Development of a Novel Injectable Antibiotic to Treat Serious Multidrug-resistant Gram-positive Infections

PROJECT SUMMARY / ABSTRACT Within the past decades, the prevalence of antibiotic-resistant (AMR) gram-positive infections have increased, and gram-positive bacteria cause the majority of nosocomial infections. It was estimated that in 2019 there were 4.95 million deaths associated with AMR and 1.27 million deaths directly attributable to AMR. In high income countries, Staphylococcus aureus was the most frequent pathogen, accounting for 26.1% of the deaths attributable to AMR. Two of the most prevalent and/or difficult-to-treat pathogens include methicillin resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE); both are on the list of WHO and CDC priority pathogens which informs the vital need for new and effective antibiotics. Unfortunately, these pathogens continue to develop new multi-drug resistance patterns reducing therapeutic options. Furthermore, the COVID- 19 pandemic has significantly increased the rates of antimicrobial resistance, and novel therapeutics will be needed in the future to combat these serious and prevalent hospital acquired infections. AimMax Therapeutics has discovered a novel antibiotic, AMX-2005, with broad spectrum and best-in-class activity against MRSA and VRE with potency superior to linezolid and no cross-resistance to vancomycin. This antibiotic has demonstrated rapid bactericidal activity in in vitro time-kill assays at concentrations as low as 2X the MIC as well as bactericidal efficacy in the in vivo murine neutropenic thigh infection model. AMX-2005 shows the potential to be a next generation therapeutic from a class with an established history of clinical safety and low rates of resistance. Collectively, these data provide a strong foundation of support for this proposal. The overall goal of this proposed Phase 1 SBIR application is to develop a novel intravenous formulation of AMX-2005 and generate proof-of-concept data to support the development of a therapeutic for difficult-to-treat indications with high unmet needs. In Aim 1, we will conduct further in vitro microbiology studies to investigate activity and attributes essential to successful therapeutics for serious infections, including an evaluation of the potential for resistance development. In Aim 2, we will develop a novel IV formulation of AMX-2005 through the use of innovative modern excipients and formulation technology. Our top two formulations will then undergo rigorous safety assessments including in vitro compatibility tests with plasma and blood, vein irritation study at the injection site to ensure safety and tolerability of the lead IV formulation, followed by determination of maximum tolerated dose in mice. The PK profiles of the top formulation will be assessed to determine the most suitable dosing regimens for efficacy studies in Aim 3, where we will assess the activity and potency of formulated IV AMX-2005 in mice models of septicemia and thigh infection against MDR strains of MRSA or VRE. Finally, we will conduct a mouse PK study to assess tissue concentrations of AMX-2005. If successful, these data will inform indication selection and a target product profile to support a subsequent Phase 2 SBIR application in which both IV and oral dosage forms of AMX-2005 will be developed.