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

BACKGROUND

Patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) have unmet clinical needs. Recently, we reported that esophageal prostaglandin E (PGE) plays a crucial role in the generation of heartburn. In the present study, we focused on the PGE receptor, EP1, and investigated the effects of ONO-8539, a novel EP1 receptor antagonist, on heartburn symptoms in healthy male volunteers.

METHODS

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 (450 mg), was administered once 4 h prior to acid perfusion test. During the test, hydrochloric acid (0.15 mol l) was perfused into the lower esophagus for 30 min. 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.

RESULTS

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 ± 4.3 min for placebo and 9.7 ± 7.2 min for ONO-8539; P < 0.05).

CONCLUSIONS

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.