Allosteric modulation company Addex Pharmaceuticals is pioneering a new approach to the treatment of gastroesophageal reflux disease (GERD), a common disorder affecting approximately 15 per cent of people. GERD is the cause of commonly recognized unpleasant symptoms like heartburn, acid brash and reflux. By inhibiting metabotropic glutamate receptor 5 (mGluR5) signalling with ADX10059, a negative allosteric modulator (NAM) of mGluR5, Addex believes that the functioning of the lower esophageal sphincter can be normalized, thereby reducing exposure of the esophagus to acidic stomach contents and treating symptoms by addressing the cause of GERD.
Clinical data, published online in the peer-reviewed journal GUT and to be presented at the Digestive Disease Week conference (DDW, May 30 to June 4, Chicago), demonstrated that following administration of ADX10059 for a single day, patients reported fewer and shorter episodes of GERD symptoms compared to when they received placebo (two versus seven episodes, with a mean total duration of five minutes versus 14 minutes for placebo). This reduction in symptoms was associated with a statistically significantly reduction in duration of esophageal acid exposure, during the 24 hour pH monitoring period, compared to placebo.
The researchers also found that night time reflux, which causes sleep disturbance and increased risk of esophageal damage, and reflux events following meals were also significantly reduced by ADX10059 therapy.
"About one-third of GERD patients have symptoms that remain inadequately controlled even after treatment with the best available medicines, which reduce acidity of stomach contents to treat symptoms," said Jan Tack co-author, leading GERD expert and chairman of the department of pathophyisology at the University of Leuven. "Thus, new approaches are needed that address the underlying cause of this common disorder. These clinical data suggest targeting glutamate signaling via negative allosteric modulation of mGluR5 using ADX10059 improves symptoms because it inhibits reflux, the cause of GERD."
Data from a phase-I study of a modified release formulation of ADX10059, which supported the findings of the above study in GERD patients, also will be presented at DDW. This study in healthy volunteers showed that, compared to placebo, the new formulation of ADX10059 reduced the occurrence of reflux events on impedance pH monitoring, following intake of a refluxogenic breakfast. The modified release formulation also achieved the objective of improving the side effect profile seen previously with the immediate release formulation, and in reducing the dosing interval to twice daily from three times daily. Phase-IIb trials with ADX10059 in GERD, both as a monotherapy and, separately, in combination with proton pump inhibitor (PPI) treatment are ongoing in the US and EU.
"mGluR5 inhibition with ADX10059 represents a novel way of potentially treating GERD. These data published in GUT and to be presented at DDW represent some of our early clinical experience with ADX10059. Our phase-IIb studies are progressing well and we expect to report data on both the monotherapy and PPI combination studies late in 2009," said Charlotte Keywood, chief medical officer at Addex.