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.
Public Health Relevance Statement: Project Narrative There were 4.95 million deaths associated with antimicrobial resistance in 2019 worldwide, with antibiotic- resistant Staphylococcus aureus as the leading causative pathogen in the US. More effective antibiotics with unique mechanisms of action are needed to combat the global crisis of antimicrobial resistance, which has further worsened due to COVID-19 pandemic. AimMax Therapeutics seeks to develop a novel antibiotic to treat serious multidrug-resistant gram-positive infections including those with MRSA and VRE.
Project Terms: Accounting; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antibiotics; Biological Assay; Assay; Bioassay; Biologic Assays; Blood; Blood Reticuloendothelial System; Cessation of life; Death; Dosage Forms; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Excipients; Foundations; Future; Goals; Gram-Positive Bacteria; Recording of previous events; History; histories; Hospitalization; Hospital Admission; Human; Modern Man; In Vitro; Income; Economic Income; Economical Income; incomes; Infection; Lead; Pb element; heavy metal Pb; heavy metal lead; Marketing; Microbiology; Modernization; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Pain; Painful; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Ribosomes; Risk; Safety; Septicemia; Blood Poisoning; septicaemia; septicemic; Staphylococcus aureus; S aureus; S. aureus; Staph aureus; Technology; Testing; Thigh structure; Thigh; Time; Tissues; Body Tissues; Veins; Generations; Microbial Biofilms; biofilm; Gram-Positive Bacterial Infections; Streptococcus enterococcus group; Enterococcus; Resistance to antibiotics; Resistant to antibiotics; antibiotic drug resistance; antibiotic resistant; Antibiotic Resistance; Injectable; density; Site; Solid; Clinical; Penetration; Phase; Hospital Infections; Hospital acquired infection; institutional infection; Nosocomial Infections; Streptogramins; Ensure; Evaluation; Susceptibility; Predisposition; Multidrug Resistance; Multiple Drug Resistance; Multiple Drug Resistant; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; Resistant to Multiple Drug; Resistant to multi-drug; Resistant to multidrug; multi-drug resistant; multidrug resistant; Multi-Drug Resistance; Therapeutic; Venous; Intravenous; Nature; irritation; Oral; Pattern; Country; quinupristin-dalfopristin; success; Linezolid; Zyvox; novel; Vancomycin Resistance; resistance to vancomycin; resistant to vancomycin; vancomycin resistant; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; Modeling; Property; Adverse event; Adverse Experience; Vancomycin-resistant enterococci; Vancomycin resistant enterococcus; MRSA; Methicillin Resistant S Aureus; Methicillin Resistant S. Aureus; methicillin-resistant S. aureus; methicillin resistant Staphylococcus aureus; Address; Dose; Antimicrobial Resistance; Antimicrobial resistant; Resistance to antimicrobial; anti-microbial resistance; anti-microbial resistant; resistance to anti-microbial; resistant to anti-microbial; resistant to antimicrobial; Data; Surveillance Program; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Update; Development; developmental; bactericide; bactericidal; attributable death; attributable mortality; Advanced Development; blood infection; bloodstream infection; Sepsis; VRSA; Vancomycin resistant S. aureus; Vancomycin resistant Staph aureus; Vancomycin-resistant S.aureus; Vancomycin-resistant Staphylococcus aureus; Vancomycin-resistant S. aureus; Resistant development; developing resistance; Resistance development; pathogen; Prevalence; innovate; innovative; innovation; resistant; Resistance; anti-microbial; antimicrobial; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; prototype; combat; Regimen; Formulation; efficacy study; clinical development; Injections; priority pathogen; safety assessment; antibiotic resistant infections; COVID crisis; COVID epidemic; COVID pandemic; COVID-19 crisis; COVID-19 epidemic; COVID-19 global health crisis; COVID-19 global pandemic; COVID-19 health crisis; COVID-19 public health crisis; COVID19 crisis; COVID19 epidemic; COVID19 global health crisis; COVID19 global pandemic; COVID19 health crisis; COVID19 pandemic; COVID19 public health crisis; SARS-CoV-2 epidemic; SARS-CoV-2 global health crisis; SARS-CoV-2 global pandemic; SARS-CoV-2 pandemic; SARS-CoV2 epidemic; SARS-CoV2 pandemic; SARS-coronavirus-2 epidemic; SARS-coronavirus-2 pandemic; Severe Acute Respiratory Syndrome CoV 2 epidemic; Severe Acute Respiratory Syndrome CoV 2 pandemic; Severe acute respiratory syndrome coronavirus 2 epidemic; Severe acute respiratory syndrome coronavirus 2 pandemic; corona virus disease 2019 epidemic; corona virus disease 2019 pandemic; coronavirus disease 2019 crisis; coronavirus disease 2019 epidemic; coronavirus disease 2019 global health crisis; coronavirus disease 2019 global pandemic; coronavirus disease 2019 health crisis; coronavirus disease 2019 pandemic; coronavirus disease 2019 public health crisis; coronavirus disease crisis; coronavirus disease epidemic; coronavirus disease pandemic; coronavirus disease-19 global pandemic; coronavirus disease-19 pandemic; severe acute respiratory syndrome coronavirus 2 global health crisis; severe acute respiratory syndrome coronavirus 2 global pandemic; COVID-19 pandemic; new chemical entity
