S187 ADS024, a Bacillus velezensis Strain, for Prevention of Recurrence of Clostridioides difficile Infection: Results From a Randomized, Placebo-Controlled, Double-Blind, Phase 1b Study

Introduction: Recurrence of C. difficile infection (CDI) is due to the failure of antibiotics to eradicate spores that can germinate post-treatment. ADS024, an orally delivered single-strain live biotherapeutic product (Bacillus velezensis), kills C. difficile and degrades its toxins. This study (NCT04891965) evaluated the safety and efficacy of ADS024 for the prevention of CDI recurrence (rCDI). Methods: The phase 1b, randomized, placebo-controlled, double-blind, multicenter study enrolled patients cured after a course of standard-of-care antibiotics for a recent CDI episode. Patients received ADS024 (5x109 CFU/daily) or placebo (3:1) orally for 7 (Cohort A, n = 8) or 28 days (Cohort B, n = 28). Patients were followed for 6 months after last dose. The primary endpoint was safety/tolerability; key secondary endpoints included evaluation of recurrence, time to recurrence (TTR), change from baseline in C. difficile toxin levels, presence of ADS024, and microbiome analyses (shallow shotgun sequencing and C. difficile qPCR). Results: Of 36 enrolled patients, 17 had prior episodes (rCDI); 31 completed the study; 69% were female, median age was 58 years, and median (range) duration of exposure was 28 days (2-28). Adverse event data show ADS024 was well-tolerated (Table 1). Recurrence was observed in 4/27 patients (15%, 3/4 rCDI) treated with ADS024 (median TTR, 10 days [range, 2-14]) and 1 (11%) with placebo (TTR, 108 days). Increase in C. difficile counts and increase in toxin levels appeared temporally associated with recurrence. C. difficile toxin levels declined from baseline to end of dosing with ADS024 vs increased with placebo (Figure 1). A decreasing trend in C. difficile counts occurred during ADS024 exposure compared with placebo. ADS024 was detected in 7 patients and did not persist after end of dosing. No significant changes in alpha-diversity between treatment arms were detected. Significant differences in beta-diversity occurred over time and between treatment arms. R2 values showed overall beta-diversity variations by time and treatment were small vs other factors (eg, inter-patient variation). Conclusion: ADS024 appears safe and well-tolerated and CDI recurrence frequency was similar between arms in this small study. ADS024 did not engraft. Overall, low variance in alpha- and beta-diversity was observed. C. difficile toxin levels declined from baseline to Week 4 with ADS024 and increased with placebo. These findings warrant further investigation of ADS024. Table 1. - TEAEs and TRAEs (Safety Analysis Set). TEAE, Treatment-Emergent Adverse Event; TRAE, Treatment-Related Adverse Event Pooled ADS024 (n = 27) Placebo (n = 9) n (%) Treatment-Emergent Adverse Events Patients with ≥1 TEAE 17 (63) 6 (67) Mild 8 (30) 3 (33) Moderate 6 (22) 3 (33) Severe 3 (11) 0 Most common TEAEs (incidence ≥20% in ADS024 arm) Diarrhea 8 (30) 3 (33) Flatulence 7 (26) 2 (22) Abdominal pain 6 (22) 1 (11) Patients with ≥1 Serious TEAE 4 (15) 1 (11) C. difficile infection 2 (7) 0 Wound infection 1 (4) 0 Abdominal pain 1 (4) 0 Treatment-Related Adverse Events Patients with ≥1 TRAE 4 (15) 1 (11) Mild 4 (15) 1 (11) Moderate 0 0 Severe 0 0 Most common TRAEs (incidence ≥10% in ADS024 arm) Flatulence 3 (11) 1 (11) Abdominal pain 3 (11) 0 Patients with ≥1 Serious TRAE 0 0 Figure 1.: Change from baseline in C. difficile toxin levels. a Evaluated using the in vitro diagnostic enzyme immunoassay (tgcBiomics ELISA) for the detection of toxin A and toxin B produced by toxigenic strains of C. difficile in human feces. b No toxin data available for placebo patients in Cohort A; 1 patient had all toxin levels below limits of quantification and samples from the other patient were not tested early enough and went out of stability. BL, baseline; OD, optical density.

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