S1783 EXE-346 Live Biotherapeutic Reduces High Bowel Movement Frequency in Subjects With an Ileal Pouch-Anal Anastomosis

Introduction: EXE-346 is an optimized, high-dose, biologic grade formulation of the commercially available food-grade probiotic VisbiomeÒ. Currently, there are limited medical options to manage increased bowel frequency in patients with ileal pouch-anal anastomosis (IPAA), which often occurs independent of inflammation. To address this unmet need, we conducted an open-label, single-arm, multi-center Phase 1B study involving patients with refractory high bowel frequency. The objective of the study was to evaluate the safety and preliminary efficacy of EXE-346 in this patient population. Methods: IPAA patients with chronically elevated bowel frequency and a 24-hour average bowel frequency (ABF) of ≥10 during a 7-day screening period, were eligible to enter the study. The patients were treated with EXE-346 (1500 × 10⁹ CFU) twice daily for 4 weeks. Bowel frequency was recorded daily throughout the study. Main study exclusion criteria were a diagnosis of Crohn’s-like disease of the pouch, known treatment-refractory pouch-anal strictures, concomitant therapy with biologics or systemic corticosteroids, or a positive Clostridoides difficile assay. Data are reported as median and interquartile range (IQR). Statistical analyses were performed using the Wilcoxon signed-rank test between baseline measurements and subsequent time point. Results: At 4 US centers, 10 patients with a median baseline ABF of 11.7 (IQR 10.5-13.6) completed the 4-week study. EXE-346 was overall well tolerated; side effects occurred in 4 of the 10 patients (n = 1 for each: decreased appetite, rash, elevation of serum calcium, and worsening of liver function tests in a patient with hepatic steatosis), all of which were judged mild in severity. Compared to baseline, the median ABF decreased by 23% to 9.1 (IQR 7.9-12.1) at week 4 (P = 0.002). The nighttime bowel frequency decreased by 48% from a median of 2.3 (IQR 1.3-3.5) at baseline to 1.2 (IQR 0.9-2.7) at week 4 (P < 0.01). Conclusion: EXE-346 was safe and well tolerated, with only mild adverse events reported. Treatment with EXE-346 resulted in a clinically meaningful reduction in overall average bowel frequency and nighttime bowel frequency. These preliminary findings support the potential of EXE-346 to improve symptoms in patients with elevated ABF and warrant further evaluation in a placebo-controlled Phase 2 study, which is currently underway.