Retinal Vein Occlusion 2010

An Evidence-Based ApproachCorticosteroids, Implants, and Anti

VEGF Therapies

Allen C. Ho, MD

Professor of Ophthalmology

Wills Eye Institute

Mid Atlantic Retina

acho@att.net

Disclosures

• Research Grant Funding: Alcon Laboratories, Allergan, Genentech, NEI/NIH, NeoVista, Ophthotech, Oraya, PRN, QLT, Regeneron, Second Sight

• Consultant / Scientific Advisory Boards:Alcon, Allergan, Centocor / Johnson and Johnson, Genentech, NeoVista, Merck, Ophthotech, Oraya, PRN, QLT, Regeneron

Retinal Vein Occlusion• Retinal vein occlusion is the second

most common cause of visual loss due to retinal vascular disease1-3

• Two major types:– Branch retinal vein occlusion (BRVO)– Central retinal vein occlusion (CRVO)

• BRVO is the most common3

– Five-year incidence of 0.6% (21/3558) for BRVO and 0.2% (7/3593) for CRVO3

• Persistent macular edema causes VA loss

1. Yau et al. Intern Med J. 2008; 2. RCO RVO guidelines. 2009; 3. Klein et al. Trans Am Ophthalmol Soc. 2000.

Clinical Trials and Venous Occlusive Diseases

• Laser studies– 1980s Branch Vein Occlusion Study (BVOS)

– 1990s Central Vein Occlusion Study (CVOS)

• 2009 Steroid studies– SCORE Study

– Ozurdex Trials

• 2010 Anti-VEGF Ranibizumab studies– BRAVO and CRUISE

Primary Results: The Standard Care versus COrticosteroid

for REtinal Vein Occlusion Study(The SCORE Study)

SCORE Study Research Group

Sponsored by the National Eye Institute, Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human ServicesNational Institutes of Health, U.S. Department of Health and Human Services

(Funded by NEI 2003)(Funded by NEI 2003)

SCORE BRVOMean Change BCVA

SCORE BRVOMean Change BCVA

M4 M8 M16 M20 M24 M28 M32 M36M12

BRVO Trial

After month 12 and through month 36, mean VA improvement was greatest in the SC group.

SCORE BRVO ConclusionSCORE BRVO Conclusion

• The SCORE-BRVO trial results support grid laser as the SC treatment for macular edema secondary to BRVO because:

– Similar efficacy in all 3 treatment arms up to month 12– Improved efficacy for laser beyond month 12– Superior safety profile of SC over 1-mg and 4-mg TA

SCORE CRVO BCVA at Month 12

SCORE CRVO BCVA at Month 12

Change in visual acuity letter score

Obs 1mg 4 mg

15 gain 7% 27% 26%

Pairwise comparisons Odds Ratio* P-Values

1 mg vs Obs

4 mg vs Obs

4 mg vs 1 mg

5.0

5.0

1.0

0.001

0.001

0.97

*Odds ratio adjusted for baseline visual acuity.

CRVO Trial

SCORE CRVO % With VA Gain of 15 letters or More

SCORE CRVO % With VA Gain of 15 letters or More

0

10

20

30

40

50

60

M4 M8 M12 M16 M20 M24

Obs 1mg 4mg

M12

CRVO Trial

Elevated IOP/GlaucomaElevated IOP/Glaucoma

Within and including 12 Months Obs

n=881 mgn=92

4 mg

n=91

Initiation of IOP-lowering meds* 8% 20% 35%

IOP >35 mm Hg 1% 5% 9%

Increase 10 mm Hg 2% 16% 26%

Laser peripheral iridotomy† n=0 n=0 n=1

Filtering surgery n=0 n=0 n=0

Tube shunt‡ n=0 n=2 n=0

Between 12 and 24 months

Laser/filtering n=0 n=0 n=0

Tube shunt‡ n=0 n=0 n=2

*P=.02 for Obs vs 1 mg; P<.0001 for Obs vs 4 mg; P=.02 for 1 mg vs 4 mg. †Procedure for angle closure glaucoma.‡Procedures to treat neovascular glaucoma.

CRVO Trial

• Both triamcinolone groups were superior to the observation group for VA at 12 months

• Visual benefit as early as 4 months • Visual benefit continued to 24 months• The 1-mg dose has a safety profile superior

to that of the 4-mg dose and similar to observation

SCORE CRVO ConclusionSCORE CRVO ConclusionCRVO Trial

OZURDEX™ (dexamethasone intravitreal implant)

• OZURDEX™ is preloaded into a sterile, single-use, specially designed applicator to facilitate injection of implant directly into the vitreous

Applicator and Extruded Implant (Not Shown Actual Size)

• Injectable, biodegradable intravitreal implant contains 0.7 mg (700 μg) dexamethasone in the NOVADUR™ solid polymer drug delivery system (preservative-free).

• Poly (D,L-lactide-co-glycolide) PLGA biodegradable polymer matrix, which slowly degrades to lactic acid and glycolic acid as dexamethasone is gradually released.

Ozurdex Mean Change BCVA BRVO Subanalysis

P<.001

P<.001

P<.001

P=.008

Sham (n=279)

OZURDEX™ (n=291)

Study Day

P values are for OZURDEX™ vs sham.

Ozurdex Mean Change BCVA CRVO Subanalysis

P<.001

P<.001

P=.005

P=.305*

Sham (n=147)

*NS at day 180.

Study Day

OZURDEX™ (n=136)

P values are for OZURDEX™ vs sham.

0

10

20

30

40

50

60

70

80

90

100

Cum

ula

tive

Res

pons

e R

ate

(%

)Ozurdex Primary Outcome = Time to Achieve ≥15-Letter Improvement From Baseline BCVA

No. at Risk

OZURDEX™ 381 309 264 149Sham 405 374 345 168

Days from the First Dose

Sham (n=426)

OZURDEX™ (n=427)Log–Rank Test P–value

OZURDEX™ vs Sham: P<.001

0 20 40 60 80 100 120 140 160 180

Ozurdex Key Adverse Events

*Intravitreal injections have been associated with endophthalmitis.

OZURDEX™

(n=421)Sham

(n=423)

Ocular

IOP increased 106 (25%) 5 (1%)

Conjunctival hemorrhage 85 (20%) 63 (15%)

Eye pain 31 (7%) 16 (4%)

Conjunctival hyperemia 28 (7%) 20 (5%)

Ocular hypertension 17 (4%) 3 (1%)

Cataract 15 (4%) 6 (1%)

Vitreous detachment 12 (3%) 8 (2%)

Sterile or infectious endophthalmitis* 0 0

Retinal detachment 1 (0.2%) 1 (0.2%)

Nonocular

Headache 14 (3%) 7 (2%)

Increased IOP with dexamethasone intravitreal implant (OZURDEX™) 0.7 mg peaked at day 60 and returned to baseline levels by day 180.

Ozurdex Trials Conclusions

• DEX groups’ time to gain 15 letters was significantly shorter than sham eyes through day 90

• Mean change in BCVA was statistically:

– Better for DEX groups for BRVO through day 180

– Better for DEX groups for CRVO through day 90

• Persistence of efficacy in 21% BRVO; 17% CRVO at month 12 required only 1 Rx

Anti-VEGF Trials

• Ranibizumab (Lucentis)

– BRAVO and CRUISE

• Afilbercept (VEGF-Trap eye, Regeneron)

– Galileo and Copernicus

– Results pending

J Lim

BRAVO Study

• Six-month phase 3 study with 6 months of follow-up; 93 sites

• 20/40 to 20/400 (mean 20/ 80)

• CST 250 microns (mean 488 µ sham, 552 µ ranibizumab)

• Foveal center ME within 12 months

• BRVO or HRVO

J Lim.

Campochiaro PA et al. Ophthalmology. 2010;117:1102-1112.

20

Mean Change from Baseline BCVA over Time to Month 12

0

2

4

6

8

10

12

14

16

18

20

0 2 4 6 8 10 12

Month

Mea

n C

han

ge

fro

m B

asel

ine

BC

VA

(E

TD

RS

Let

ters

)

Day 0–Month 5 Monthly Treatment

Months 6–11PRN Treatment

*P<0.0001 vs. sham. Earliest statistically significant group difference (P<0.0001 vs. sham) was at Day 7. Vertical bars are ±1 standard error of the mean. The last-observation-carried-forward method was used to impute missing data. BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study.

+16.6*

+18.3*

+7.3

+16.4*

+18.3*

+12.1

Sham/0.5 mg (n=132) 0.3 mg Ranibizumab (n=134) 0.5 mg Ranibizumab (n=131)

7

CRUISE Study

• Six-month phase 3 study, with 6 months of follow-up; 95 sites; 392 patients

• 20/40 to 20/400 (mean 20/100)

• CST 250 microns (mean 687 µ sham, 689 µ ranibizumab)

• Foveal center ME within 12 months

• CRVO

Brown DM et al. Ophthalmology. 2010;117:1124-1133.

22

Mean Change from Baseline BCVA over Time to Month 12

-2

0

2

4

6

8

10

12

14

16

18

2 4 6 8 10 120 7

+14.9*

+12.7*

+0.8

*p<0.0001 vs. sham. Earliest statistically significant group difference (p<0.0001 vs. sham) was at Day 7. Vertical bars are ±1 standard error of the mean. The last-observation-carried-forward method was used to impute missing data. BCVA=best-corrected visual acuity, ETDRS=Early Treatment Diabetic Retinopathy Study.

Sham/0.5 mg (n=130) 0.3 mg Ranibizumab (n=132) 0.5 mg Ranibizumab (n=130)

+13.9+13.9

+7.3

Mea

n C

han

ge

fro

m B

asel

ine

BC

VA

(E

TD

RS

Let

ters

)

MonthDay 0–Month 5

Monthly TreatmentMonths 6–11

PRN Treatment

Key Study Eye Adverse Events Through Month 6

Adverse Events, n (%)Sham

(n=129)

Ranibizumab0.5 mg(n=129)

Any intraocular inflammation event 5 (3.9) 2 (1.6)

Iridocyclitis 0 0

Iritis 3 (2.3) 2 (1.6)

Endophthalmitis 0 0

Lens damage 0 0

Cataract 0 2 (1.6)

Iris neovascularization 9 (7.0) 1 (0.8)*

Neovascular glaucoma 2 (1.6) 0

Rhegmatogenous retinal detachment 0 0

Retinal tear 0 0

Vitreous hemorrhage 9 (7.0)† 7 (5.4)

*Reported as serious. †One vitreous hemorrhage was reported as serious.

BRVO Summary

• BRVO: – SCORE: Laser better than IVTA

– OZURDEX: Dexamethasone better than sham (no laser arm)

– BRAVO: Ranibizumab monthly for 6 months better than observation/laser in BRAVO. Improved VA: 61% vs 29% eyes gained 15 or more letters

CRVO Summary

• CRVO treatment options– Steroids beneficial in phase 3 studies

SCORE Study: IVTA vs observation

OZURDEX Trials: dexamethasone vs sham

– Anti-VEGFsCRUISE: Ranibizumab monthly for 6 months better

than observation. Improved VA: 48% vs 17% eyes gained 15 or more letters

VEGF Trap: Galileo and Copernicus pending

Retinal Vein Occlusion 2010

• Allen C. Ho, MD

• Wills Eye Institute Philadelphia

• acho@att.net