Efficacy, safety, pharmacokinetics, and associated microbiome changes of ibezapolstat compared with vancomycin in adults with Clostridioides difficile infection: a phase 2b, randomised, double-blind, active-controlled, multicentre study

Abstract

Background: Clostridioides difficile infection is a common health-care-associated and community-acquired disease with few antibiotic treatment options. We aimed to assess the safety, efficacy, pharmacokinetics, and associated microbiome changes of ibezapolstat, an antibiotic that inhibits the PolC-type DNA polymerase III α subunit C, versus vancomycin for the treatment of C difficile infection in adults.

Methods: This was a phase 2b, randomised, double-blind, active-controlled study conducted at 15 centres, primarily outpatient clinics and hospitals, in the USA. Adults aged 18-90 years, with signs and symptoms of C difficile infection and a positive toxin stool test were recruited. Participants were randomly assigned (1:1) with block assignment by study site using an interactive web response system to receive oral ibezapolstat (450 mg twice daily) or oral vancomycin (125 mg every 6 h) for 10 days. Masking was achieved by over-encapsulation of both study drugs (ibezapolstat and vancomycin) and placebo into identically sized capsules. Participants were excluded if they had received more than 24 h of treatment with oral vancomycin, fidaxomicin, or metronidazole for the current episode of C difficile infection before the first dose of study drug or any other antibacterial therapy within 48 h, had had more than three episodes of C difficile infection in the previous 12 months, or had had more than one previous episode in the past 3 months (excluding the current episode). The primary efficacy endpoint was initial clinical cure maintained for at least 48 h after the end of treatment. All individuals with C difficile infection who met inclusion and exclusion criteria, were randomly assigned, and were administered at least one dose of study drug were included in the efficacy analysis. The safety and tolerability of ibezapolstat was assessed in all individuals who were administered at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04247542.

Findings: Between March 12, 2021, and Oct 27, 2023, 39 individuals were assessed for eligibility, 32 of whom were recruited and randomly assigned to ibezapolstat (n=18) or vancomycin (n=14). Two participants were excluded from the efficacy analysis: one participant in the ibezapolstat group withdrew consent before receiving the study drug and another was identified after random assignment as having an exclusion criterion. The primary efficacy analysis included 16 participants in the ibezapolstat group and 14 in the vancomycin group; 24 (80%) participants were female and six (20%) were male. 15 (94%) of 16 participants in the ibezapolstat group had initial clinical cure compared with 14 (100%) of 14 participants in the vancomycin group (treatment difference -6·3% [95% CI -30·7 to 19·4]; p=1·0). Ibezapolstat was well tolerated with a safety profile similar to vancomycin. No drug-related serious adverse events, drug-related treatment withdrawal, or treatment-related deaths occurred in either group.

Interpretation: Ibezapolstat is a Gram-positive selective spectrum antibiotic that shows potential in the treatment of initial C difficile infection and prevention of recurrence. Further clinical development is warranted.

Funding: Acurx Pharmaceuticals.