IW-3718, a Novel Gastric-Retentive Bile Acid Sequestrant, Improved Symptoms of Refractory GERD in a Double-Blind, Placebo-Controlled Phase 2a Study

Abstract

Introduction: Refractory GERD (rGERD) is characterized by continued heartburn (HB) and/or regurgitation (RG) despite PPI treatment. Bile acid reflux appears to be an important contributing factor in rGERD. IW-3718 is a novel, investigational, gastric-retentive formulation of a bile acid sequestrant designed to bind to bile acids in the refluxate. Our aim was to determine if IW-3718 improves HB and/or RG in patients with continued symptoms despite receiving standard dose PPI therapy (SD PPIs). Methods: We conducted a phase 2a, double-blind, placebo-controlled study with a 2-week baseline and a 4-week treatment period. Eligible patients were taking SD PPIs, had HB or RG ≥2 days/week for 8 weeks before the study, and reported HB ≥4 of the last 7 days of baseline. Patients underwent optional 24h ambulatory Bilitec monitoring on SD PPI therapy and were stratified: pathological bile reflux (PBR=esophageal bilirubin absorbance >0.14 for >6% of time), normal bile reflux (NBR), and unknown bile reflux (UBR) if Bilitec was declined. Patients continued their SD PPIs and were randomly assigned 1:1 to IW-3718 1000 mg BID or placebo within each stratum. GERD symptoms were assessed twice daily via e-diary. Treatment satisfaction and degree of relief were measured weekly. This exploratory study included no predefined primary or secondary endpoints. AEs were recorded. Results: ITT Population included 93 patients (33 PBR, 19 NBR, 41 UBR). Demographics were generally similar between the IW-3718 and placebo groups within each stratum. Overall, the percent of patients free of RG at Week 4 was significantly higher among patients on IW-3718 compared with placebo (p=0.03), with greater improvement seen in PBR patients (p=0.01) (Figure). Degree of relief for overall GERD symptoms (p=0.07) and % of patients free of HB (p=0.25) were numerically greater for IW-3718 vs placebo (Figure). Change from baseline in severity of daytime HB, severity of daytime RG, and percent of days free of HB and RG were also improved at Week 4 for IW-3718 patients (vs placebo) in the overall population and in the PBR subgroup (Table). AEs were reported by 48% and 32% of IW-3718 and placebo patients, respectively; the most common AE was constipation (13% vs 0%, respectively). Conclusion: IW-3718 was well tolerated and improved RG and HB in GERD patients with continued symptoms while taking SD PPIs. The results of this study support the hypothesis that bile acid sequestration can reduce rGERD symptoms.Figure 1Table 1: Improvement in Heartburn and Regurgitation from Baseline to Week 4 (ITT Population)