Research Project
9553958
Bloodstream infections (BSIs) caused by Gram-negative bacterial pathogens are associated with significant morbidity and mortality due to the antibiotic-resistant nature of the pathogens. Infections caused by multi-drug resistant (MDR) bacterial pathogens result in substantial health and economic impact due to the lack of effective therapeutic options. This lack of treatment options is particularly relevant for MDR Gram-negative pathogens, such as Pseudomonas aeruginosa and Acinetobacter baumannii, which have shown a great propensity to challenge the clinical care of patients suffering from such infections. Arrevus is developing a novel approach to addressing Gram-negative MDR infections through the use of Designer Proline-rich Antimicrobial peptide Chaperone protein inhibitors (DPCs) derived from insects, which serve as inhibitors to one of the critical bacterial proteins responsible for bacterial protein folding, DnaK. As an adjuvant therapy to current antibiotics, DPCs have the potential to provide a much-improved treatment option for MDR Gram- negative bacterial infections. Preliminary studies have displayed the potential of ARV-1501, the lead DPC, as an antibiotic potentiating agent against MDR Gram-negative bacterial pathogens. Our efforts have shown that: 1) ARV-1501 via an intramuscular route is effective against MDR A. baumannii in a bacteremia model; 2) ARV-1501 enhances the activity of colistin and imipenem; 3) ARV-1501 has a favorable preliminary safety profile; and 4) ARV-1501 enhances the effects of legacy antimicrobials through a novel mechanism of action. Collectively, these data support the continued development of AVR-1501 through a Fast-Track program that is geared toward characterizing the therapeutic potential and safety profile of ARV-1501 in order to construct a target product profile (TPP). This overall goal will be met through the execution of the following aims: Phase I Specific Aims are: 1) To define the spectrum of activity of ARV-1501. 2) To evaluate the efficacy of intravenous dosing of ARV-1501 for the treatment of Gram-negative BSIs. The measures of success to advance to Phase II are 1) Identification of an optimal antibiotic for use as a co-treatment with ARV-1501 against Gram-negative pathogens; and 2) Determination of the efficacy of ARV-1501 when delivered intravenously in a Gram-negative BSI mouse model. Phase II Specific Aims are: 1) To characterize the pharmacological properties and therapeutic activity of ARV-1501. 2) To obtain a preliminary safety profile of ARV-1501. The measure of success for Phase II is to complete key pharmacological and safety assessments to craft the TPP.
