Bacteria have developed resistance to beta-lactam (BL) antibiotics by producing beta-lactamase enzymes, which catalytically inactivate BL antibiotics. Today, over 70% of hospital-based infections caused by gram-negative bacteria are associated with an antibiotic resistant organism.1 To overcome this kind of resistance, BL antibiotics have been successfully combined in the past with beta-lactamase inhibitors (BLI) (Amoxicillin/Clavulanic acid, Piperacillin/Tazobactam). Unfortunately, the suite of existing BLIs are not sufficiently broad in their effectiveness against the extended spectrum beta-lactamases (ESBLs) and different subtypes of carbapenem-hydrolyzing beta-lactamases (carbapenemases), including against the superbugs that express NDM and VIM metallo-beta-lactamases.
VenatoRx’s most advanced development-stage product is VNRX-5133, an injectable beta-lactamase inhibitor (BLI) that features selective and potent in vitro activity against both serine- and metallo-beta-lactamases, including ESBL, OXA, KPC, NDM, and VIM enzymes. VenatoRx believes that VNRX-5133, in a fixed combination with the fourth generation cephalosporin, cefepime, has the potential to provide a valuable broad-spectrum treatment option to meet unmet medical need in patients with infections due to carbapenem-resistant pathogens including carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA), suspected polymicrobial infections caused by both gram-negative and gram-positive susceptible pathogens, and engineerable MDR bioterror pathogens such as Burkholderia spp. and Salmonella spp. Early clinical studies of cefepime/VNRX-5133 have been completed and VenatoRx intends to initiate Phase 3 pivotal trials during the second quarter 2019.
This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201300019C, and The Wellcome Trust under Award No. 360G-Wellcome-101999/Z/13/Z.
VenatoRx’s second development-stage product in clinical development is VNRX-7145, an orally bioavailable BLI that in a fixed combination with the third generation orally bioavailable cephalosporin, ceftibuten, has the potential to rescue activity of the partner antibiotic against ESBLs and key carbapenem-resistant Enterobacteriaceae, including those expressing KPC and OXA carbapenemases.
This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201600029C.
Penicillin Binding Protein (PBP) Inhibitor Program
VenatoRx is developing a novel class of non-beta-lactam molecules that kill bacteria by the same selective mechanism as BLs: blocking cell wall synthesis via binding to the bacterial penicillin binding proteins (PBPs). Chemically distinct from the BLs, these new molecules have been designed to be impervious to degradation by any beta-lactamases. By circumventing over seventy years of beta-lactamase-driven resistance, this new class of PBP inhibitors has the potential to usher in a new wave of antibacterial therapeutics. CARB-X and DTRA (HDTRA117C0070) are providing financial support for the development of this platform.