Charlotte Keywood

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

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 (nu200a=u200a12 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% (pu200a=u200a0.01). 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 (pu200a=u200a0.03). 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.

Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease

Aliment Pharmacol Ther 2011; 33: 911–921

A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease.

The metabotropic glutamate receptor 5‐negative allosteric modulator dipraglurant reduces levodopa‐induced dyskinesia in the MPTP‐macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa‐induced dyskinesia in Parkinsons disease (PD).

The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model

Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa‐induced dyskinesias (LID) in Parkinsons disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold‐standard LID macaque model.

Metabotropic glutamate receptor 5: a target for migraine therapy

Many patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine‐specific target, the mGlu5 receptor.

935 Effect of mGluR5 Negative Allosteric Modulator (NAM) ADX10059, Monotherapy, on Reflux Events and Lower Esophageal Sphincter (LES) Function in Patients With Gastro-Esophageal Reflux Disease (GERD)

BACKGROUND: In patients with proton pump inhibitors (PPI) resistant reflux symptoms, ambulatory 24-hour pH-impedance monitoring can be used to assess whether a relationship exists between symptoms and reflux episodes. Using this technique we aimed to distinguish patients with hypersensitive esophagus and evaluate the effect of selective serotonin reuptake inhibitors (SSRI) on their symptoms. METHODS: Patients with normal endoscopy and typical reflux symptoms (heartburn, chest pain, regurgitation), despite PPI twice daily, underwent ambulatory 24-hour pH-impedance monitoring. Distal esophageal acid exposure (% time pH < 4) was measured. Reflux episodes were detected by impedance channels located 3, 5, 7, 9, 15 and 17cm above the lower esophageal sphincter (LES) and classified into acid or non-acid based on pH data from 5cm above the LES. A positive symptom index (SI) was declared if at least half of each specific symptom events were preceded by reflux episodes within five minutes. Patients with a normal distal esophageal acid exposure time, but with a positive symptom index for either acid and/or non acid reflux were classified as having hypersensitive esophagus and were randomized to receive citalopram 20mg or placebo once daily for 6 months. Data were analyzed using Fischers exact test. RESULTS: A total of 84 patients (50 females (59.5%) and 34 males (40.5%); mean age 55 (range 18-75) years) with reflux symptoms despite taking PPI twice daily underwent 24-hour pH-impedance monitoring. Seventy three patients (86.9%) recorded symptoms during the study day, while 35 (47.9%) of those had a positive symptom index for at least one symptom (8 (22.9%) with acid and 27 (77.1%) with non acid reflux). Among those 35 patients, 25 (71.4%) had normal distal esophageal acid exposure time (i.e. hypersensitive esophagus) and were randomized to receive citalopram 20mg (group A, n=13) or placebo (group B, n=12) once daily for a period of 6 months. At the end of the follow up period, 3 out of the 13 patients of group A (23%) and 8 out of the 12 patients of group B (67%) continue to report reflux symptoms (p=0.047). CONCLUSIONS: Treatment with selective serotonin reuptake inhibitors is effective for patients with hypersensitive esophagus as defined by the use of 24-hour pH-impedance monitoring.

268 A NOVEL APPROACH TO TREAT OVERACTIVE BLADDER BY POSITIVE MODULATION OF THE GABA-B RECEPTOR (GABA-BR) WITH ADX71441

INTRODUCTION AND OBJECTIVES: GABA is important for micturition control. The GABA-BR agonist baclofen reduces urethral resistance and detrusor overactivity in patients with spasticity. However, baclofen’s side effects limit its use in overactive bladder (OAB). Anti-muscarinics are standard treatment for OAB, but these have use-limiting anticholinergic effects. ADX71441 is a novel, orally active GABA-BR positive allosteric modulator with potentially improved safety and pharmacokinetics over baclofen and no anticholinergic side effect profile. ADX71441 was studied in a diuretic stress-induced preclinical model of OAB and its efficacy compared to the muscarinic oxybutynin. METHODS: Male C57BL/6 mice, food-restricted pre-experiment, were left untreated or given vehicle, ADX71441 1, 3, 10 mg/kg or oxybutynin 100 mg/kg p.o. (n 8/group). Treated mice received water 1ml s.c. 55 min later, followed by furosemide. First micturition event latency, micturition frequency, total and average micturition volumes were assessed for 90 min post diuretic. RESULTS: Administration of ADX71441 dose-dependently prolonged micturition latency, reduced micturition frequency, and volumes. Efficacy was statistically significant for ADX71441 (10 mg/kg) which returned most parameters to untreated control levels and was similar to oxybutynin. CONCLUSIONS: In the diuretic stress-induced OAB model, ADX71441 showed clinically relevant improvements on urinary parameters, comparable to oxybutinin at the 10 mg/kg dose. GABA-BR positive modulation by ADX71441 has potential as a novel approach to OAB treatment.

774 Effect of mGluR5 Inhibition with ADX10059, On Day and Night Time Reflux and Clinical Symptoms, in Patients with Gastro-Esophageal Reflux Disease (GERD): A Proof of Concept Study

in the number of postprandial reflux episodes at 5cm distal to the LES compared to placebo. The reductions at 5cm were significant at the 10% significance level (p=0.0961 and p= 0.0905 for capromorelin and ghrelin respectively). The high doses of capromorelin (20 mg) and ghrelin (5 pmol/kg/min) demonstrated significant reductions (39% and 47%, respectively) in the number of reflux events measured at 15 cm above the LES compared to placebo. These reductions were statistically significant at the 5% significance level (p= 0.042 and p=0.012, respectively). Increases in distal esophageal amplitude were observed on average for all active treatments during both saline and viscous swallows compared to placebo. For the high doses of capromorelin and ghrelin, the increases were statistically significant at the 1% level for saline swallows (p=0.006 and p=0.009, respectively). There were no serious adverse events. CONCLUSION:. The highest tested doses of capromorelin and human recombinant ghrelin had effects on reflux parameters and on esophageal physiology, at doses that appear to be well tolerated. Further studies are warranted to evaluate the role of capromorelin in the therapeutic armamenterium for GERD.