Efficacy and Safety of ASP7147, a Bombesin-2 Receptor Antagonist, in Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D): Results of a Multicenter, Double-Blind, Placebo-Controlled Trial

Background: The bombesin-2 receptor (BB-2) and its endogenous ligand, gastrin-releasing peptide, are expressed in the epithelial, myenteric plexus and muscle layers of the colon and are involved in the regulation of GI motility and secretion. ASP7147 is a highly selective oral BB-2 antagonist with efficacy in animal models of IBS-D. ASP7147 distributes to its site of action in GI tissues with minimal systemic exposure, offering targeted therapy for GI conditions. Aim: The aim of this study was to evaluate the effectiveness and safety of ASP7147 in patients with IBS-D. Methods: Patients with IBS-D (Rome III) between 18-75 years of age who reported a mean worst abdominal pain (WAP) score of at least 3.0 out of 10 with at least one stool Bristol Stool Scale (BSS, 1-7) score of Type 6 or 7 at least 2 days per week during the screening period were randomized 1:1 to ASP7147 300 mg or placebo BID for 4 weeks followed by a 2-week treatment-free period. The primary endpoint was the change in mean WAP between treatment groups at Week 4. Secondary endpoints included changes in BSS and stool frequency over the 4 weeks of treatment. Statistical comparisons were made using repeated measures analysis (RMA) for overall (Weeks 1-4) and weekly comparisons and ANCOVA adjusting for baseline. Results: A total of 64 patients (23 male, 41 female) were enrolled. Baseline scores (ASP7147 vs. placebo) for BSS (6.0 vs. 5.9) and stool frequency per week (5.4 vs. 5.6) were evenly matched, with a small but insignificant imbalance in WAP (7.3 vs. 6.2). Significant improvement compared to baseline in WAP was noted at Week 4 (-2.5 vs.-1.7, ASP7147 vs. placebo) (p = 0.046 RMA; p = 0.095 ANCOVA), beginning at Week 1 and persisting each week through Week 4 (p = 0.039 RMA overall) and the 2-week treatment-free period. Improvement in BSS compared to baseline was also noted at Week 4 (-1.1 vs.-0.7, p = 0.077 RMA; p = 0.075 ANCOVA), commencing at Week 1 and persisting each week through both Week 4 (p = 0.033 RMA S-69 overall) and the 2-week treatment-free period. Similar improvements were noted in stool frequency, bloating, urgency, and loss of control, demonstrating consistent superiority of ASP7147 over placebo at each week of treatment. No differences in response were apparent between male and female patients. The frequency of adverse events was similar between treatment groups, with no constipation or use of rescue medications and no serious events attributable to active treatment. Conclusions: ASP7147 holds promise as a safe and effective new therapy for both men and women with IBS-D, demonstrating improvement in multiple symptoms of IBS-D. The persistence of treatment effect suggests the possibility of retained efficacy with less frequent dosing in follow-on trials.