Acurx Pharmaceuticals presented findings from its Phase 2 clinical trial of ibezapolstat (IBZ) at the Peggy Lillis Foundation Inaugural CDI Scientific Symposium in November 2024. The study investigated ibezapolstat, a small-molecule inhibitor of DNA polymerase IIIC, compared to vancomycin for the treatment of Clostridioides difficile infection (CDI). The presentation highlighted the drug's potential to restore the normal gut microbiota while effectively treating the infection.
Pathophysiology and the Role of Microbiota
The presentation emphasized the importance of a healthy gut microbiome in preventing CDI. Clostridioides difficile requires dysbiosis to cause infection. A healthy microbiota maintains gut health, particularly through the conversion of primary bile acids (BAD), which promote C. difficile germination, into secondary bile acids, which inhibit its growth. Key taxa responsible for this conversion are Clostridiales.
Ibezapolstat: A Gram-Positive Selective Spectrum Antibiotic
Ibezapolstat (IBZ; ACX362E) is designed as a small-molecule inhibitor of DNA polymerase IIIC, an enzyme essential for DNA replication in low G+C content Gram-positive bacteria, including certain Firmicutes. This novel mechanism of action gives IBZ a Gram-Positive Selective Spectrum (GPSS), selectively targeting certain Firmicutes while sparing others. Preclinical studies have shown that other DNA pol IIIC inhibitors exhibit in vitro activity against Bacillus anthracis, including ciprofloxacin-resistant strains.
Phase 2b Study Design and Results
The Phase 2b study (ClinicalTrials.gov ID NCT04247542) enrolled patients with mild to moderate CDI, diagnosed using an EIA free toxin kit. Participants were randomized to receive either ibezapolstat 450 mg BID or vancomycin 125 mg QID for 10 days. The primary outcome measures included initial clinical cure (day 12), sustained clinical cure (day 38), and extended clinical cure (3 months). Secondary endpoints included time to resolution of diarrhea, safety, pharmacokinetics, microbiome changes (qPCR and 16S rRNA), and bile acid changes (LC-MS/MS).
Baseline demographics were similar between the ibezapolstat (n=16) and vancomycin (n=14) groups. The mean age was 64 years in the IBZ group and 62 years in the VAN group. The majority of patients were female (81% in IBZ, 79% in VAN) and White (100% in IBZ, 93% in VAN). Both treatments were well-tolerated, with no drug-related serious adverse events or drug-related treatment withdrawals.
Efficacy Analysis: Time to Resolution of Diarrhea
Cumulative incidence of unformed bowel movement (UBM) resolution was high in both groups: 94% in the ibezapolstat group and 86% in the vancomycin group. This suggests comparable efficacy in resolving diarrhea associated with CDI.
