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

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.

Trial registration: ClinicalTrials.gov NCT04247542.

Keywords: Clostridioides difficile; DNA polymerase IIIC; Enterocolitis; Female; Male; humans.

Conflict of interest statement

Potential conflicts of interest. K. W. G. received research grant support from Acurx Pharmaceuticals, Paratek, and Summit Pharmaceuticals. M. H. S. is a shareholder and paid consultant for Acurx Pharmaceuticals and received consulting fees from Summit, Paratek, Tetraphase, and Seres. M. H. S. is a shareholder of and paid consultant to Acurx Pharmaceuticals, Inc. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Ibezapolstat pharmacokinetics in plasma (A) and stool (B) samples. Values represent means with standard deviations.

Figure 2.

Summary estimates of changes in alpha diversity over time with the Shannon diversity (A) and inverse Simpson (B) indexes.

Figure 3.

Effects of ibezapolstat on relative abundance of taxa by phylum (A), class (B), order (C), and family (D).

Figure 4.

Changes over time in primary (A) and secondary (B) bile acid concentrations and the ratio of secondary to primary bile acid concentrations (C). Values represent means with standard errors.