Pre-clinical Safety and Toxicology Studies of a PO-administered b-lactam-tarocin combination agent to treat methicillin susceptible and resistant staphylococci

Hackensack University Medical Center, Hackensack NJ

Investigators

Abstract

SUMMARY Antimicrobial resistance (AMR) poses a serious global threat to human health. A recent analysis estimated approximately 1.3 million deaths in 2019 alone, with methicillin resistant Staphylococcus aureus (MRSA) representing the second leading AMR pathogen. More worrisome, only a single class of orally-bioavailable (PO) and bacteriostatic antibiotics – the oxazolidinones, represented by linezolid (LZD) and tedizolid (TZD) – exist to treat such infections. Oxazolidinones also have significant adverse effects, including myelosuppression, peripheral neuropathy, and optic neuropathy following extended treatment. As an alternative to this antibiotic class, we aim to develop a first-in-class, bactericidal, and orally bioavailable combination product comprising generic antibiotic dicloxacillin (DCX) and the b-lactam potentiator P911 for step-down and out-patient treatment of staphylococcal infections, irrespective of methicillin resistance or resistance to standard of care antibiotics. Specific Aims. The following aims reflect IND-enabling studies involving pharmacology, drug metabolism, and toxicology to support preclinical candidate (PCC) development of P911 and identify a backup: Aim 1. Complete PCC Package and Identify backup. P911 PCC activities include i) non-GLP compound scale up, ii) in vitro genotoxicity studies, and iv) single dose monkey PK studies to complete interspecies PK analysis. Additionally, 2 potential PCC backup compounds will be assessed according to microbiology, ADME, PK, efficacy, and toxicity as previously performed to identify P911. Aim 2. Expanded Efficacy in Rodent Models and in vivo ADME Studies. Expanded efficacy studies will be performed in rodent thigh, bacteremia, and endocarditis models of MRSA infection. Aim 3. GLP Process Optimization and Synthesis of P911. Establish a production protocol for 5 kg scale synthesis of P911 GLP-grade material to support genotoxicity, safety, and toxicology IND-enabling studies. Aim 4. Safety, Pharmacology, and Genotoxicity Studies. Complete genotoxicity studies as well as CNS and respiratory studies in rat and CV safety study in dog. We will also prepare a background brochure and data summary of P911 to share with FDA prior to a pre-meeting. Aim 5. IND-enabling Clearance, in vivo Metabolism, and 14-Dat Toxicology Studies. Bile duct cannulated excretion (BCE) studies are planned in rat and dog to inform principal pathways of clearance and excretion as well as understand the biodistribution, metabolism, and how both parent and metabolites are eliminated from the body. 14-day toxicology and recovery studies in two species using GLP material are also planned but outside the scope of the proposal due to budget limitations. Completing these aims will support IND registration of P911.