Oral Biotherapeutic ADS024 Safe, Tolerable for Recurrent C difficile Prevention

Jessica R. Allegretti, MD, MPH

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A promising live biotherapeutic agent in development for the prevention of recurrent Clostridiodes difficile infection (rCDI) now has early-stage data supporting its safety and tolerability—and potential efficacy—in patients recovering from CDI.

In new phase 1B data presented in an abstract at the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting in Vancouver, BC this weekend, an international team of investigators reported that ADS024, an investigative, orally administered single-strain live biotherapeutic product (Bacillus velezensis) from Adiso Therapeutics, was associated with C difficile toxin level reduction over 4 weeks while maintaining favorable safety and tolerability versus placebo in patients at risk of rCDI.

Investigators led by Jessica R. Allegretti, MD, MPH, of the Brigham and Women's Hospital and Harvard Medical School, conducted the phase 1B, randomized, controlled, double-blind, multicenter trial to evaluate the safety and efficacy of ASD024. Similar to previously investigated live biotherapeutics, the understood potential of the agent in the prevention of rCDI is aspirational.

“Recurrence of C. difficile infection is due to the failure of antibiotics to eradicate spores that can germinate post-treatment,” Allegretti and colleagues wrote. “(ADS024) kills C. difficile and degrades its toxins.”

Investigators enrolled patients cured of a recent CDI following a standard-care course of antibiotics into the trial. Two cohorts of patients were randomized 3:1 to either 5x109 CFU/daily oral ADS024 or placebo. Cohort A (n = 8) received care for 7 days; cohort B (n = 28) received care for 28 days. All patients were followed for 6 months following their final dose.

The team sought a primary endpoint of safety and tolerability associated with ADS024, as well as key secondary endpoints of evaluation of recurrence; time to recurrence (TTR); change in C difficile toxin levels from baseline; presence of ADS024 in the system; and microbiome analyses.

Among the 36 trial participants, 17 had experienced rCDI. Another 31 (86.1%) completed the phase 1b trial. Median age was 58 years old, and 69% of patients were female. Median duration of treatment exposure was 28 days (range, 2 – 28).

Among the 27 patients to receive ADS024 in either cohort, 17 (63) experienced ≥1 treatment emergent adverse event (TEAE). A majority of patients (n = 14 [52%]) reported a TEAE mild to moderate in severity. The most common events were diarrhea (n = 8), flatulence (n = 7) and abdominal pain (n = 6). Among the 4 (15%) patients to report a serious TEAE, 2 reported CDI; the other 2 reported a wound infection and abdominal pain.

Regarding tolerability, Allegretti and colleagues reported that 4 (15%) treated patients experienced rCDI, with a median TTR of 10 days (range, 2 – 14), versus just 1 patient on placebo (TTR, 108 days). They noted a temporal association between increased C difficile counts and toxin levels, and recurrence. However, counts and toxin levels declined overall from baseline to end of dosing with ADS024 versus placebo.

Though ADS024 was detected in 7 (29.2%) of patients receiving ADS024, it did not persist after the end of the dosing period. “No significant changes in alpha-diversity between treatment arms were detected,” investigators noted. “Significant differences in beta-diversity occurred over time and between treatment arms.”

The team concluded that ADS024 was linked to declining C difficile count and toxin levels from baseline to week 4, versus an increase with placebo, and that patients at risk of rCDI reported low variance and alpha- and beta-diversity with the investigative drug.

“ADS024 appears safe and well-tolerated and CDI recurrence frequency was similar between arms in this small study,” they wrote. “These findings warrant further investigation of ADS024.”

References

^{Allegretti JR, Gupta R, Aguilar H, Pullman J, et al. P0173 - ADS024, a Bacillus velezensis Strain, for Prevention of Recurrence of Clostridioides difficile Infection: Results From a Randomized, Placebo-Controlled, Double-Blind, Phase 1b Study. Paper presented at: ACG 2023 Annual Scientific Meeting. Vancouver, BC, Canada. October 20 – 25, 2023.}