A novel prostanoid EP1 receptor antagonist, ONO-8539, reduces acid-induced heartburn symptoms in healthy male volunteers: a randomized clinical trial.

Abstract

Patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) have unmet clinical needs. Recently, we reported that esophageal prostaglandin E2 (PGE2) plays a crucial role in the generation of heartburn. In the present study, we focused on the PGE2 receptor, EP1, and investigated the effects of ONO-8539, a novel EP1 receptor antagonist, on heartburn symptoms in healthy male volunteers. This prospective, double-blind, placebo-controlled, two-period crossover study was performed in 20 healthy male subjects. The novel prostanoid EP1 receptor antagonist, ONO-8539 (450mg), was administered once 4h prior to acid perfusion test. During the test, hydrochloric acid (0.15moll-1) was perfused into the lower esophagus for 30min. Acid perception threshold was quantified by the time to first sensation of heartburn and intensity of GI symptoms determined using a validated categorical rating scale, and the area under the curve (AUC) as the total symptom score. ONO-8539 significantly reduced a total heartburn symptom score, not other upper GI symptom scores, during acid perfusion compared with placebo (AUC for heartburn, 85.0±10.6 for placebo and 56.5±7.2 for ONO-8539; P< 0.01), and significantly extended the time to first sensation of heartburn compared with placebo (5.7±4.3min for placebo and 9.7±7.2min for ONO-8539; P<0.05). ONO-8539 attenuated acid-induced heartburn in healthy male subjects, suggesting that EP1 receptors play a role in generation of heartburn symptoms. ONO-8539 is a potential novel therapeutic option for controlling heartburn symptoms in GERD patients. Clinical Trials Registry No: UMIN000015753.