Venatorx Pharmaceuticals Inc

Novel Cyclic Boronate Penicillin Binding Protein Inhibitors to Eliminate the Threat Posed by ?-lactamases and Enable a Future Treatment Option for Carbapenem-resistant Enterobacterales Infections - Project Summary Carbapenem-resistance in Enterobacterales Has Steadily Increased Over the Past Decade, Leading to Multidrug and Pan-drug Resistance (mdr/pdr), Further Emphasizing the Need for New Innovative Therapies. Carbapenem- Resistant Enterobacterales (CRE) Is a Serious Global Health Problem Classified by the Us Centers for Disease Control and Prevention as an “urgent Threat” and by the World Health Organization as a “priority 1 Critical Threat”. the Ss-lactams Have Long Been the Front Line Therapeutic Option for Such Infections, But Efficacy of These Agents, Including Last Resort Carbapenems, Is Threatened by Recent Expansion of Ss-lactamases, Particularly Subtypes (e.g., NDM) Spreading Rapidly Among Enterobacterales That Are Unaffected by Clinically-available Ss-lactam/ss- Lactamase Inhibitor Combinations. to Address the Medical Need, Venatorx Has Identified a Novel Series of Highly Selective Cyclic Boronates That Bind to and Disrupt Penicillin-binding Protein (PBP) Transpeptidase (TPASE) Function While Avoiding the Action of All Current and Future Ss-lactamases. This Approach Creates the First Prospect and “rare” New Class Gram Negative Agent to Treat Infections Caused by Any Ss-lactamase-producing Cre Pathogen. Significant Strides in Microbiological Activity Have Already Been Achieved Within the Series by the Lead Compound VNRX-6736, With an MIC90 of 32 ΜG/ML Relative to 128 ΜG/ML for Meropenem-vaborbactam and =1,024 ΜG/ML for Ceftazidime-avibactam in a Recent Challenge Set of 100 Cre Isolates. Not Only Does VNRX- 6736 Outperform These Clinical Comparators From an MIC90 Perspective, But Does So With a Narrow Range of Mic Owing to Ss-lactamase Avoidance, a Feature That Will Ultimately Benefit Setting of Breakpoints. the Series Is Rapidly Bactericidal, Exhibits a Low Spontaneous Mutational Frequency (frequency of Resistance at 4X Mic of <2.7 X 10-11 in E. Coli Atcc 25922) and Has Favorable Adme and PK Properties. Proof of Concept Efficacy Has Been Achieved by VNRX-6736 in the Murine Thigh Model of Carbapenem-resistant E. Coli Infection and Pharmacokinetics Modeling Suggests That 30-45% Time Above Mic Is Required to Achieve Efficacy. Optimization Efforts Proposed Herein Are Targeting an 8-FOLD Improvement in Antibacterial Activity Driven by Rational Structure-guided Design to Improve PBP Binding Interaction Kinetics to Enable an MIC90 = 4 ΜG/ML. Such an Optimized Cyclic Boronate Pbpi Could Be a 1ST New Class Antibiotic Addressing Resistance to Ss-lactams for the Treatment of Infections Caused by Cre and a Long Term Therapeutic Solution to Resistance Development in Enterobacterales.