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Gut 58:1192-1199 doi:10.1136/gut.2008.162040
  • Oesophagus

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-oesophageal reflux disease

Open Access
  1. C Keywood1,
  2. M Wakefield1,
  3. J Tack2
  1. 1
    Addex Pharma, Plan-les-Ouates, Switzerland
  2. 2
    Department of Gastroenterology, University of Leuven, Leuven, Belgium
  1. Correspondence to Dr C Keywood, Addex Pharma SA, Plan-les-Ouates, CH-1228 Switzerland; charlotte.keywood{at}addexpharma.com
  • Revised 19 April 2009
  • Accepted 21 April 2009
  • Published Online First 20 May 2009

Abstract

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

Methods: Two groups of patients with GORD (n = 12 per group) underwent 24-h oesophageal pH-metry on two sequential treatment days. The patients received oral placebo three times daily (tds) 30 min before a high-fat meal on Day 1 and oral ADX10059 50 mg (Group 1) or 250 mg (Group 2) tds 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 tds significantly decreased the percentage of time with pH<4 from 7.2% to 3.6% (p = 0.01). ADX10059 250 mg tds reduced pH-metry-measured oesophageal acid exposure, throughout the 24 h period, nocturnally and postprandially, and significantly reduced the number and duration of symptomatic reflux episodes (p = 0.03). ADX10059 50 mg tds was not significantly superior to placebo. ADX10059 was generally well tolerated.

Conclusion: The mGluR5 negative allosteric modulator ADX10059 reduced acid reflux which was associated with improvement in clinical symptoms in patients with GORD. ADX10059 appears to have a potential role in the clinical management of GORD.

Footnotes

  • Funding Addex Pharma was the sponsor of this study and determined the design.

  • Ethics approval Approval was given by the Ethics Committee (CPP) of Robert Ballanger Hospital, Aulnay-sous-Bois, on 10 July 2006.

  • Clarifications: The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and secondary major efficacy endpoints) and safety have been independently confirmed by a biostatistician who is not employed by the corporate entity.

    CK had full access to all of the data and takes full responsibility for the veracity of the data and analysis.

    Data collection and analysis was performed by a clinical research facility.

    Data interpretation was performed by JT.

  • ▸ Competing interests: Declared (the declaration can be viewed on the Gut website at http://gut.bmj.com/content/vol58/issue9).