FDA approves new drug application for difluprednate 0.05%

Tampa, FL-The FDA in late June approved a new drug application for difluprednate 0.05% ophthalmic emulsion (Durezol, Sirion Therapeutics), a topical corticosteroid indicated for the treatment of postoperative ocular inflammation and pain. The Tampa, FL-based company plans to make the drug commercially available late this year.

The approval was announced after a 6-month priority review on the basis of outcomes of two identically designed phase III clinical trials that assessed the drug dosed either two times or four times daily versus placebo, said Michael S. Korenfeld, MD, the principal investigator. Dr. Korenfeld is an assistant clinical professor in the Department of Ophthalmology and Visual Sciences, Washington University in St. Louis.

The studies included a total of 438 subjects who had an anterior chamber cell grade 2 or higher (>10 cells) the day after surgery. Patients were randomly assigned to four equal groups and assigned to receive difluprednate or vehicle two times daily or four times daily. The drug will be labeled for four-times-daily dosing.

Study had postop dosing

In both studies, dosing began 24 hours after ocular surgery, which was a cataract procedure in the vast majority of cases. The timing has bearing on the results, according to Dr. Korenfeld.

"In some of the newer studies, we're dosing the drugs that are used for cataract surgery inflammation before the surgery even begins, but with this particular drug, the studies were begun only after the surgical trauma had been produced, which means you're playing catch-up," he said. "It's been shown that for any kind of inflammation, you're far, far better off starting with the anti-inflammatory medicine on board before you actually induce the trauma, so the results that they obtained should be interpreted in that light."

"They showed statistically significant differences from placebo from the first postoperative visit after the drug was started on day three/four. That difference from placebo increased with time in both the b.i.d. and q.i.d. arms of the study. That was not only for their primary endpoint, which was an anterior chamber cell grade of 0 (one or no cells), but also pain," Dr. Korenfeld continued.

"This is the first time that a steroid medication was used and studied as far as its ability to control pain. They found that it was very effective not only for cell flare and other signs of inflammation such as redness and chemosis, but people were also made much more comfortable with this drug in terms of pain and discomfort compared with placebo," he said.

The two regimens had similar efficacy in reduction of anterior chamber cells, Dr. Korenfeld said. Two weeks postoperatively, both the b.i.d. and q.i.d. arms had reductions of 87% in the number of anterior chamber cells. The q.i.d. regimen had a small numerical advantage in the number of patients who were completely free of inflammation (0 cells) at the 1-week time point. Because of this numerical advantage and the desire to treat inflammation aggressively, the FDA chose the q.i.d. dosing regimen for recommendation to doctors.

IOP rise

One of the most common side effects seen with corticosteroids in ophthalmic use is a rise in IOP. Few patients in the trials of difluprednate experienced a significant pressure increase, however. Three percent of subjects in each of the b.i.d. and q.i.d. groups, and 1% in the placebo group, met criterion for a clinically significant rise in IOP, defined as an observed value of ≥21 mm Hg and a change from baseline of 10 mm Hg.

Dr. Korenfeld said the trials were not designed to compare the two dosing regimens, and no statistical analyses were performed comparing b.i.d. and q.i.d. dosing for the primary or secondary endpoints. In all analyses, the safety and effectiveness of difluprednate were compared with those of the placebo. Speaking as a clinician familiar with the study results rather than on behalf of the FDA or Sirion, Dr. Korenfeld said either dose might be effective.

"If you look at the data for how the b.i.d. dose performed, it looks like it did very well at the job it had to do. If people wound up using the drug b.i.d. instead of q.i.d., they might find that it works well," he said. "Knowing what I know, if I had a patient who had cataract surgery, and on the first postoperative day he or she had a minimal or moderate amount of inflammation, I would be perfectly comfortable using the drug twice a day. In addition, people are more compliant with twice-a-day than with four-times-a-day medicine.

"If they have a lot of inflammation, then I might be more compelled to ask them to use it four times a day," he continued. "If they used it twice a day and the inflammation wasn't going away as fast as I would like it to do, I might suggest that they bump it from two times to four times."

Difluprednate's ability to reduce postoperative pain results from molecular engineering of side chains to make the steroid stronger, improve its ability to enter the eye at a high concentration, and ensure that it becomes inactivated relatively quickly after performing its anti-inflammatory actions, Dr. Korenfeld said.

Unique molecular structure

Difluprednate is the first innovation in the strong steroid class in more than 35 years, according to Barry Butler, president and chief executive officer of Sirion Therapeutics. Stronger corticosteroids typically cause more side effects, he said, and it has been difficult to design a drug that had enhanced strength and an acceptable safety profile since the introduction of prednisolone acetate (Pred Forte, Allergan).

Difluprednate is a promising addition to its class because of its unique molecular structure, its emulsion formulation, which enhances penetration, and its strong affinity for steroid receptors, Butler said. "It's really the science behind the product that makes it very strong," he said.

Indications for difluprednate could be expanded in the future, Butler continued. Phase IIIb studies evaluating the compound in cases in which treatment was initiated 1 day before surgery have been completed, and a phase III study evaluating it in the treatment of anterior uveitis is under way. Findings from the uveitis study should be available later this year.

In Japan, several studies have shown that difluprednate is effective in the treatment of severe cases of inflammatory uveitis, including panuveitis, at q.i.d. dosing, which is considered to be infrequent dosing for that condition, Butler said.