1. Retinal Vein Occlusion 2010 An Evidence-Based Approach Corticosteroids, Implants, and Anti VEGF Therapies Allen C. Ho, MD Professor of Ophthalmology Wills Eye Institute Mid Atlantic Retina acho@att.net

2. 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

3. Retinal Vein Occlusion Retinal vein occlusion is the second most common cause of visual loss due to retinal vascular disease 1-3 Two major types: – Branch retinal vein occlusion (BRVO) – Central retinal vein occlusion (CRVO) BRVO is the most common 3 – Five-year incidence of 0.6% (21/3558) for BRVO and 0.2% (7/3593) for CRVO 3 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.

4. 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

5. 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, National Institutes of Health, U.S. Department of Health and Human Services (Funded by NEI 2003)

6. SCORE BRVO Mean Change BCVA M4 M8 M16 M20 M24 M28 M32 M36 M12 BRVO Trial After month 12 and through month 36, mean VA improvement was greatest in the SC group.

7. SCORE 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

8. SCORE CRVO BCVA at Month 12 Change in visual acuity letter score Obs1mg4 mg  15 gain 7%27%26% Pairwise comparisonsOdds Ratio* P-Values 1 mg vs Obs 4 mg vs Obs 4 mg vs 1 mg 5.0 1.0 0.001 0.97 *Odds ratio adjusted for baseline visual acuity. CRVO Trial

9. SCORE CRVO % With VA Gain of 15 letters or More M12 CRVO Trial

10. Elevated IOP/Glaucoma Within and including 12 MonthsObs n=88 1 mg n=92 4 mg n=91 Initiation of IOP-lowering meds*8%20%35% IOP >35 mm Hg1%5%9% Increase  10 mm Hg 2%16%26% Laser peripheral iridotomy † n=0 n=1 Filtering surgeryn=0 Tube shunt ‡ n=0n=2n=0 Between 12 and 24 months Laser/filteringn=0 Tube shunt ‡ 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

11. 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 Conclusion CRVO Trial

12. 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.

13. Ozurdex Mean Change BCVA BRVO Subanalysis P<.001 P=.008 Sham (n=279) OZURDEX ™ (n=291) Study Day P values are for OZURDEX™ vs sham.

14. Ozurdex Mean Change BCVA CRVO Subanalysis 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.

15. 0 10 20 30 40 50 60 70 80 90 100 Cumulative Response Rate (%) Ozurdex Primary Outcome = Time to Achieve ≥15-Letter Improvement From Baseline BCVA No. at Risk OZURDEX™381309264149 Sham405374345168 Days from the First Dose Sham (n=426) OZURDEX™ (n=427) Log–Rank Test P–value OZURDEX™ vs Sham:P<.001 020406080100120140160180

16. Ozurdex Key Adverse Events *Intravitreal injections have been associated with endophthalmitis. OZURDEX ™ (n=421) Sham (n=423) Ocular IOP increased106 (25%)5 (1%) Conjunctival hemorrhage85 (20%)63 (15%) Eye pain31 (7%)16 (4%) Conjunctival hyperemia28 (7%)20 (5%) Ocular hypertension17 (4%)3 (1%) Cataract15 (4%)6 (1%) Vitreous detachment12 (3%)8 (2%) Sterile or infectious endophthalmitis* 00 Retinal detachment1 (0.2%) Nonocular Headache14 (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.

17. 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

18. Anti-VEGF Trials Ranibizumab (Lucentis) – BRAVO and CRUISE Afilbercept (VEGF-Trap eye, Regeneron) – Galileo and Copernicus – Results pending J Lim

19. 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. 20 Mean Change from Baseline BCVA over Time to Month 12 0 2 4 6 8 10 12 14 16 18 20 024681012 Month Mean Change from Baseline BCVA (ETDRS Letters) Day 0–Month 5 Monthly Treatment Months 6–11 PRN 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

21. 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. 22 Mean Change from Baseline BCVA over Time to Month 12 -2 0 2 4 6 8 10 12 14 16 18 2468101207 +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 +7.3 Mean Change from Baseline BCVA (ETDRS Letters) Month Day 0–Month 5 Monthly Treatment Months 6–11 PRN Treatment

23. Key Study Eye Adverse Events Through Month 6 Adverse Events, n (%) Sham (n=129) Ranibizumab 0.5 mg (n=129) Any intraocular inflammation event5 (3.9)2 (1.6) Iridocyclitis00 Iritis3 (2.3)2 (1.6) Endophthalmitis00 Lens damage00 Cataract02 (1.6) Iris neovascularization9 (7.0)1 (0.8)* Neovascular glaucoma2 (1.6)0 Rhegmatogenous retinal detachment00 Retinal tear00 Vitreous hemorrhage9 (7.0) † 7 (5.4) *Reported as serious. † One vitreous hemorrhage was reported as serious.

24. 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

25. CRVO Summary CRVO treatment options – Steroids beneficial in phase 3 studies  SCORE Study: IVTA vs observation  OZURDEX Trials: dexamethasone vs sham – Anti-VEGFs  CRUISE: 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

26. Retinal Vein Occlusion 2010 Allen C. Ho, MD Wills Eye Institute Philadelphia acho@att.net