Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial

Kevin W. Garey, Jacob Mcpherson, An Q. Dinh, Chenlin Hu, Jinhee Jo, Weiqun Wang, Chris K. Lancaster, Anne J. Gonzales-Luna, Caroline Loveall, Khurshida Begum, M. Jahangir Alam, Michael H. Silverman, Blake M. Hanson

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Background: This study was the first human validation of the gram-positive bacterial DNA polymerase IIIC target in patients with Clostridioides difficile infection. The primary objectives were to assess clinical cure rates and adverse events (AEs). Secondary objectives were to evaluate plasma/fecal pharmacokinetics, microbiologic eradication, microbiome and bile acid effects, and sustained clinical cure (SCC) with ibezapolstat. Methods: This single-arm, open-label, phase 2a study enrolled adults with C. difficile infection at 4 US centers. Patients received ibezapolstat 450 mg orally every 12 hours for 10 days and followed for an additional 28 days to assess study objectives. Results: Ten patients with a mean (standard deviation [SD]) age of 49 [15] years were enrolled. Seven AEs were reported classified as mild-moderate. Plasma levels of ibezapolstat ranged from 233 to 578 ng/mL while mean (SD) fecal levels were 416 (494) μg/g stool by treatment day 3 and >1000 μg/g stool by days 8-10. A rapid increase in alpha diversity in the fecal microbiome was noted after starting ibezapolstat therapy, which was maintained after completion of therapy. A proportional decrease in Bacteroidetes phylum was observed (mean change [SD], -10.0% [4.8%]; P = .04) with a concomitantly increased proportion of Firmicutes phylum (+14.7% [5.4%]; P = .009). Compared with baseline, total primary bile acids decreased by a mean (SD) of 40.1 (9.6) ng/mg stool during therapy (P < .001) and 40.5 (14.1) ng/mg stool after completion of therapy (P = .007). Rates of both initial clinical cure and SCC at 28 days were 100% (10 of 10 patients). Conclusions: In this phase 2a study, 10 of 10 patients achieved SCC, demonstrated favorable pharmacokinetics, minimal AEs, and beneficial microbiome and bile acids results. These results support continued clinical development.

Original languageEnglish (US)
Pages (from-to)1164-1170
Number of pages7
JournalClinical Infectious Diseases
Volume75
Issue number7
DOIs
StatePublished - Oct 1 2022

Keywords

  • Clostridioides difficile
  • DNA polymerase IIIC
  • Enterocolitis
  • Female
  • humans
  • Male

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

Fingerprint

Dive into the research topics of 'Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial'. Together they form a unique fingerprint.

Cite this