Phase II SBIR: Responding to NDM-1 - Advancement of a new MBL inhibitor to IND

DESCRIPTION provided by applicant Multi drug resistance in Enterobacteriaceae is regarded as a healthcare crisis While carbapenems are among the most prescribed antibiotics for infections caused by these organisms carbapenem resistance conferred by zinc based metallo carbapenemases Amber Class B is a growing global health concern that threatens to erode the efficacy of these antibiotics both in the hospital and community settings Members of this family of resistance enzymes such as NDM are found on promiscuous plasmids with other MDR resistance mechanisms and are rapidly spreading throughout Enterobacteriaceae The concern now is that in the absence of clinically available MBL inhibitors i e MBLs are refractory to clinically available legacy inhibitors tazobactam clavulanic acid and sulbactam MBLs such as NDM could become the dominant carbapenemases in clinical settings As there are currently no MBL inhibitors in pharmaceutical development there is an urgent need to progress compounds into the drug development pipeline to address this growing issue and safeguard carbapenems In the Phase I work we identified a pre development candidate VNRX meeting or exceeding established success criteria including potent and selective inhibitory activity against NDM and VIM MBLs rescue of Meropenem activity in recent and representative NDM VIM producing clinical isolates of Enterobacteriaceae P aeruginosa and A baumannii established in vivo efficacy in a murine septicemia model and preliminary pharmacokinetics compatible with t i d dosing with Meropenem We also identified potential backup compounds to VNRX as contingencies The Phase II application endeavors to drive this andquot first in classandquot MBL inhibitor candidate VNRX through IND enabling studies to an Investigational New Drug filing PUBLIC HEALTH RELEVANCE Metallo lactamase enzymes such as NDM and VIM variants are spreading throughout Enterobacteriaceae and pose a serious threat to lactam efficacy in both the hospital and community settings The increased use of generic carbapenems will impose further selective pressure for these enzymes As there are currently no available inhibitors for Metallo lactamases MBLs nor any prospects in pharmaceutical development the future utility of carbapenems is uncertain To address this medical need we have selected a pre development candidate MBL inhibitor VNRX with potent inhibitory activity against NDM and VIM variants capable of rescuing meropenem activity in NDM VIM producing clinical isolates of Enterobacteriaceae and select non fermenters Pseudomonas aeruginosa and Acinetobacter baumannii We believe that VNRX will fill the gap in lactamase coverage and safeguard the future utility of carbapenems