Dry Eye Symptoms Eased by Rebamipide, a Mucin Secretagogue

Neil Osterweil

April 04, 2013

What works for the stomach may also work for the eyes: a 2% rebamipide suspension was objectively and subjectively superior to a 0.1% sodium hyaluronate solution for treatment of dry eye, according to Shigeru Kirsohita, MD, PhD, from the Department of Ophthalmology, Kyoto Prefectural University of Medicine, Japan, and colleagues.

In a multicenter randomized clinical trial in 188 patients with dry eye, rebamipide ophthalmic suspension (OPC-12759, Otsuka Pharmaceuticals) met the threshold of noninferiority and superiority to sodium hyaluronate in corneal and conjunctival staining tests and was judged by patients to be significantly better at relieving foreign-body sensation and eye pain, the authors report.

"These results suggest that rebamipide may lead to improved treatment of corneal and conjunctival epithelial damage and improvement in symptoms in patients with dry eye. Such efficacy, in addition to the well-tolerated profile of rebamipide, makes it a potentially useful treatment option for dry eye," they write in an article published online March 13 in Ophthalmology.

Rebamipide, a derivative of quinolone-class antibiotics, is a mucin secretagogue approved in Japan for protection of gastric mucosa and for treatment of dry eye. It has been shown in human and animal studies to enhance secretion of mucin to support tear film adhesion and slow tear film break-up time.

In phase 2 studies, 2% rebamipide suspension was shown to be superior to placebo at improving objective measures of dry eye, including fluorescein corneal staining score (FCS) and lissamine green conjunctival staining (LGCS). Subjectively, patients reported significantly more relief from photophobia, dryness, foreign body sensations, pain, and blurred vision.

The study reported here was a phase 3 comparison trial performed for Japanese drug-registration purposes. The drug is also currently being investigated in phase 3 trials in the United States.

Pedram Hamrah, MD, director of the ocular surface imaging center at the Massachusetts Eye and Ear Infirmary in Boston, who was not involved in the study, tells Medscape Medical News that mucin secretagogues have a theoretical advantage over artificial tears but may not benefit patients with inflammatory conditions that lead to dry eye.

"With mucin you're lubricating the surface in a better way than with artificial tears, with which it was compared," he said. "Cyclosporine [Restasis, Allergan] actually treats the underlying inflammation that's causing the problem, but only 25% to 30% of patients have underlying T-cell-mediated disease, and cyclosporine doesn't work in every patient either. [Rebamipide] may have a place as a drug for dry eye disease in conjunction with other drugs, but not to replace them."

Dr. Hamrah noted that a different mucin secretagogue, diquafasol tetrasodium (Inspire Pharmaceuticals), failed to meet target endpoints in a phase 3 trial because of stringent US Food and Drug Administration requirements for showing complete resolution of staining or other clinical signs, a goal that is very hard to reach, he said.

No Benefit for Sjögren's

The investigators enrolled 188 adults aged 20 years or older who had dry eye symptoms that could not be completely relieved by artificial tears or other therapies. After a 2-week run-in phase, during which patients used only study-provided preservative-free artificial tears, they were randomly assigned to receive either 2% rebamipide, as1 drop in each eye 4 times daily, or 0.1% sodium hyaluronate, as 1 drop in each eye 6 times daily. Each group was treated for 4 weeks.

Analysis was by intention to treat; 182 patients (91 in each group) completed the study.

The mean FCSs at baseline were 7.0 in each group. The mean change from baseline to last observation carried forward (LOCF) in FCS (1/2 primary endpoints) was −3.7 for patients treated with rebamipide and −2.9 for those treated with sodium hyaluronate. The upper limit of the confidence interval of the difference between the treatment groups was below the prespecified noninferiority margin, indicating that rebamipide was not inferior to sodium hyaluronate. In addition, the upper limit of the confidence interval (−0.24) did not cross 0, rebamipide, indicating rebamipide was significantly better than the active control (P < .01), the authors report.

Baseline mean LGCS scores were 9.8 in the rebamipide group and 10.1 in the hyaluronate group. The respective mean changes from baseline were −4.5 for patients treated with rebamipide and −2.4 for those treated with sodium hyaluronate, indicating superior efficacy for rebamipide (P < .001; 2/2 primary endpoints). Mean changes were significantly greater in patients receiving rebamipide at week 2, week 4, and LOCF.

Among 34 patients (17 in each group) with Sjögren's syndrome, however, there were no significant differences in either FCS or LGCS, although there was a trend that appeared to favor rebamipide for each test, the authors write.

For the secondary endpoints of patient-rated improvements in foreign body sensation and eye pain, changes from baseline to LOCF were significantly greater with rebamipide than with sodium hyaluronate. There were no significant differences between groups for change from baseline to LOCF in dryness, photophobia, or blurred vision.

Sixty patients (64.5%) in the rebamipide group rated their symptoms as "improved" or "markedly improved" compared with 33 patients (34.7%) in the sodium hyaluronate group (P <.001).

Nine patients treated with rebamipide complained of a bitter taste, which was judged to be treatment-related; no patients treated with sodium hyaluronate complained of dysgeusia. There were no serious adverse events in either group; however, a single patient in the rebamipide group and 3 patients in the sodium hyaluronate group discontinued treatment because of adverse events.

Coauthor Kazuhide Oshiden, MS, a research scientist at Otsuka Pharmaceutical in Tokyo, told Medscape Medical News that cyclosporine ophthalmic solution is not approved for dry eye in Japan, and thus was not included in the head-to-head comparison.

"On the other hand, rebamipide demonstrated a marked improvement in FCS...not only at week 4 but also week 2 compared to the 0.1% sodium hyaluronate, which was commonly prescribed for dry eye patients in Japan. Based on this information, we speculated that rebamipide [would] tend to show its efficacy a little bit [more] rapidly compared to cyclosporine ophthalmic solution," Oshiden said in an email.

The study was sponsored by Otsuka Pharmaceuticals. Dr. Kinoshita is a consultant for Otsuka Pharmaceutical Co, Ltd, and Dr. Oshiden and 3 coauthors are employees of the company. Dr. Hamrah has received grant/research/clinical Support from Alcon and has served in a consulting or advisory capacity for Inspire, Allergan, Bausch & Lomb, and Revision Optics.

Ophthalmology. Published online March 13, 2013. Abstract