A Novel Gyrase Inhibitor for the Treatment of Drug-susceptible and Multidrug-resistant Mycobacterium tuberculosis Infections

ABSTRACT TuberculosisTBcaused by the bacterial pathogen Mycobacterium tuberculosisMtbremains a leading cause of death in the world today despite the availability of therapeutic drugs for more than sixty yearsThe disease also exacts a significant economic toll in countries where it is prevalentoften in poorer areas of the worldMultidrug resistant TBMDR TB and XDR TBis an increasing problemwith nearly one half million cases worldwide per yearadding to the difficulty of controlling this diseaseThereforeeffective new drugswith novel mechanisms of action that can be included in treatment regimens for both drug susceptible and MDR TB are urgently neededSpero Therapeutics has inlicensed SPRformerly Vertex VXcan inhibitor of the B subunitGyrBATPase activity of the essential DNA replication gyrase enzymethat possesses excellent in vitro anti mycobacterial activity and in vivo efficacy in mouse models of TB infectionGyrB ATPase represents a relatively na ve drug target andthereforepre existing resistance to drugs against this target should be rare in patientsThe scope of this application includes additional mouse infection model studies to assess treatment efficacy when SPRis included in drug regimens that contain an increased dose level of rifampin for drug susceptible TB and in combinations with existing standard of care drugs used for MDR TBFor the formera goal in this proposal is to shorten the duration of treatment while for MDR TBgoals are to identify new drugs to replace those to which isolates are no longer susceptible and also hopefully shorten duration of treatmentAdditional profiling of SPRindicated favorable drug like properties including good pharmacokineticsPKin multiple animal speciesno significant off target or cytotoxic findingsand no significant toxicities in non GLP studies in two animal speciesIn this proposalwe will also work to improve the oral drug formulation as well as assess toxicity in a six month rat GLP toxicity model in anticipation of future human dosing regimensIn paralleloutside of the scope of this proposalSpero will run additional studies to complete a full IND enabling package with an IND filing planned inBased on the microbiology results and other strong preclinical data to dateSpero believes that this compound is poised for rapid progression into the clinic as a new agent to treat mycobacterial infections and is committed to progressing this compound through full clinical development and entry into the marketplace