N8. Clostridium difficile
Late Breaking Abstract Submission
Background: ACX-362E, a novel DNA polIIIC inhibitor, is a narrow-spectrum antibacterial selectively active against certain Gram-positive bacteria, including Clostridioides difficile (MIC90 = 4 µg/mL). The objectives of this phase I study was to assess the safety, pharmacokinetics, and fecal microbiome effects of ACX-362E
Methods: This 3-part FIH phase 1, double-blind, randomized healthy volunteer trial determined the safety profile, food effect, and systemic/stool pharmacokinetics of escalating single (150, 300, 600, and 900 mg) and multiple (300 and 450 mg) doses of oral ACX-362E versus placebo (PBO). Fecal microbiome effects (metagenomic sequencing and qPCR) of multiple-dose ACX-362E were compared to 6 subjects receiving concomitant open-label vancomycin 125 mg four times daily. Dose-escalation to each new cohort occurred following review of safety and PK data by a safety oversight committee.
Results: Forty-four subjects received ACX-362E (single dose = 24, multiple doses = 12, food effect = 8) and 12 PBO. Overall, ACX-362E was well-tolerated at all dose levels. Adverse events were generally mild and transitory, and no moderate, severe, cumulative, or dose-limiting drug-related adverse events leading to discontinuation were observed. Mean plasma half-life was approximately 2 hours and no accumulation occurred with repeated dosing (Figure 1). Systemic exposure was less than 1 ug/mL and decreased with food. Fecal concentrations during multiple dosing exceeded the C. difficile MIC by multiples of up to ~2500. ACX-362E had minimal effect on Bacteroidetes phylum and caused significantly less dysbiosis than vancomycin (Figure 2).
Conclusion: This FIH clinical trial with ACX-362E demonstrated a favorable safety profile, low systemic and high fecal concentrations, and favorable gut microbiome changes compared to vancomycin. These results shows promise for further clinical development to treat C. difficile infections.