New potent difluprednate advances through phase III studies

September 15, 2007

The potent corticosteroid difluprednate is being developed as an emulsion for topical use. Phase III clinical trials of the treatment of postoperative inflammation have been completed and a phase III study of anterior uveitis treatment is under way. Positive efficacy and safety results were achieved in phase III clinical trials in Japan.

Key Points

Data are expected to be released soon from two phase III trials investigating the efficacy and safety of the potent topical corticosteroid difluprednate 0.05% ophthalmic emulsion (ST-601, Sirion Therapeutics) in the treatment of postoperative inflammation. A third study is under way to evaluate difluprednate for the treatment of anterior uveitis.

Difluprednate is a derivative of prednisolone, but based on standard glucocorticoid assays, it is several-fold more potent than prednisolone acetate. The agent is being developed in an emulsion based on preclinical pharmacokinetics studies demonstrating that the emulsion offered higher ocular bioavailability compared with a suspension.

Although not yet approved in the United States, difluprednate already has undergone extensive preclinical efficacy and safety testing. The agent has been shown to be safe and effective for treating postoperative inflammation and anterior uveitis in several phase II and phase III clinical trials conducted in Japan including one trial conducted with patients with intractable disease not responsive to other steroids.

"There have been no new strong corticosteroids introduced for topical use in ophthalmology for many years," Dr. Korenfeld told Ophthalmology Times. "The data that have been reported for difluprednate indicate it is likely more potent than our current gold standard, prednisolone acetate, and may have the potential for controlling inflammation with a more convenient, less frequent dosing schedule."

Postop inflammation

In the U.S. postoperative inflammation studies, difluprednate was investigated in both b.i.d. and q.i.d. dosing schedules and was compared against placebo. Sirion said it is planning to submit a new drug application to the FDA for the postoperative inflammation indication by the end of this year.

The Japanese postoperative inflammation study was a double-masked, active-controlled trial that randomly selected 200 patients to receive treatment with difluprednate 0.05% or betamethasone 0.1% for 14 days beginning on the day after surgery. Bethamethasone is used routinely as a reference drug in clinical trials of new steroids that are conducted outside the United States. Enrolled subjects were required to have an anterior chamber cell score of at least 2 following cataract or vitreous surgery.

The study achieved its primary objective in demonstrating that difluprednate was not inferior to betamethasone. In the primary efficacy analysis of change from baseline in anterior chamber cell score on day 14, no significant difference was seen between corticosteroid treatment groups. By day 3 in both study groups, the mean inflammation scores had already decreased by about one severity grade.

In secondary efficacy analyses evaluating changes in total scores for five objective signs and five subjective symptoms of inflammation, mean improvements from baseline were consistently greater in the difluprednate group. The difference between groups was statistically significant showing greater improvement with difluprednate for the change in total sign score at day 7 and for the change in total symptom score at all follow-up visits (days 3, 7, and 14).

Uveitis control

The U.S. phase III uveitis study was launched in May and is comparing a 2-week course of treatment with difluprednate 0.05% dosed 4 times daily with prednisolone acetate 1% dosed eight times daily. In Japan, the efficacy and safety of difluprednate 0.05% for the treatment of anterior uveitis/panuveitis was evaluated in a double-blind, non-inferiority study that randomly selected 136 patients to receive treatment with difluprednate or betamethasone 0.1%. Eligible patients had an anterior chamber cell score of 2 or 3 and were treated four times a day for 14 days.

Three patients treated with betamethasone-but no patients treated with difluprednate-discontinued study participation because of aggravation of uveitis. In the analysis of change from baseline in anterior chamber cell score, no significant differences were seen between groups at the primary efficacy endpoint at day 14.

Significant differences were observed favoring difluprednate in analyses of data collected earlier in the study, however. At day 7, improvement from baseline in anterior chamber cell score was greater in the difluprednate group compared with that seen in the betamethasone-treated controls. At that visit, a significantly higher proportion of patients treated with difluprednate had an anterior chamber cell score of 1 or lower (94%) compared with the betamethasone group (81%). Significantly greater improvements also were seen in the anterior chamber flare score and total sign score favoring difluprednate at day 7.