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

• Published in: Journal of gastroenterology Vol. 52; no. 10; pp. 1081 - 1089
• Main Authors: Kondo, Takashi, Sei, Hiroo, Yamasaki, Takahisa, Tomita, Toshihiko, Ohda, Yoshio, Oshima, Tadayuki, Fukui, Hirokazu, Watari, Jiro, Miwa, Hiroto
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01-10-2017; Springer; Springer Nature B.V
• Subjects: Abdominal Surgery; Adult; Clinical trials; Colorectal Surgery; Cross-Over Studies; Double-Blind Method; Esophagus; Gastroenterology; Gastroesophageal reflux; Gastroesophageal Reflux - drug therapy; Gastroesophageal Reflux - pathology; Gastrointestinal Agents - pharmacology; Health aspects; Health risk assessment; Heart; Heartburn; Heartburn - drug therapy; Heartburn - pathology; Hepatology; Humans; Hydrochloric acid; Male; Medical colleges; Medicine; Medicine & Public Health; Middle Aged; Original Article—Alimentary Tract; Perfusion; Prospective Studies; Prostaglandin E2; Prostaglandins; Proton pump inhibitors; Receptors, Prostaglandin E, EP1 Subtype - antagonists & inhibitors; Receptors, Prostaglandin E, EP1 Subtype - metabolism; Surgical Oncology; Time Factors; Treatment Outcome; Young Adult; GERD; PGE2; ONO-8539; Heartburn; EP1
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-017-1308-3

Background
Patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) have unmet clinical needs. Recently, we reported that esophageal prostaglandin E
2
(PGE
2
) plays a crucial role in the generation of heartburn. In the present study, we focused on the PGE
2
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
−1
) 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.