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.

Abstract

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. 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. 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. 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.