutics, Inc. — Department of Health and Human Services SBIR Phase I: 300

Description

Immunometabolic NLRXTherapeutics for IBD Biotherapeutics IncBTIis an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and healthThis SBIR application stems from data showing a vital role for nucleotide binding oligomerization domainleucine rich repeat containing XNLRXas a new therapeutic target for IBDOur ProductBTI has identified the first family of small molecule compounds that bind and activate the novel regulatory moleculeNLRXThe goal of this project is to validate NLRXas a target and develop NXas the lead NLRXbasedoral first in class therapeutic for IBDBackgroundIBD is a chronic widespread and debilitating illness that afflicts overmillion people worldwideCurrent treatments are only modestly successful with significant adverse side effectsincluding cancerinfection and deathThusthere is an unmet clinical need for safermore efficacious IBD therapeuticsNLRXcan suppress intestinal inflammation during infections and autoimmune disordersBTI has validated that loss of NLRXcauses reduced mucosal healingincreased fibrosisandgtfold up regulation in inflammatory cytokine biomarkersand complete restructuring of gut microbiome ecology during IBDAdditionallyour top NLRXligand exerts therapeutic actions in models of IBDThis SBIR Phase I application will characterize ligandprotein interactions of NXand NLRXdefine the NXcellular mechanism of action and validate its safety and specificity to NLRXThe Specific Aims are toAIMEvaluate NXinteractions with purified and in situ NLRXby CD spectroscopy and isothermal calorimetry on purified WT and mutant NLRXand by cellular thermal shift assaysAIMDetermine the cellular mechanism of action of NXin vivo in the DSS model of colitis using crelox cell specificCDmyeloidepithelialknockouts of NLRXAIMConduct preliminary ADME Tox and specificity assays with NXin off target binding assaysd dose range finding toxicity studies in rats and ADME Tox assayshERGAmesCYPP gpExpected OutcomesValidation of NXas a lead molecule for targeting NLRXthroughiengagement of NLRXin situ at concentrationsMiiidentification of cellular mechanism of action by loss of efficacy in cell specific KO miceiiia benign safety profile with NOAELmg kg oral in ratsSBIR Phase II will validate the implication of NLRXin human IBDdetermine PK in ratsdefine anti fibrotic effects in mouse models of intestinal fibrosis and advance NXto IND enabling GLP toxicology studiesCommercial ApplicationSuccess in this project will launch a new drug development pipeline at BTI centered on NLRXactivating therapeutics with anti inflammatory and anti fibrotic effectsBTIandapos s new NLRXtargeting oral therapeutics could disrupt a market of over $B annually growing atannual rates Public Health Relevance The spread of Inflammatory bowel diseaseIBDis growing globally and it afflicts overmillion people in the United States and overmillion people worldwideThis SBIR Phase I has the potential to develop a novel class of potent oral drugs for IBD that exert their therapeutic actions by acting on the novel targetNLRXIn addition to the mechanism of action and efficacy workthis project will perform preliminary safety and ADME studies to advance the compound along the FDA regulatory pipeline into INDThe proposed studies will lay the groundwork for developing NXa small molecule therapeutic with the potential to selectively engage and activate NLRXin the gut and discovering how NXmodulates immune and inflammatory responses in the gastrointestinalGItract in IBD