Selection and preclinical development of a bacteria-targeting, non-antibiotic lead candidate to improve cancer chemotherapy outcomes

SELECTION AND PRECLINICAL DEVELOPMENT OF A BACTERIA TARGETINGNON ANTIBIOTIC LEAD CANDIDATE TO IMPROVE CANCER CHEMOTHERAPY OUTCOMES ABSTRACT The long term objective of this project is a therapeutic adjunct to prevent chemotherapy induced diarrheaCIDbased on a completely new mechanism of action targeting enteric bacteriaThis Fast Track SBIR proposal outlines the strategy for selecting a lead development candidate to be evaluated in investigational new drugINDenabling studies to support a first in human trialThe focus of this project is prevention of diarrhea associated with irinotecanIRIan important drug used to treat advanced colorectal and pancreatic cancer patientsIntensedelayed diarrhea is the major reason for reducingpostponing or stopping IRI chemotherapyThe cancer killingactive agent of IRI is SNa potent topoisomerase I inhibitorAs part of its elimination from the bodySNis detoxified primarily by the liver to an inactive glucuronideSNGthat is subsequently shuttled to the lower gastrointestinal tractTheglucuronidase enzymeGUSexpressed in a subset of gut bacteria metabolizes SNG back into SNwhich is highly toxic to enterocytesThis reactivation of SNby bacterial GUS in the gut microbiome is a key triggering event leading ultimately to seriousdelayed diarrheaA selectivenon proprietary bacterial GUS inhibitorSBXwas previously shown to alleviate IRI induced diarrhea in rodentsPhaseof this project discloses five proprietary analogs of SBXand outlines the efficacy tolerability studies to enable selection of the two most promising analogs to advance into PhaseSBIR studiesThe lead candidate will be selected in the first aim of PhaseThe remaining Phaseactivities include chemistry manufacturing controlCMCrelated work and regulatory safety preclinical studies that will transition this project from drug discovery to preclinical developmentAimPhaseProfile novel SBXanalogs in vitro for their off target pharmacologycytotoxicitymetabolism liability and stability in plasmaAimPhaseIdentify the two most promising SBXanalogs based on their therapeutic window and candidacy for formal preclinical studiesAimPhaseSelect lead candidateGenerate CMC and additional non GLP preclinical data to support a pre IND meeting with the FDAAimPhaseConduct CMC related activities to enable formal evaluations of the formulated lead candidate in GLP toxicology and safety pharmacology studiesA key deliverable in the proposed Phasework is a preclinical data package that will adequately qualify the lead candidate for further evaluation in an acuteadministrationfirst in human clinical trial in advanced colorectal and or pancreatic cancer patients undergoing irinotecan containing chemotherapy PROJECT NARRATIVE Symberix is pioneering a new class of medicines that works by eliminating harmful bacterial activity in the gut microbiome without killing its vast populations of beneficial bacteriaThis project aims to discover and develop a microbiome targeted therapeutic that selectively blocks the activity of a bacterial enzyme responsible for triggering the debilitating and sometime deadly diarrhea that can occur in cancer patients using irinotecanan important chemotherapeutic agentThis project also sets the stage for potentially expanding this unique microbiome targeted approach to other anti cancer drugs to enhance the quality of life and survival outcomes for cancer patients at risk of suffering or dying from chemotherapy induced diarrhea