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Gut doi:10.1136/gut.2008.162040

A Proof Of Concept Study Evaluating The Effect Of ADX10059, A Metabotropic Glutamate Receptor-5 Negative Allosteric Modulator, On Acid Exposure And Symptoms In Gastro-Esophageal Reflux Disease

  1. Charlotte Keywood (charlotte.keywood{at}addexpharma.com)
  1. Addex Pharma, Switzerland
    1. Mark Wakefield (mark.wakefield{at}addexpharma.com)
    1. Addex Pharma, Switzerland
      1. Jan Tack (jan.tack{at}med.kuleuven.be)
      1. University of Leuven, Belgium
        • Published Online First 20 May 2009

        Abstract

        Background: In preclinical models, antagonism of metabotropic glutamate receptor 5 (mGluR5) reduces transient lower esophageal sphincter relaxations (TLESRs) and increases LES pressure. This study evaluated the effect of ADX10059, a potent, selective, negative allosteric modulator (NAM) of mGluR5, on esophageal pH-metry and clinical symptoms in GERD.

        Methods: Two groups of GERD patients (N=12 per group) underwent 24-hour esophageal pH-metry on 2 sequential treatment days. The patients received oral placebo t.i.d. 30 min before a high fat meal on Day 1 and oral ADX10059 50 mg (Group 1) or 250 mg (Group 2) t.i.d. 30 min before a high fat meal on Day 2. The primary variable was acid exposure (%time pH<4). Secondary variables included number and duration of reflux episodes, number and duration of symptomatic episodes and symptoms recorded in diaries. Comparisons were made for Day 2 (active) versus Day 1 (placebo) treatment and for Group 1 versus Group 2.

        Results: ADX10059 250 mg t.i.d. significantly decreased the percentage of time with pH<4 from 7.2% to 3.6% (p=0.01). ADX10059 250 mg t.i.d. reduced pH-metry measured esophageal acid exposure, throughout the 24-hour period, nocturnally and postprandially and significantly reduced the number and duration of symptomatic reflux episodes (p=0.03). ADX10059 50 mg t.i.d. was not significantly superior to placebo. ADX10059 was generally well tolerated.

        Conclusion: The mGluR5 NAM ADX10059 reduced acid reflux which was associated with improvement in clinical symptoms in GERD patients. ADX10059 appears to have a potential role in clinical management of GERD.


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