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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.

Keywood C, Wakefield M, Tack J - Gut (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Addex Pharma SA, Plan-les-Ouates, CH-1228 Switzerland. charlotte.keywood@addexpharma.com

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.

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Related in: MedlinePlus

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gut-58-09-1192-f01: Patient disposition.

Mentions: Thirty-two patients were screened, of which 24 were randomised (eight were not eligible, four had abnormal laboratory values, three withdrew consent and one had an abnormal ECG). All 24 randomised patients (12 in Group 1 comparing ADX10059 50 mg to placebo, and 12 in Group 2 comparing ADX10059 250 mg to placebo) completed the study and were included in the safety and pharmacokinetic analyses. One male patient in Group 2 was excluded from the pharmacodynamic population due to missing pH-metry data on Study Day 1 when his pH probe became displaced. Subject disposition is shown in fig 1. The treatment groups had similar demographic and baseline characteristics (table 1).


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.

Keywood C, Wakefield M, Tack J - Gut (2009)

Patient disposition.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2719084&req=5

gut-58-09-1192-f01: Patient disposition.
Mentions: Thirty-two patients were screened, of which 24 were randomised (eight were not eligible, four had abnormal laboratory values, three withdrew consent and one had an abnormal ECG). All 24 randomised patients (12 in Group 1 comparing ADX10059 50 mg to placebo, and 12 in Group 2 comparing ADX10059 250 mg to placebo) completed the study and were included in the safety and pharmacokinetic analyses. One male patient in Group 2 was excluded from the pharmacodynamic population due to missing pH-metry data on Study Day 1 when his pH probe became displaced. Subject disposition is shown in fig 1. The treatment groups had similar demographic and baseline characteristics (table 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Addex Pharma SA, Plan-les-Ouates, CH-1228 Switzerland. charlotte.keywood@addexpharma.com

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.

Show MeSH
Related in: MedlinePlus