Durezol™ (difluprednate ophthalmic emulsion) 0.05% BID or QID starting 1 day before cataract surgery for treatment of postoperative inflammation and pain

Dr Peace has consulting and research agreements with Alcon Laboratories; Allergan, Inc.; Ista Pharmaceuticals; and Sirion Therapeutics, Inc. He has only received financial interest from Sirion Therapeutics in the subject matter of this poster.

Dr Vogel is an employee of Sirion Therapeutics, Inc.

Study sponsored by Sirion Therapeutics, Inc.

James H. Peace, MDUnited Medical Research Institute431 North Prairie Avenue, Inglewood, California 90301310-671-7172 • drjpeace@pacbell.net

Roger Vogel, MDSirion Therapeutics9314 E Broadway Ave, Tampa, FL 33619813-496-7325 • rvogel@siriontherapeutics.com

Abstract

Purpose: Evaluate the efficacy and safety of difluprednate ophthalmic emulsion 0.05% (DFBA), BID or QID, versus placebo BID or QID for the treatment of postoperative inflammation and pain following cataract extraction (CE).

Methods: Two randomized, double-masked trials were conducted in 245 subjects comparing DFBA 0.05% BID vs placebo BID, and DFBA 0.05% QID vs placebo QID. Treatment was initiated 24 hours prior to surgery and continued for 16 consecutive days. Subjects aged 2 years or older undergoing unilateral CE (with or without IOL implantation) were enrolled and randomized in a 2:1 ratio to receive either difluprednate or its vehicle (placebo). The primary endpoint was clearing of anterior chamber (AC) inflammation, defined as an AC cell and flare grade of 0 on Day 14. Pain was evaluated using a Visual Analog Scale (VAS).

Results: The percentage of DFBA subjects with cleared AC inflammation at Day 14 showed a statistically significant difference compared with placebo: 74.7% DFBA BID (P < 0.001), and 81.3% DFBA QID (P < 0.0001), vs 42.5% placebo BID and 25% placebo QID. The percentage that were pain/discomfort free (a VAS score of 0, or no pain) by Day 14 was also statistically significant: 64.6% (P < 0.001) DFBA BID group vs 30% placebo BID, and 72.5% (P < 0.001) DFBA QID vs 40% placebo QID. AEs were predominantly related to the surgery. IOP elevation occurred in < 6% of subjects.

Conclusion: Difluprednate administered BID or QID is efficacious in clearing postoperative ocular inflammation and relieving ocular pain/discomfort by Day 14. This benefit was maintained through Day 28, demonstrating definitive efficacy that did not decrease over time. Difluprednate dosed BID or QID was well tolerated.

Introduction•Even with recent improvements in technique, cataract extraction (CE) surgery carries the possibility of postoperative inflammation, which generally manifests as mild iritis with increased cells and protein (flare) in the anterior chamber (AC). Though this inflammation is often self-limiting, left untreated it has the potential to interfere with the patient’s visual rehabilitation and/or lead to further complications such as pain, discomfort, cystoid macular edema (CME), posterior capsule fibrosis, keratopathy, fibrin reaction, or chronic uveitis.1–3 The use of anti-inflammatory agents results in a more rapid resolution of CE-related inflammation, and the likelihood of a more comfortable patient who experiences an optimal surgical outcome.

•Topical corticosteroids have been a mainstay of therapy for postoperative inflammation. In June 2008 the US Food and Drug Administration expanded the list of available ocular therapies by approving a new, potent topical steroid indicated to treat both postoperative inflammation and postoperative pain. The steroid, difluprednate ophthalmic emulsion 0.05% (Durezol,™ Sirion Therapeutics, Tampa, FL), is approved for dosing four times daily (QID). Two earlier phase 3 trials demonstrated that both QID and twice-daily (BID) dosing of Durezol begun 24 hours after surgery effectively reduced inflammation and pain when compared with placebo.4 These multicenter, randomized, placebo-controlled trials involved 438 patients who were experiencing moderate or severe postoperative ocular inflammation (>10 AC cells).

•The phase 3B studies detailed in this presentation further evaluated the efficacy and safety of Durezol when dosed BID and QID, compared to placebo dosed likewise, in patients undergoing CE with or without IOL implantation. Treatment began 24 hours prior to surgery and continued for 14 days, followed by 2 weeks of tapering as needed. Both Durezol regimens resulted in statistically significant reductions in signs and symptoms of AC inflammation and statistically significant reductions in pain/discomfort.

1. Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol 1992;37(2):73–116.2. Gass JD, Norton EW. Cystoid macular edema and papilledema following cataract extraction. A fluorescein fundoscopic and

angiographic study. Arch Ophthalmol 1966;76(5):646–661.3. Miyake K, Maekubo K, Miyake Y, Nishi O. Pupillary fibrin membrane. A frequent early complication after posterior chamber lens

implantation in Japan. Ophthalmology 1989;96(8):1228–1233.4. Korenfeld M, Silverstein, SM, Cooke, DL, et al. Difluprednate for postoperative inflammation and pain. J Cataract Refract Surg.

2009;35(1):26–34.

Study criteria

Study designTwo phase 3B, multicenter, randomized, double-masked, placebo-controlled, parallel-group trials

Primary efficacy endpoint

On Day 14, the percentage of patients having both an anterior chamber cell grade of 0 (count of ≤ 5 cells) and an anterior chamber flare grade of 0 (complete absence of flare)

Efficacy endpoint grading criteria

Note: Recorded as actual number of cells observed if ≤ 15

AC cell grade0 ≤ 5 cells1 6–15 cells2 16–25 cells3 26–50 cells4 >50 cells

AC flare grade0 Complete absence1 Very slight2 Moderate3 Marked 4 Intense

Secondary endpoint (symptom assessment)

On Day 14, the percentage of patients having an ocular pain/discomfort score of 0 based on visual analog scale (VAS) measurement (0 = absence of pain and 100 = maximal pain or discomfort)

Inclusion criteria Unilateral ocular surgery Age 2 years or older on day of consent Negative urine pregnancy test, administered as deemed necessary Provide signed, written consent

MethodsAll patients (BID N = 121; QID N = 124) were randomized 2:1 to topical treatment with either Durezol or placebo

BID dosing regimen1 drop of Durezol or placebo administered BID for 16 days (initiated 24 hours prior to surgery), followed by a 14-day tapering period

QID dosing regimen1 drop of Durezol or placebo administered QID for 16 days (initiated 24 hours prior to surgery), followed by a 14-day tapering period

Demographics

Safety population

Durezol BID

Placebo BID Durezol QIDPlacebo QID

Number of patients

81 40 83 41

Mean age, years 69.4 71.3 67.5 70.4

Male, percent 37 65 45.8 41.5

Caucasian, percent

84 80 91.6 92.7

Iris color, n (%)BrownBlueGreenHazel

42 (51.9%)24 (29.6%)

5 (6.2%)8 (9.9%)

18 (45.0%)9 (22.5%)3 (7.5%)

10 (25.0%)

38 (45.8%)26 (31.3%)

2 (2.4%)17 (20.5%)

18 (43.9%)14 (34.1%)

1 (2.4%)8 (19.5%)

Durezol BID: Primary endpointPercentage of subjects with AC cell grade of 0 (≤ 5 cells) and flare grade of 0

(absence)

Significantly more patients in the Durezol group had clinical resolution of AC inflammation compared to the placebo group at Days 7, 14, and 28.

Primary Endpoint (Day 14): 59 patients (74.7%) in the Durezol group had clinical resolution of AC inflammation compared with 17 patients (42.5%) in the placebo group (P = 0.0006).

Durezol BID: Secondary endpointPercentage of subjects who were pain free (VAS score of 0)

A significantly greater percentage of patients in the Durezol group were pain/discomfort free compared to the placebo group at all time points.

Secondary Endpoint (Day 14): 51 subjects (64.6%) in the Durezol group were pain free compared with 12 subjects (30.0%) in the placebo group (P = 0.0004).

Durezol QID: Primary endpointPercentage of subjects with AC cell grade of 0 (≤ 5 cells) and flare grade of 0

(absence)

The percentage of patients in the Durezol group who achieved clinical resolution of AC inflammation (5 or fewer AC cells and no flare) when compared with the placebo group was significant at every time point.

Primary Endpoint (Day 14): Clinical resolution of inflammation in 65 subjects (81.3%) in the Durezol group compared with 10 subjects (25.0%) in the placebo group (P < 0.0001).

Durezol QID: Secondary endpointPercentage of subjects who were pain free (VAS score of 0)

Significantly more patients in the Durezol group than in the placebo group were reported to have no pain/discomfort at all time points.

Secondary Endpoint (Day 14): 58 subjects (72.5%) in the Durezol group were pain free compared with 16 subjects (40.0%) in the placebo group (P = 0.0006).

System organ class and preferred term(MedDRA 10.0)

Durezol BID(N = 81)

Placebo BID

(N = 40)

Eye disorders* 15 (18.5%) 19 (47.5%)

Visual acuity reduced 6 (7.4%) 7 (17.5%)

Conjunctival hyperemia

4 (4.9%) 12 (30.0%)

Eye pain 2 (2.5%) 6 (15.0%)

Ocular hyperemia 2 (2.5%) 4 (10.0%)

Ciliary hyperemia 2 (2.5%) 4 (10.0%)

AC inflammation 1 (1.2%) 2 (5.0%)

Macular edema 1 (1.2%) 2 (5.0%)

Photophobia 1 (1.2%) 2 (5.0%)

Vision blurred 1(1.2%) 2 (5.0%)

AC cell 0 4 (10.0%)

AC flare 0 3 (7.5%)

Corneal edema 0 2 (5.0%)

System organ class and preferred term (MedDRA 10.0)

Durezol QID(N = 83)

Placebo QID

(N = 41)

Eye disorders* 12 (14.5%) 13 (31.7%)

Corneal erosion 8 (9.6%) 2 (4.9%)

Conjunctival hyperemia

7 (8.4%) 6 (14.6%)

AC inflammation 2 (2.4%) 4 (9.8%)

Ciliary hyperemia 2 (2.4%) 4 (9.8%)

Corneal edema 1 (1.2%) 3 (7.3%)

Treatment-related adverse events occurring

in the study eye of ≥ 5% of subjects

* Note: Subjects could report more than one AE. At each level of summarization, subjects reporting the same AE more than once were only counted once.

IOP increases: ITT population, number of patients

Patient categoriesDurezol BID

Placebo BID

Durezol QID

Placebo QID

IOP rise clinically significant*

3 (3.7%) 0 5 (6.0%) 0

IOP rise requiring treatment 1 (1.2%) 0 5 (6.0%) 0

Discontinued study as a result of increased IOP

2 (2.5%) 0 0 1 (2.4%)* Defined as an observed value ≥ 21 mm Hg pressure that was also ≥10 mm Hg greater than baseline at the same visit.

Withdrawals due to lack of efficacy

* P < 0.0001

Note: There was no clinically significant difference between the treatment groups in the percentage of patients having an IOP rise ≥5 mm Hg, ≥8 mm Hg, or ≥10 mm Hg at any of the time points.

Number and percentage of patients

Durezol BID

Placebo BID

Durezol QID

Placebo QID

3 (3.7%)* 13 (32.5%) 6 (7.2%)* 17 (41.5%)

In both the BID and QID studies, significantly more patients receiving placebo withdrew due to lack of efficacy than did those receiving Durezol.

• In two randomized, double-masked studies, Durezol, dosed BID or QID beginning 1 day prior to ocular surgery, was significantly more effective than placebo in clearing postoperative ocular inflammation and relieving ocular pain and discomfort.

• Both studies showed significantly more patients treated with Durezol had clinical resolution of AC inflammation at days 7, 14 (primary endpoint), and 28 than patients treated with placebo.

• In both studies, significantly more patients treated with Durezol reported no pain or discomfort (VAS = 0) at every timepoint: days 3/4, 7, 14 (secondary endpoint), and 28.

• Adverse events that occurred were predominantly related to surgery. Clinically significant IOP elevation was observed in 3.7% of the patients dosed with Durezol BID and 6% dosed with Durezol QID.

• The number of patients withdrawn from the trial due to lack of efficacy was significantly greater in the BID and QID placebo groups than in the Durezol groups (P < 0.0001 for each).

• Inflammation reduction and pain resolution observed in the Durezol-treated groups were maintained through the tapering period to day 28.

Summary