1. 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

2. Diabetes Atlas, 3rd ed, International Diabetes Federation, 2006. World Diabetes Trends

3. CDC Web site. www.cdc.gov; Mokdad et al. Diabetes Care. 2000;23:1278-1283; J Am Med Assoc. 2001;286:10; ADA. 19901995 2001 By the year 2025 an estimated 30 million Americans will be living with diabetes No Data 10% Diabetes Trends Among US Adults (Includes Gestational Diabetes) BRFSS, 1990,1995, and 2001

4. Percentage of Diabetic Macular Edema Increases as NPDR Progresses % Patients With Macular Edema NPDR: nonproliferative diabetic retinopathy. N=1585 n=228 n=114 n=47 Figure reproduced from Henricsson M et al. Acta Ophthalmol Scand. 1999;77:218–223. Increased Risk of Diabetic Macular Edema

5. ETDRS Laser Photocoagulation: Prevented Moderate Visual Loss * 1 ETDRS. Arch Ophthalmol 1995;113:1144-1145. 50% reduction in moderate visual loss In CSME and Less Severe DR 1 % of Patients with Moderate Visual Loss Years after randomization Focal + FU Scatter (N=299) Deferral (N=611) *3-step loss on ETDRS chart 1 2 34 33% 13% 60 50 40 30 20 10 0  P<0.01  P<0.001

6. 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 1 AAO. 2003. Preferred Practice Pattern ® : Diabetic retinopathy 2003; 2 ETDRS Research Group. Ophthalmology 1991;98(5 suppl):766-785. Focal

7. After Grid Laser Treatment 3 Months

8. Initial Acuity Worse Than 20/40 Years of Follow-up % Eyes with Vision Gain Improvement in Visual Acuity > 1 Line *Unpublished data Less than 3% of patients improve at least 15 letters at 3 years

9. Pharmacologic Targets to Inhibit Diabetic Retinopathy  Specific growth factors1 IGF-1 inhibition VEGF inhibition PEDF expression  Intracellular signaling1 PKC inhibition MAPK pathway inhibition  Extracellular matrix and integrin factors1 Integrin inhibition Matrix metalloproteases inhibition Steroid compounds  Inflammation2  Reactive oxygen species2  Nonenzymatic glycation inhibition2  Nitric oxide synthase2 1 Speicher MA et al. Expert Opin Emerg Drugs 2003;8:239-250; 2 Frank RN. NEJM 2004;350:48-58.

10. Diabetic Macular Edema Contributing Anatomical Changes Diabetic Macular Edema Vision loss Chronic inflammation Leukostasis Capillary nonperfusion Pericyte loss Thickened basement membrane Hypoxia Tight junctions Antioxidant capacity of RPE Taurine transport of RPE Corticosteroid x x x x x x

11. Intraocular Steroids in Development NOVA63035 NVG Posurdex Allergan Kenalog BMS I-Vation SurModics Retaane Alcon Retisert B&L Medidur Alimera API Dexamethasone palmitate DexamethasoneTriamcinolone acetonide TriamcinoloneAnecortave acetate Fluocinolone acetonide Administration Injectable emulsion Injectable implant Injectable suspension ImplantJuxtascleral injection ImplantInjectable implant Duration 6-9 months1-3 months 12 months6 months30 months18-36 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

12. 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

13. Primary Outcome: Mean Change in Visual Acuity at 2 Years Mean Change in VA (letter score) Laser N=330 1 mg N=256 4 mg N=254 +1-2-3 Pairwise Comparisons Mean Difference*P value* Laser vs. 1 mg+3.5 letters0.02 Laser vs. 4 mg+4.6 letters0.002 1 mg vs. 4 mg+1.1 letters0.49 * Adjusted for baseline VA and prior focal/grid laser

14. 14 Months Visual Acuity Score 20/80 20/50 20/32 20/40 20/63 0 12 16 20 24 4 828 32 36 Mean Visual Acuity Over 3 Years in All Eyes

15. Baseline Va# Eyes Laser, 1 mg, 4 mg 20/32 - 20/63189 149 149 20/63 -1 - 20/200 +1 129 94 92 20/200 – 20/320 -1 12 13 13 Protocol B: Subgroup Analysis Table 5. Change in Visual Acuity at 2-Year Primary Outcome among Subgroups >10-Letter Worsening (%) >10-Letter Improvement (%) Laser1mg4mgLaser1mg4mg 232833231716 122426433339 17150424677 Baseline Data2 Year Data

16. FAME Phase III Study 24 Month Results

17. 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 Drug Delivery Insert Iluvien is under review by the FDA, it is not approved in the United States.

18.  Near zero-order kinetics  Submicrogram daily dose delivery  Posterior point of release Active compound:Fluocinolone acetonide (FAc) Total dose:0.19 mg Approximate daily release:0.2 µg/d and 0.5 µg/d Method of delivery: Intravitreal Injection Approximate duration of action:At least 2 years Kane FE, et al. Expert Opin Drug Deliv. 2008;5:1039-1046. Iluvien. Draft package insert. Iluvien Technology ®

19. Primary Efficacy Analysis: Percent of Patients With ≥ 15-Letter Improvement Over Baseline 28.6% 28.7% 16.2% 03691215182124 0 5 10 15 20 25 30 35 40 Time (Months) Patients (%) Sham (n = 185) 0.2 µg/d FAc (n = 376) 0.5 µg/d FAc (n = 395) Alimera Sciences. Data on File. P =.002 for both doses The 0.2 µg/d dose of FAc has been submitted for regulatory approval.

20. Ciulla T, et al. Data presented at Association for Research in Vision and Ophthalmology. Ft Lauderdale, FL. May, 2010. P =.002 40 35 30 25 20 15 10 5 0 Baseline369121518212427 17.5% 39.8% 30 Patients (%) Time (Months) % of Patients with ≥ 15-Letter Improvement in BCVA Over Baseline Through 30 Months Sham (n = 185) 0.2 µg/d FAc (n = 376) n = 63 n = 123

21. Cataract-Related Events Subjects, % (Study Eye) Sham (N = 121) Low Dose (N = 235) High Dose (N = 265) Cataract considered as an AE * 46.3%80.0%87.5% Cataract extraction performed*23.1%74.9%84.5% * Phakic subjects only. Alimera Sciences. Data on File. Subjects, % (Study Eye) Sham (N = 185) Low Dose (N = 375) High Dose (N = 393) IOP > 30 mm Hg2.7%16.3%21.6% Trabeculoplasty0.0%1.3%2.5% Incisional IOP lowering surgery0.5%3.7%7.4% IOP-Related Events

22. Mean BCVA Letter Change in Iluvien (0.2 µg/d FAc) Patients Months Mean Change From Baseline in BCVA Letter Score Alimera Sciences. Data on File.

23. VEGF in Human Ocular Fluids Aiello et al. NEJM 1994;331:1480-7.

25. 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.

26. DA VINCI: VEGF trap versus laser Mean Change in Visual Acuity ETDRS letters *P < 0.0001 ^ P = 0.0085 + P = 0.0004 † P = 0.0054 vs. laser (ANCOVA) No statistical differences among VTE arms. LOCF analysis; n=44 (laser, 0.5q4, 2q4); n=42 (2q8); n=45 (2prn) 2q4* 11.4 0.5q4 † 8.6 2q8^ 8.5 2prn + 10.3 Laser 2.5 Week

27. 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)Sham + Prompt Laser (N = 293) Ranibizumab + Prompt Laser (N = 187)Ranibizumab + Prompt Laser (N = 187) Ranibizumab + Deferred Laser (N = 188)Ranibizumab + Deferred Laser (N = 188) Triamcinolone + Prompt Laser (N = 186)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.

28. DRCR Protocol I  Visual acuity 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.

31. BOLT  Prospective, randomized, masked, single-center, 2-year, 2-arm clinical trial.  Randomized to: Laser group (N = 38).Laser group (N = 38). Bevacizumab group (N = 42).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):1078- 1086.e2.

32. BOLT * * * * * = p < 0.05

33. BOLT Bevacizumab groupLaser group Mean number of treatments 9 injections3 lasers

34. 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