| | June 1, 2000 BELLFLOWER, Calif. — When used as an eye drop, cyclosporine A is safe and effective in treating moderate to severe dry eye disease, according to the results of two phase 3 multicenter, randomized studies that appeared recently in Ophthalmology. “This is a new application for cyclosporine,” lead author Kenneth N. Sall, MD, a general ophthalmologist in private practice here, told Ocular Surgery News. “The new drug application for cyclosporine eye drops in patients with moderate to severe dry eye is currently under review at the Food and Drug Administration.” The two studies evaluated both 0.05% and 0.1% dosages of cyclosporine twice daily. “There really wasn’t a big difference between the two doses,” Dr. Sall said. “The lower dose is what Allergan intends to market.” Previous studies have suggested that dry eye disease is the result of an underlying cytokine and receptor-mediated inflammatory process affecting both the lacrimal gland and the ocular surface. “There is this feedback loop between the cornea and the lacrimal gland that tells the gland to produce more tears,” Dr. Sall said. “This feedback loop is not working properly in patients with moderate to severe dry eye.” Animal and human studies also have demonstrated that topical treatment with the immunomodulatory agent cyclosporine A “can have beneficial effects on the underlying inflammatory pathologic condition of dry eye disease, as well as improve the signs and symptoms of this condition,” he said. “Cyclosporine helps restore the feedback loop so it functions better and returns everything to a more normal state.” ![[bar]](OSN%20Cyclosporine%20_files/gradient.gif)
Study design
The two identical multicenter studies had a combined enrollment of 877 patients, mostly women (82%) and Caucasian (84%). Patients were divided in approximately equal numbers into three treatment groups: cyclosporine 0.05%, cyclosporine 0.1% and placebo. During the 6-month treatment phase, patients were instructed to instill one drop of study medication twice daily in each eye (one on waking in the morning and the other at bedtime). Individually packaged preservative-free artificial tears (Refresh Lubricant Eye Drops; Allergan) also were provided as an adjunctive treatment to be used as frequently as needed. About 76% (671 out of 877) of enrolled patients completed the study. The results of the two trials were combined for analysis. Among the objective findings, “there was an improvement in corneal staining,” Dr. Sall said. The improvement in corneal staining was significantly greater in both cyclosporine groups than in the placebo group (P=.044) at 4 months and in the cyclosporine 0.05% group at 6 months (P=.008). There also was a trend (P=.062) toward a significantly greater improvement in the cyclosporine 0.1% group compared with the placebo group at 6 months. The Schirmer tear test also reflected a statistically significant improvement with cyclosporine. “The cyclosporine patients had an increase in tear production,” Dr. Sall said. At 3 months, there was a significant worsening in the placebo group (P=.014) and a significant difference among the treatment groups, with the cyclosporine group significantly greater than the placebo group (P=.009). Furthermore, at 6 months, there was a statistically significant improvement from baseline for both cyclosporine groups.
Subjective symptoms improve
The most notable change in subjective ocular symptoms was blurred vision. The decrease from baseline was statistically significant in both cyclosporine groups at all follow-up visits (P=.012), but only at 6 months with the placebo group (P=.039). “The improvement in blurred vision also was significantly greater in the cyclosporine 0.05% group compared with the placebo group at all follow-up visits (P=.014),” Dr. Sall said. Moreover, “The patients on the drug compared with those on placebo needed to use less additional supplemental eye drops for control of their symptoms. This is a significant factor,” Dr. Sall said. “Here we have patients all day long taking eye drops to keep their eyes moist, but the patients on cyclosporine had to use less supplemental drops. It indicates that their comfort improved.” In addition, the investigator’s evaluation of global response to treatment “felt that patients on cyclosporine were better,” he said. “The drug is very safe and side effects are minimal,” Dr. Sall said. “There were no serious adverse reactions.” The most commonly reported treatment-related adverse event with cyclosporine was mild ocular burning and stinging, followed by discharge in the eye and foreign body sensation. “It also is important to note that only two patients experienced ocular infection during treatment, and both of these patients were in the placebo group,” Dr. Sall said.
Even greater benefit
Dr. Sall is optimistic that patients will enjoy an even greater benefit from cyclosporine when used in combination with other drugs, such as “a low-dose steroid eye drop to calm the eye.” He believes that many patients will probably continue some artificial tear use but patient compliance will be enhanced because “it will make them less dependent on artificial tears.” Prior to cyclosporine, “the whole therapy of dry eye has been ‘Okay, your eyes are dry. We don’t have anything to make your eyes more moist except a bottle of tears that you buy at the drugstore,’” Dr. Sall said. “This therapy is new in that it helps your own lacrimal gland produce more and better quality tears. So it’s therapeutic versus palliative.” In essence, the treatment “represents a significant breakthrough in the management of this common and frustrating condition. Physicians will be very pleased when they start adding cyclosporine to their armamentarium with other treatments for dry eye,” Dr. Sall said. For Your Information: - Kenneth N. Sall, MD, can be reached at 9604 Artesia Blvd., Ste. 203, Bellflower, CA 90706; (562) 804-1974; fax: (562) 804-4350; e-mail: salleyectr@aol.com. Dr. Sall has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
Reference: - Sall K, Stevenson OD, Mundorf TK, et al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology. 2000;107: 631-639.
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