Functional and Metagenomic Evaluation of Ibezapolstat for Early Evaluation of Anti-Recurrence Effects in...

Reduction of Clostridioides difficile infection (CDI) recurrence is an essential endpoint for CDI-directed antibiotic development that is often not evaluated until Phase III trials. The purpose of this project was to use a functional and metagenomic approach to predict the potential anti-CDI recurrence effect of ibezapolstat, a DNA polymerase IIIC inhibitor, in clinical development for CDI. As part of the Phase I ibezapolstat clinical study, stool samples were collected from 22 healthy volunteers, who were given either ibezapolstat or vancomycin. Stool samples were evaluated for microbiome changes and bile acid concentrations. Ibezapolstat 450 mg and vancomycin, but not ibezapolstat 300 mg, showed statistically significant changes in alpha diversity over time compared to that of a placebo. Beta diversity changes confirmed that microbiota were significantly different between study groups. Vancomycin had a more wide-ranging effect on the microbiome, characterized by an increased proportion of Gammaproteobacteria. Ibezapolstat demonstrated an increased proportion of Actinobacteria, including the Bifidobacteriaceae family. Using a linear regression analysis, vancomycin was associated with significant increases in primary bile acids as well as primary:secondary bile acid ratios. An overabundance of Enterobacteriaceae was most highly correlated with primary bile acid concentrations (r = 0.63; P < 0.0001). Using Phase I healthy volunteer samples, beneficial changes suggestive of a lower risk of CDI recurrence were associated with ibezapolstat compared to vancomycin. This novel omics approach may allow for better and earlier prediction of anti-CDI recurrence effects for antibiotics in the clinical development pipeline.