Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double-blind, placebo-controlled pharmacodynamic study R. S. CHOUNG,*, † G. R. LOCKE III ,* D. D. FRANCIS,* D. KATZKA,* P. J. WINKLE, ‡ W. C. ORR, § M. D. CROWELL, ¶ K. DEVAULT,** W. S. HARMSEN, †† A. R. ZINSMEISTER†† & N. J. TALLEY‡‡ *Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA †Division of Gastroenterology and Hepatology, Korea University College of Medicine, Korea University, Seoul, South Korea ‡Advanced Clinical Research Institute, Anaheim, CA, USA §Lynn Health Science Institute, Oklahoma City, OK, USA ¶Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ, USA **Division of Gastroenterology, Mayo Clinic, Jacksonville, FL, USA ††Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA ‡‡University of Newcastle, Callaghan, NSW, Australia Key Messages • Gastroesophageal reflux disease (GERD) is a common chronic condition but 15% to 20% of patients with GERD experience persistent symptoms despite taking proton pump inhibitors. • Pumosetrag is a novel selective partial 5HT3 receptor agonist and has shown promise increasing lower esophageal sphincter pressure (LESP) in animal models. • We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, LESP and specific symptoms in patients with GERD after a refluxogenic meal. We postulated the drug would reduce reflux episodes in patients on or off acid suppression. • In 223 patients with GERD who were randomized to 1 of 3 dose levels of pumosetrag (0.2 mg, 0.5 mg or 0.8 mg) or placebo, pumosetrag significantly reduced the rate of acid reflux events, although no benefit was demonstrated on the total rate of reflux events. • Pumosetrag did not significantly change LESP or symptoms over a one-week treatment period. • 5HT3 agonists appear unlikely to be of benefit for breakthrough GERD symptoms on acid suppression. Abstract Background Low basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a reflux- ogenic meal. Methods Patients with GERD, who developed heartburn and/or regurgitation after inges- tion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichan- Address for Correspondence Nicholas J. Talley, MD, PhD, Pro Vice-Chancellor and Dean (Health and Medicine), University of Newcastle, Callaghan, NSW 2308, Australia. Tel.: +61 2 4921 6378; fax: +61 2 4921 5669; e-mail: Nicholas.Talley@newcastle.edu.au Received: 7 June 2012 Accepted for publication: 21 July 2013 © 2013 John Wiley & Sons Ltd 13 Neurogastroenterol Motil (2014) 26, 13–20 doi: 10.1111/nmo.12214 Neurogastroenterology & Motility