Durezol

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

• James H. Peace, MD
• United Medical Research Institute
• 431 North Prairie Avenue, Inglewood, California
  90301
• 310-671-7172 drjpeace_at_pacbell.net
• Roger Vogel, MD
• Sirion Therapeutics
• 9314 E Broadway Ave, Tampa, FL 33619
• 813-496-7325 rvogel_at_siriontherapeutics.com

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.
2
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 21 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 lt 0.001), and
  81.3 DFBA QID (P lt 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 lt 0.001) DFBA BID group vs
  30 placebo BID, and 72.5 (P lt 0.001) DFBA QID
  vs 40 placebo QID. AEs were predominantly
  related to the surgery. IOP elevation occurred
  in lt 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.

3
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 patients 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.13 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 (gt10 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
199237(2)73116. 2. Gass JD, Norton EW.
Cystoid macular edema and papilledema following
cataract extraction. A fluorescein fundoscopic
and angiographic study. Arch Ophthalmol
196676(5)646661. 3. Miyake K, Maekubo K,
Miyake Y, Nishi O. Pupillary fibrin membrane. A
frequent early complication after posterior
chamber lens implantation in Japan. Ophthalmology
198996(8)12281233. 4. Korenfeld M,
Silverstein, SM, Cooke, DL, et al. Difluprednate
for postoperative inflammation and pain. J
Cataract Refract Surg. 200935(1)2634.
4
Study criteria
Study design Two phase 3B, multicenter, randomized, double-masked, placebo-controlled, parallel-group trials Two 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) 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 grade 0 5 cells 1 615 cells 2 1625 cells 3 2650 cells gt50 cells AC flare grade 0 Complete absence 1 Very slight 2 Moderate 3 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) 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 ? Unilateral ocular surgery ? Age 2 years or older on day of consent ? Negative urine pregnancy test, administered as deemed necessary ? Provide signed, written consent
Methods All patients (BID N 121 QID N 124) were randomized 21 to topical treatment with either Durezol or placebo All patients (BID N 121 QID N 124) were randomized 21 to topical treatment with either Durezol or placebo
BID dosing regimen 1 drop of Durezol or placebo administered BID for 16 days (initiated 24 hours prior to surgery), followed by a 14-day tapering period 1 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 regimen 1 drop of Durezol or placebo administered QID for 16 days (initiated 24 hours prior to surgery), followed by a 14-day tapering period 1 drop of Durezol or placebo administered QID for 16 days (initiated 24 hours prior to surgery), followed by a 14-day tapering period
5
Demographics
Safety population Durezol BID Placebo BID Durezol QID Placebo 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 () Brown Blue Green Hazel 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)
6
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).

7
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).

8
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 lt 0.0001).

9
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).

10
Treatment-related adverse events occurring in
the study eye of 5 of subjects
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)
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)
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.
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IOP increases ITT population, number of patients
Patient categories Durezol 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.
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.
Withdrawals due to lack of efficacy
Number and percentage of patients Number and percentage of patients Number and percentage of patients 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.
P lt 0.0001
12
Summary

• 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 lt 0.0001 for each).
• Inflammation reduction and pain resolution
  observed in the Durezol-treated groups were
  maintained through the tapering period to day 28.