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 (CDI). The primary objectives were to assess clinical cure rates and adverse events (AE). Secondary objectives were to evaluate plasma/fecal pharmacokinetics (PK), microbiologic eradication, microbiome and bile acid effects, and sustained clinical cure (SCC) of ibezapolstat. Methods This single-arm, open-label, phase 2a study enrolled adults with CDI at four 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 aged 49±15 years were enrolled. Seven AEs were reported classified as mild-moderate. Plasma levels of ibezapolstat ranged from 233-578 ng/mL while fecal levels averaged 416±494 µg/g (mean±SD) stool by treatment day 3 and >1,000 µg/g stool by days 8-10. A rapid increase in alpha diversity in the fecal microbiome was noted after starting ibezapolstat therapy that was maintained following completion of therapy. A proportional decrease in Bacteroidetes phylum was observed (10.0±4.8% decrease; p=0.043) with a concomitantly increased proportion of Firmicutes phylum (14.7±5.4% increase; p=0.009). Compared to baseline, total primary bile acids decreased by 40.1±9.6 ng/mg stool during therapy (p=0.0002) and 40.5±14.1 ng/mg stool after completion of therapy (p=0.0066). Rates of both initial clinical cure and SCC at 28 days were 100% (10 of 10 patients). Conclusions In this phase 2a study, ten of ten patients achieved SCC, demonstrated favorable pharmacokinetics, minimal adverse events, and beneficial microbiome and bile acids results. These results support continued clinical development.

HUMAN FECAL BILE ACID ANALYSIS AFTER INVESTIGATIONAL MICROBIOTA-BASED LIVE BIOTHERAPEUTIC DELIVERY FOR RECURRENT CLOSTRIDIOIDES DIFFICILE INFECTION

“…Acknowledging the low sample numbers and lack of head-to-head data, secondary BA appeared to restore more efficiently after RBX2660 administration in this trial than after antibiotics alone, including some in late-stage clinical development (32,33).…”

Essential Paralogous Proteins as Potential Antibiotic Multitargets in Escherichia coli

“…The γ, τ, and δ′ proteins have a similar ATPase core structure ( 27 ), although only the γ and τ subunits appear to have nucleotide-binding and hydrolysis capacity. Inhibitors of core DNA polymerase III enzymes have recently shown promise ( 59 , 60 ), with one inhibitor in clinical trials for treatment of C. difficile infection ( 61 ). However, inhibitors of the clamp loader complex have not been described.…”

Pathogenicity and virulence of Clostridioides difficile

“…Despite these recent disappointments, several interesting candidate drugs remain at various stages in the development pipeline. Ibezapolstat, a potent DNA polymerase IIIC inhibitor [ 248 ], is currently in phase IIb after a successful initial phase II trial [ 249 ]. Ibezapolstat has a favorable pharmacokinetic profile, promoting high concentrations at the site of infection in the colon [ 249 ], and appears to induce less harmful changes in microbiota composition and diversity than vancomycin [ 250 ].…”