Developing a peptide-based oral drug to prevent kidney stones

Project Summary Abstract Kidney stonesKSare highly prevalentexcruciatingand associated with long term complications of chronic kidney diseaseCKDand end stage renal diseaseESRDThey account forM ER visits and andgt $B of medical costs annually and have a striking recurrence rate ofinyears and up toinyearsreflecting the inadequacies of current interventionsof KS are composed of calcium oxalate and small increases in urine oxalate significantly enhance the risk for stone developmentReducing urine oxalate levels results in a lower CaOx supersaturation and decreased KS recurrenceNo approved drugs can specifically reduce urine oxalateThe gut bacterium Oxalobacter formigenesOfinduces colonic oxalate secretion and reduces urinary oxalate excretion via an unknown secretagogueUse of Of as a therapeutic agent remains problematic given difficulties with recolonizationunderscoring the need to identify the factors inducing colonic oxalate secretionOxalo Therapeutics has shown that Of derived factorsby itselfsignificantly reduced urinary oxalate in hyperoxaluric mice by andgtand identified a family of signaling proteins as the major Of derived factorsThese proteins and a series of identified peptides also significantly stimulated oxalate transport by CcellsImportantly several peptides also similarly stimulated oxalate transport by human organoidsan ex vivo intestinal epithelium model fully mimicking the gutunderscoring the human relevanceThrough this STTR Fast track proposalOxalo Therapeutics aims to develop an oral drug based on these peptides to prevent KS by lowering oxalate in the urine and bloodSpecific aims for Phase IOptimize lead peptides for stability using structural modificationsEvaluate the therapeutic effects of the optimized peptides in primary hyperoxaluriaPHmouse modelOptimized peptide sthat significantly reduce urine andampplasma oxalate levels will be taken to Phase IISpecific aims for Phase IIDevelop novel peptidesNPbased on modeling of the identified crystal structuresEvaluate the effects of the optimized peptides or NPs in reducing urine andampplasma oxalate levels in PHmice and entericsecondaryhyperoxaluria miceDevelop enteric coated capsules containing best performing peptides for oral administration and evaluate effects on the above micePerform preclinical toxicology and pharmacokinetics studies in rats and nonhuman primatesSinceof urine oxalate is derived from diet andcomes from the liverthe Oxalo product has a mechanistic advantage over competitors by addressing both sourcesby extracting oxalate from blood and enhancing its intestinal excretionCompetitors are developing drugs that only target either dietary oxalate or liver oxalateBy lowering plasma oxalate levelsthere are also therapeutic implications for hyperoxalemia seen in ESRDandampCKDand the genetic disease primary hyperoxaluriaPHThis drug can immediately helpM patients in the US suffering from recurrent KS as a result of hyperoxaluriarepresenting a$B initial marketOxalo will focus initial efforts on critical translational research and early drug development milestones Project Narrative Kidney stones affectinmen andinwomenaccount forM ER visits and andgt $B of medical costs annually and have a striking recurrence rate ofinyears andinyearsreflecting the urgent need for novel therapiesCalcium oxalate stones make up the majority of cases and high levels of oxalate is currently a major risk factor that lacks an approved and effective targeted therapyThis Fast track STTR project focuses on developing a first in class peptide based drug to reduce urine oxalate in order to prevent oxalate containing kidney stones