521. Investigating the Gram-Positive Selective Spectrum of Ibezapolstat, a First-in-Class DNA Polymerase IIIC (Pol IIIC) Inhibitor

BACKGROUND: Ibezapolstat (IBZ) is a non-absorbable antimicrobial currently in phase 2 clinical trials for the treatment of Clostridioides difficile infection (CDI). In vitro and human studies have shown potent activity of IBZ against C. difficile but selective activity against other beneficial Gram-positive gut microbiota shown to reduce the risk of recurrent CDI. As the target DNA Pol IIIC enzyme is present in most Gram-positive species, the reasons for this selectivity are unclear. The purpose of this study was to assess the selectivity of IBZ against Gram-positive gut microbiota. METHODS: Using stool samples and microbiome data from the phase 1 and 2 studies, changes in proportional abundance of gut microbiome species were analyzed over time in healthy volunteers or patients with CDI given IBZ. Using a separate collection of gut microbiota species, MIC determinations against a variety of Gram-positive gut species were assessed by broth microdilution. RESULTS: Baseline gut microbiota from healthy volunteers were primarily Firmicutes, Bacteroidetes, or Actinobacteria. Actinobacteria increased in abundance after starting IBZ (primarily Bifidobacteriales or Coriobacteriales) and persisted for the entire dosing period. In comparison to the phase 1 study, the phase 2a CDI study baseline microbiota had a lower proportion of Actinobacteria and Firmicutes and increased Bacteroidetes. In CDI patients, Actinobacteria increased in abundance after starting IBZ (primarily Coriobacteriales) followed within 2-3 days by decreased abundance of Bacteroidetes, and an increased abundance of Lachnospiraceae and Ruminococcaceae. Using isolated gut microbiota species, IBZ was inactive (MIC >64 µg/mL) against representative Actinobacteria (Bifidobacteriaceae and Coriobacteriaceae) and certain Firmicutes (Lachnospiraceae and Lactobacillaceae) but highly active against strains of C. difficile (MIC<2 µg/mL). CONCLUSION: Microbiome changes with IBZ were dependent on underlying composition of the baseline microbiome but consistently demonstrated increased abundance of Actinobacteria after starting therapy. IBZ microbiome data coupled with in vitro MIC determinations demonstrated persistence or regrowth of healthy microbiota associated with beneficial physiologic effects. DISCLOSURES: Kevin W. Garey, PharmD, MS, Acurx Pharmaceuticals: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support|Summit Pharmaceuticals: Grant/Research Support.