A Novel Partial 5HT3 Agonist Pumosetrag after a Standard Refluxogenic Meal Reduces Acid Reflux Events in GERD Patients: A Randomized, Double-Blind, Placebo-Controlled Pharmacodynamic Study

Abstract

Purpose: Transient lower esophageal sphincter relaxations (TLESRs) are a major cause of gastro-esophageal reflux disease (GERD). Pumosetrag, a selective partial agonist at 5HT3 receptors, increases LES pressure and gastrointestinal motility in experimental animal models. In a previous study, it was shown to reduce the rate of reflux episodes after a refluxogenic meal in healthy subjects. Aims: To evaluate the effect of pumosetrag on esophageal related pharmacodynamic measurements, including changes in reflux episodes, lower esophageal sphincter pressure, and specific symptoms (heartburn, regurgitation, acid taste) in GERD patients receiving a refluxogenic meal, and to assess the safety and tolerability of pumosetrag. Methods: A randomized, double-blind, placebo-controlled study evaluated the pharmacodynamic effects of pumosetrag. Subjects were randomized to one of three dose levels of pumosetrag (0.2 mg, 0.5 mg, or 0.8 mg) or placebo. Before and after 7 days of treatment, GERD patients underwent manometry, and intraesophageal multichannel intraluminal impedance and pH (MII-pH) after a standard refluxogenic meal (a sausage-and-egg based meal [300 kCal, 60% fat] with eight ounces of Hershey's chocolate milk). Intent to treat analysis of covariance models were used to assess treatment effects. For evaluating the safety and tolerability of pumosetrag, each subject was monitored from the time of the first dose of study medication until the end of the study. Results: A total of 223 GERD patients (125[56%] females, mean [SD] age = 36[12] years) were enrolled. No overall treatment effects were detected for the total number of reflux episodes (p>0.5); however, significant treatment effects (p<0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared to placebo (13.3 ± 1.1) (Table). Significant treatment effects (p<0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8mg (10%) compared to placebo (16%). Differences in LESP (p>0.5), the number of nonacid reflux episodes after a refluxogenic meal (p>0.15), and specific symptom scores (p>0.4) were not detected (table). No serious adverse events on pumosetrag were reported.Table: Table. Reflux events, post-treatment mean LESP, and proportion time with pH < 4 (mean±SEM unless otherwise noted)Conclusion: In GERD patients, the partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events and proportion of time that pH <4 after a refluxogenic meal challenge, but did not affect the total number of reflux episodes or LES pressure. The results of the study suggest pumosetrag has effects on some pharmacodynamic endpoints associated with GERD and is worthy of additional study. Supported by Edusa Pharmaceuticals, Inc, Princeton, NJ. Disclosure: All authors - Grant research support from Edusa Pharmaceuticals, Inc.