Sirion Therapeutics sNDA for Durezol to treat uveitis accepted for FDA review

Sirion Therapeutics, Inc. announced today that its supplemental New Drug Application (sNDA) submitted to the U.S. Food and Drug Administration (FDA) seeking market approval of Durezol(TM) (difluprednate ophthalmic emulsion) 0.05% to treat endogenous anterior uveitis has been accepted for review.

Durezol, developed and marketed by Sirion Therapeutics, was approved by the FDA in June 2008 for the treatment of post-operative inflammation and pain associated with ocular surgery.

"Uveitis is a debilitating and painful condition, and is one of the leading causes of blindness in the US," said Barry Butler, CEO of Sirion Therapeutics. "We are encouraged that the FDA is reviewing the application for our drug, which has the potential to treat this sight threatening condition."

The supplemental application includes data from several clinical studies, including one recently completed trial in the US of 90 patients with endogenous anterior uveitis that compared Durezol dosed QID to Pred Forte(R) (prednisolone acetate ophthalmic suspension) 1%, Allergan, dosed 8 times a day. In this study, Durezol was found to be non-inferior to Pred Forte in reducing the mean anterior chamber cell grade at Day 14 (mean cell grade reduction of 2.1 compared to 1.9). In addition, Durezol was numerically superior in almost every efficacy measure, including the reduction of anterior chamber flare and the reduction of signs and symptoms of inflammation. Notably, 12.5% of patients in the Pred Forte group were withdrawn from the trial due to lack of efficacy, while no patients were withdrawn from the Durezol group for this reason.

Two phase 3 clinical trials, conducted in Japan by Senju Pharmaceuticals, Ltd, were also part of the application. In one trial of 136 patients with anterior uveitis and panuveitis, those treated with Durezol QID had a significantly greater improvement on Day 7 compared to those treated with betamethasone ophthalmic solution, 0.1% QID on the measures of anterior chamber cell score and total sign score. Betamethasone is a strong steroid approved outside of the US to treat ocular inflammation. In another trial of 19 patients with severe endogenous anterior uveitis and panuveitis (more than 50 anterior chamber cells) that did not respond to previous therapies, Durezol QID was effective in reducing anterior chamber cell, flare, and total sign and symptom scores. After 14 days of Durezol treatment, 72% of patients had less than 10 cells and 11% had no cells in the anterior chamber.

In the US and Japanese uveitis trials mentioned above, adverse events were generally mild to moderate. In the US trial, clinically significant IOP rise (a rise of greater than or equal to 10 mm Hg from baseline with an observed pressure of greater than or equal to 21 mm Hg) was 6% for Durezol QID and 5% for Pred Forte. In the larger Japanese trial for anterior uveitis, the clinically significant IOP rise for Durezol QID and betamethasone QID was 2.9% and 3%, respectively. In the Japanese trial for severe refractory anterior uveitis, the clinically significant IOP rise for Durezol QID was 5.3%.

"The studies included in this application demonstrate the efficacy of Durezol in quickly resolving uveitis, a disease state in which prompt eradication of inflammation is key in preserving vision," stated Roger Vogel, MD, Chief Medical Officer of Sirion Therapeutics. "In the U.S. trial, Durezol achieved these impressive results when dosed half as frequently as Pred Forte, and may potentially provide clinicians with a more powerful and convenient treatment for uveitis."

The FDA has issued an action date of October 24, 2009 for the supplemental NDA.

About Uveitis

Uveitis is inflammation of the middle three layers of the eye: iris, choroid, and ciliary body. The most common form of the condition is anterior uveitis, associated primarily with inflammation of the iris. If left untreated or under treated, uveitis can cause permanent damage and vision loss due to the development of glaucoma, cataract, or retinal edema. In addition to potential vision loss, the severe pain and photophobia that accompany anterior uveitis can be debilitating.

About Durezol

Durezol (difluprednate ophthalmic emulsion) 0.05% is a topical ophthalmic corticosteroid approved for the treatment of inflammation and pain associated with ocular surgery. Difluprednate, the active ingredient in Durezol, is a difluorinated prednisolone derivative that has potent anti-inflammatory activity. Durezol does not contain benzalkonium chloride (BAK), an ocular preservative known to cause corneal toxicity with chronic use. This may also be important consideration for patients with uveitis, who often use steroids long-term.

Dosage and Administration

The recommended dosage and administration of Durezol in the treatment of postoperative inflammation and pain associated with ocular surgery is to instill one drop into the conjunctival sac of the affected eye(s) 4 times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the postoperative period, followed by 2 times daily for a week with tapering based on the response.

Important Safety Information

Like other corticosteroids, Durezol is contraindicated in patients with viral diseases of the cornea and conjunctiva, and those with fungal or mycobacterial infections of the eye or ocular structures. Prolonged use of corticosteroids may increase the hazard of secondary ocular bacterial infections, exacerbate the severity of ocular viral infections, and increase the development of fungal infections of the cornea. It is important to monitor intraocular pressure when using ophthalmic steroids. The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. Ocular adverse reactions occurring in 5-15% of subjects in clinical studies with Durezol included corneal edema, ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule opacification, anterior chamber cells, anterior chamber flare, conjunctival edema, and blepharitis. Other ocular adverse reactions occurring in 1-5% of patients included reduced visual acuity, punctate keratitis, eye inflammation, and iritis. Ocular adverse events occurring in < 1% of patients included application site discomfort or irritation, corneal pigmentation and striae, episcleritis, eye pruritis, eyelid irritation and crusting, foreign body sensation, increased lacrimation, macular edema, scleral hyperemia, and uveitis. Most of these events may have been the consequence of the surgical procedure.