Novel treatments of GERD: focus on the lower esophageal sphincter.

Up to 50% of patients with gastroesophageal reflux disease (GERD) still suffer from GERD symptoms despite proton pump inhibitor (PPI) therapy, indicating a need for new treatments. The lower esophageal sphincter (LES) plays a crucial role in maintaining the mechanical barrier necessary for prevention of gastric reflux. Transient LES relaxation (TLESR) is an important factor behind the occurrence of reflux, and preclinical studies have identified a number of targets for pharmacologic modification of TLESR. However, only gamma-aminobutyric acid (GABA) type B receptor (GABA(B)) agonists and metabotropic glutamate receptor 5 (mGluR5) modulators have shown positive proof of concept in the clinical setting. The mGluR5 negative allosteric modulator ADX10059 improved symptoms in GERD patients, but was associated with central side effects such as dizziness. Baclofen, a GABA(B) receptor agonist, reduces the incidence of TLESR and improves GERD symptoms in both adult and pediatric GERD patients. However, the utility of baclofen is similarly limited by poor tolerability and recent research has focused on the development of GABA(B) receptor agonists with improved tolerability. XP19986, a prodrug of R-baclofen, reduced the number of reflux episodes in a dose-ranging study and was similarly tolerated to placebo. AZD3355 and AZD9343 are GABA(B) receptor agonists with limited central nervous system activity that have been shown in preclinical studies to reduce the incidence of TLESR and decrease esophageal acid exposure; data from clinical studies of these agents in GERD patients are awaited with interest. Agents that target TLESR activity may therefore offer a promising new add-on treatment for patients who suffer from GERD symptoms despite PPI therapy.