Transcript Cytokine therapy for RCC - American Academy of Ophthalmology

Diabetic Macular Edema 2010
Pravin U. Dugel, MD
Managing Partner, Retinal Consultants of Arizona, Phoenix, AZ
Clinical Associate Professor, Doheny Eye Institute, Los Angeles, CA
Founding Partner, Spectra Eye Institute, Phoenix, AZ
World Diabetes Trends
Diabetes Atlas, 3rd ed, International Diabetes Federation, 2006.
Diabetes Trends Among US Adults
(Includes Gestational Diabetes)
BRFSS, 1990,1995, and 2001
1990
1995
2001
By the year 2025 an
estimated 30 million
Americans will be living
with diabetes
No Data
<4%
4%-6%
6%-8%
CDC Web site. www.cdc.gov; Mokdad et al. Diabetes Care. 2000;23:1278-1283; J
Am Med Assoc. 2001;286:10; ADA.
8%-10%
>10%
Percentage of Diabetic Macular Edema
Increases as NPDR Progresses
N=1585
% Patients With Macular Edema
100
90
80
70
60
50
40
30
20
10
0
Increased Risk of Diabetic
Macular Edema
n=47
n=114
n=228
Mild NPDR
Moderate NPDR
Severe NPDR
NPDR: nonproliferative diabetic retinopathy.
Figure reproduced from Henricsson M et al. Acta Ophthalmol Scand. 1999;77:218–223.
ETDRS Laser Photocoagulation:
Prevented Moderate Visual Loss
In CSME and Less Severe DR1
% of Patients with Moderate Visual Loss
60
*3-step loss on
ETDRS chart
Focal + FU Scatter (N=299)
Deferral (N=611)
50
33%
40
30
*
20
 P<0.01
10
 P<0.001
13%
0
2
1
3
4
Years after randomization
50% reduction in moderate visual loss
1ETDRS.
Arch Ophthalmol 1995;113:1144-1145.
Treatment Options: Laser
Photocoagulation
 Focal or Grid Photocoagulation
• Focal PC: light, small-sized burns to leaking
microaneurysms
• Grid PC: a grid of burns to areas of edema from capillary
leakage or nonperfusion
Focal
1AAO.
2003. Preferred Practice Pattern®: Diabetic retinopathy 2003;
Research Group. Ophthalmology 1991;98(5 suppl):766-785.
2ETDRS
After Grid Laser Treatment
3 Months
3 Months
Pharmacologic Targets to Inhibit
Diabetic Retinopathy
 Specific growth factors1
• IGF-1 inhibition
• VEGF inhibition
• PEDF expression
 Extracellular matrix and
integrin factors1
• Integrin inhibition
• Matrix metalloproteases
inhibition
• Steroid compounds
 Intracellular signaling1
• PKC inhibition
• MAPK pathway inhibition
 Inflammation2
 Reactive oxygen species2
 Nonenzymatic glycation
inhibition2
 Nitric oxide synthase2
1Speicher
2Frank
MA et al. Expert Opin Emerg Drugs 2003;8:239-250;
RN. NEJM 2004;350:48-58.
Diabetic Macular Edema
Contributing Anatomical Changes
Chronic inflammation
Leukostasis
Taurine transport
of RPE
Antioxidant capacity
of RPE
x
x
x
x
x
Diabetic
Macular
Edema
Vision loss
Corticosteroid
Pericyte loss
Hypoxia
Thickened basement
membrane
Tight junctions
x
Capillary nonperfusion
Intraocular Steroids in Development
NOVA63035
NVG
Posurdex
Allergan
Kenalog
BMS
I-Vation
SurModics
Retaane
Alcon
Retisert
B&L
Medidur
Alimera
API
Dexamethasone
palmitate
Dexamethasone
Triamcinolone
acetonide
Triamcinolone
Anecortave
acetate
Fluocinolone
acetonide
Fluocinolone
acetonide
Administration
Injectable
emulsion
Injectable
implant
Injectable
suspension
Implant
Juxtascleral
injection
Implant
Injectable
implant
Duration
6-9 months
1-3 months
1-3 months
12 months
6 months
30 months
18-36 months
Indication /
Dev
DME
Phase I
ME
Phase III
All
Off label
DME
Phase I
ARMD
Phase III
Uveitis
Approved
DME
Phase III
Comment
Reduction of
side effects ?
Toxic excipients
$ 18,250
The Diabetic Retinopathy Clinical
Research Network
 A Randomized Trial Comparing Intravitreal
Triamcinolone Acetonide to Focal/Grid
Photocoagulation for Diabetic Macular Edema
 2 and 3 Year Results
 Sponsored by the National Eye Institute,
 National Institutes of Health, U.S. Department of
Health and Human Services
Primary Outcome:
Mean Change in Visual Acuity at 2 Years
Mean Change in
VA (letter score)
Pairwise
Comparisons
Laser vs. 1 mg
Laser
N=330
1 mg
N=256
4 mg
N=254
+1
-2
-3
Mean Difference*
P value*
+3.5 letters
0.02
Laser vs. 4 mg
+4.6 letters
0.002
1 mg vs. 4 mg
+1.1 letters
0.49
* Adjusted for baseline VA and prior focal/grid laser
Mean Visual Acuity Over 3 Years in All Eyes
20/32
Laser (All eyes)
1 mg (All eyes)
4 mg (All eyes)
20/40
Visual
Acuity
Score
20/50
20/63
20/80
0
4
8
12
20
16
Months
24
28
32
36
14
Protocol B: Subgroup Analysis
Baseline Data
Baseline Va
2 Year Data
>10-Letter
>10-Letter
Worsening (%)
Improvement (%)
Laser
1mg
4mg
Laser
1mg
4mg
# Eyes
Laser, 1 mg, 4 mg
20/32 - 20/63
189
149
149
23
28
33
23
17
16
20/63-1 - 20/200+1
129
94
92
12
24
26
43
33
39
20/200 – 20/320-1
12
13
13
17
15
0
42
46
77
Table 5. Change in Visual Acuity at 2-Year
Primary Outcome among Subgroups
FAME
Phase III Study
24 Month Results
Iluvien Drug Delivery Insert
• Non-bioerodable
cylindrical tube 3.5 mm
long, 0.37 mm in diameter
• Injected through a self
sealing wound via 25-gauge
proprietary inserter
• Two doses compared
0.2µg (Low Dose) and
0.5µg (High Dose) of FAc
per day
Iluvien is under review by the FDA, it is not approved in the United States.
Iluvien Technology
 Near zero-order
kinetics
 Submicrogram daily
dose delivery
 Posterior point of
release
®
•
•
•
•
•
Active compound:
Total dose:
Approximate daily release:
Method of delivery:
Approximate duration of action:
Fluocinolone acetonide (FAc)
0.19 mg
0.2 µg/d and 0.5 µg/d
Intravitreal Injection
At least 2 years
Kane FE, et al. Expert Opin Drug Deliv. 2008;5:1039-1046.
Iluvien. Draft package insert.
Primary Efficacy Analysis: Percent of Patients With
≥ 15-Letter Improvement Over Baseline
40
Sham (n = 185)
P = .002 for both doses
0.2 µg/d FAc (n = 376)
35
0.5 µg/d FAc (n = 395)
28.7%
Patients (%)
30
28.6%
25
20
16.2%
15
10
5
0
0
3
6
9
12
15
18
21
24
Time (Months)
The 0.2 µg/d dose of FAc has been submitted for regulatory approval.
Alimera Sciences. Data on File.
% of Patients with ≥ 15-Letter Improvement in BCVA Over Baseline Through 30
Months
n = 123
40
39.8%
Sham (n = 185)
35
0.2 µg/d FAc (n = 376)
Patients (%)
30
P = .002
25
20
17.5%
15
n = 63
10
5
0
Baseline
3
6
9
12
15
18
21
24
27
30
Time (Months)
Ciulla T, et al. Data presented at Association for Research in
Vision and Ophthalmology. Ft Lauderdale, FL. May, 2010.
Cataract-Related Events
Subjects, %
Sham
Low Dose
High Dose
(Study Eye)
(N = 121)
(N = 235)
(N = 265)
Cataract considered as an AE*
46.3%
80.0%
87.5%
Cataract extraction performed*
23.1%
74.9%
84.5%
IOP-Related Events
Subjects, %
Sham
Low Dose
High Dose
(Study Eye)
(N = 185)
(N = 375)
(N = 393)
IOP > 30 mm Hg
2.7%
16.3%
21.6%
Trabeculoplasty
0.0%
1.3%
2.5%
Incisional IOP lowering surgery
0.5%
3.7%
7.4%
* Phakic subjects only.
Alimera Sciences. Data on File.
Mean Change From Baseline in BCVA Letter Score
Mean BCVA Letter Change
in Iluvien (0.2 µg/d FAc) Patients
Months
Alimera Sciences. Data on File.
VEGF in Human Ocular Fluids
VEGF (ng/ml)
30
= aqueous fluid
= vitreous fluid
25
= mean
20
15
10
5
0
No Proliferative DM,
Diseases Without PDR
Aiello et al. NEJM 1994;331:1480-7.
DM,
Q-PDR
DM,
Active PDR
Iris NV,
regressed
Iris NV,
active
CRVO,
active
READ-2
 Month 12: Mean Change in Visual Acuity from
Baseline
Nguyen QD, Shah SM, Heier JS, Do D, Lim J, Boyer D, Abraham P, Dugel P, Campochiaro P, for the READ-2
Research Group. Ranibuzumab for Edema of the Macula in Diabetes (READ-2) Preliminary one year updates.
DA VINCI: VEGF trap versus laser
ETDRS letters
Mean Change in Visual Acuity
2q4*
2prn+
11.4
10.3
2q8^
0.5q4†
8.5
8.6
Laser
Week
4
8
12
LOCF analysis; n=44 (laser, 0.5q4, 2q4); n=42 (2q8); n=45 (2prn)
16
20
2.5
*P < 0.0001
^P = 0.0085
+P = 0.0004
†P = 0.0054
vs. laser
24
(ANCOVA)
No statistical differences
among VTE arms.
DRCR Protocol I
 Primary outcome: Change in visual acuity from baseline
to 1 year (intent to treat analysis).
 Eyes Randomized: N = 854 (691 Participants)
• Sham + Prompt Laser (N = 293)
• Ranibizumab + Prompt Laser (N = 187)
• Ranibizumab + Deferred Laser (N = 188)
• Triamcinolone + Prompt Laser (N = 186)
The Diabetic Retinopathy Clinical Research Network. Randomized Trial Evaluating Ranibizumab Plus Prompt
or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology.
Jun;117(6):1064-1077.
DRCR Protocol I
 Visual acuity
11
Sham+prom
pt laser
10
9
8
7
6
Primary outcome time point
5
4
3
Ranibizuma
b+prompt
laser
Ranibizuma
b+deferred
laser
Triamcinolo
ne+prompt
laser
2
1
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96100104
The Diabetic Retinopathy Clinical Research Network. Randomized Trial Evaluating Ranibizumab Plus Prompt
or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology.
Jun;117(6):1064-1077.
BOLT
 Prospective, randomized, masked, single-center, 2-year,
2-arm clinical trial.
 Randomized to:
• Laser group (N = 38).
• Bevacizumab group (N = 42).
 Primary outcome: Comparison of mean ETDRS BCVA at
12 months between Laser and Bevacizumab arms.
Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, Bunce
C, Leslie RD, Hykin PG. A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the
Management of Diabetic Macular Edema (BOLT Study): 12-Month Data Report 2. Ophthalmology. 2010 Jun;117(6):10781086.e2.
BOLT
*
*
*
*
* = p < 0.05
BOLT
Mean number of
treatments
Bevacizumab group
Laser group
9 injections
3 lasers
Conclusion
1.Diabetic macular edema is a
multi-factorial disease
2.Laser remains the standard of
care in most cases, although
combination treatment holds
promise
3.The socio-economic impact of
practicing evidence-based
medicine must be considered