Cyclic Orynotides for Systemic MDR Candidiasis

This Fast Track SBIR grant proposal seeks to develop a new class of macrocylic peptide drugs for treatment of systemic candidiasisan increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patientsMortality rates associated with these infections have risen sharply due to the emergence of multidrug resistantMDRstrains of Calbicans and other Candida sppCurrentlythere are but three classes of antifungal drugs available for treatment of invasive fungal diseasespolyenesazolesand echinocandinsand it has been nearly two decades since the last new class of antifungalsechinocandinswas approvedMDR isolates of Candida sppthat are resistant to all azoles and echinocandins are increasingly commonhighlighting the urgent need for new antifungal therapeuticsThis project seeks to develop a new class of proprietary antifungal peptidesOrynotidesTMthe design of which was bioinspired bydefensinscyclic hostdefense peptides expressed in Old World monkeys but not humansA lead series ofOrynotidesdownselected from a larger proprietary libraryis composed of macrocyclic peptides that are potently fungicidal against clinical isolates of MDR Calbicans and other pathogenic Candida sppincluding Cauris a highly virulent globally emerging pathogenEach of the Orynotide candidates has been prequalified as being fungicidalhighly stable in biological matricesstable to proteases in fungal lysatesnon toxic to miceand readily manufacturableAmong the prequalified Orynotides are compounds that markedly enhance survival in two models of systemic candidiasis including infections caused by caspofungin resistant Calbicans and MDR CaurisBased on these findingswe propose in Phaseof the project to identify at least three peptidesfrom the prequalified panel ofOrynotidesthat are equal or superior to a reference Orynotide that is effective in murine Calbicans candidiasisComparative efficacy metrics will include enhanced survivalreduction of fungal burdenand maintenance of body weightAchievement of this Phasemilestone would trigger PhasestudiesThe first of two PhaseAims will identify a lead Orynotidefromlead finalistsfor preclinical development based on therapeutic efficacysafetyand exposure response analyses in immunocompetent and neutropenic micePhasestudies will then focus on IND enabling GLP toxicology studies of the lead Orynotidewith the goal being to file an IND by the end of the third year of PhaseCompletion of this objective will position the applicant and its partners to introduce a new class of antifungal drugs for treatment of systemic candidiasisThis would represent the first new antifungal class to be introduced for human mycoses in nearly two decades Project Narrative Invasive fungal diseases represent a growing threat to human health worldwideexacerbated by the increasing incidence of multi drug resistance among fungal pathogensCurrently there are but three classes of antifungal drugs that may be used to treat these infectionsthe last class of which was introduced nearly two decades agoThe proposed research seeks to develop a new class of antifungal drugs to address this unmet clinical need