1. The Diabetic Retinopathy Clinical Research Network 11

2. Background: The Problem  52% of Protocol I ranibizumab eyes didn’t achieve ≥2 vision-line improvement, and more than 40% did not have resolution of retinal thickening (<250 µm) at year 2.  Protocol I data suggest that eyes that remain edematous at 6 months and 1 year following ranibizumab treatment have been consistently thickened throughout the treatment period.  21% percent of ranibizumab eyes still had retinal thickness ≥ 300 μm, with vision of 20/32 or worse at 1 year. 39% had persistent CST ≥300 μm during year 1 2

3. Studies have shown the benefits of intravitreal steroids for DME  Protocol I, pseudophakic subgroup had a visual gain similar to the Ranibizumab treated groups  FAME study of intravitreal fluocinolone demonstrated benefits over 3 years  MEAD study results show benefit of Ozurdex over three year treatment period Cataracts and IOP rise are issues

4. Dexamethasone May Help StudyDesign # Eyes SettingSummary Dutra, Ophthalmologica 2013 Retrospect. Review 58 “Refractory” DME Decrease in foveal thickness and increase in VA at 3 and 6 mo. Pacella, Clin Ophthalmol. 2013 Single center uncontrolled prospective study 20 DME ≥275 μm with “previous” anti-VEGF Improve in ret. thickness and VA 1-3 months then decline through 6 months Zucchiatti, Ophthalmologica 2012 Retrospec. interventional study 9 “Persistent” DME Improvement in VA and ret. Thickness maintained through 4 th month Maturi, et al. 2013 ASRS talk (submitted, 2014) Prospective controlled 40 DME – 88% with previous Avastin Edema much less in combo group. 4

5. Rationale  There is a need for alternative or additional treatments due to incomplete response to ranibizumab in about ½ the eyes.  Protocol I data showed that the pseudophakic subgroup achieved the same results as ranibizumab at 2 yrs (this was not a prespecified subgroup, however).  As intravitreal steroids have been shown to have a positive effect on DME in some eyes, despite safety issues, and might add benefit in eyes that are already receiving anti-VEGF, where benefits might outweigh risks. 5

6. Objectives  To assess short-term effects of combination steroid+anti-VEGF therapy on OCT retinal thickness and visual acuity in comparison with that of continued anti-VEGF therapy alone in pseudophakic eyes with persistent DME and visual acuity impairment despite previous anti- VEGF treatment.  To provide more information needed for future conduct of a definitive phase III clinical trial. 6

7. Rationale for a Phase II Trial  Currently, there are limited data on combination steroid+anti-VEGF injections for DME  A large treatment effect on pseudophakic eyes is needed before considering combination therapy as a long-term treatment in eyes at risk for development of cataract  Before embarking on a phase III study, we need: To determine whether the conduct of a phase III trial has merit based on anatomic and functional outcomes To estimate recruitment potential of a phase III trial To assess safety of combination steroid+anti-VEGF in eyes with persistent DME, removing confounding of cataract and cataract surgery 7

8. Study Drugs Dexamethasone (OZURDEX®)  Sustained-release biodegradable polymer matrix that provides 700 μg of preservative-free dexamethasone  FDA-approved for noninfectious post. uveitis and macular edema due to retinal vein occlusion  Provided by Allergan Inc. Ranibizumab 0.3mg (LUCENTIS®) 8  Anti-human VEGF monoclonal antibody  FDA-approved for treatment of wet AMD, macular edema following RVO, and DME  Provided by Genentech Inc.

9. Dexamethasone  Decreases inflammation by suppression of neutrophil migration, decreased production of inflammatory mediators, and reversal of increased capillary permeability, and suppresses normal immune response *  Onset of action * BRVO/CRVO: Improvement observed in 20% to 30% of patients within first 2 months following intravitreal injection  Duration of effect * BRVO/CRVO: 1-3 months (following onset of improvement)  Absorption * Systemic levels negligible in majority of patients ≤90 days following implant 9 * AccessPharmacy: McGraw-Hill Global Education

10. Dexamethasone  Size: 0.45 mm in diameter, and 6.5 mm in length  Administered through a single-use 22 gauge injection system  Common adverse events include * : Cataract (nuclear, cortical, PSC) (22%) Conjunctival hemorrhage (21%), Increased IOP (15%) Reduced VA (10%) Vitreous hemorrhage (10%)  Rare reported adverse events Migration to ant. chamber Endophthalmitis  DRCR.net investigators’ experience 88% have performed Dex. implant in clinical practice; of the 12% who haven't, 75% have performed a training Dex implant (pig or cadaver eye) 10 * Callanan et al; Ozurdex PLACID Study Group: Ophthalmology May 2012

11. METHODS 11

12. Study Design  Phase II, multicenter, controlled, participant-masked, clinical trial  Duration of Follow-up 12 Run-in Phase 12 Weeks Randomized Phase 24 Weeks Purpose To ensure that enrolled eyes truly have “persistent DME” with decreased visual acuity despite prior anti-VEGF therapy.

13. Study Overview 13 Week 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 0 Week 4 Week 8 Week 12 VGF Enrollment SHM VGF Dex VGF SHM Dex Group A: Sham + Ranibizumab Group B: Dexamethasone+ Ranibizumab Run-In Phase (3 months) Randomization Phase (6 months) Assess Eligibility For Randomization

14. Study Eye  Both eyes can be enrolled if eligible for the run-in phase  Both eyes can be randomized if criteria met for randomization  Two eyes from the same participant will be randomized to different treatment arms 14

15. Study Sample Size A minimum of 75 study eyes in each group (from approximately 62 participants) 15

16. Major Eligibility Criteria  Age ≥18 years  Type 1 or type 2 diabetes  At least 1 eye meeting study eye eligibility criteria  No history of chronic renal failure requiring dialysis or kidney transplant  BP <180/110  No history of cardiac event or stroke within 1 month prior to enrollment 16

17. Major Study Eye Eligibility Criteria  Pseudophakic  At least 6 injections of anti-VEGF drugs (aflibercept, bevacizumab, or ranibizumab) within the prior 36 weeks (9 months)  Visual acuity letter score ≤78 and ≥24 (20/32 to 20/320)  Central-involved DME on clinical exam  OCT CSF thickness within 8 days of enrollment  ≥340 on Zeiss Cirrus  ≥360 on Zeiss Stratus  No macular laser or PRP within 4 months or anticipated need for PRP in next 6 months  No previous history of glaucoma or steroid intraocular pressure response in either eye 17

18. Other Study Eye Exclusion Criteria  Substantial posterior capsule opacity likely to be decreasing visual acuity by 3 lines or more  History of major ocular surgery within 4 months of enrollment or anticipated within 6 in study, or any history of vitrectomy  History of cataract extraction within 6 months or YAG capsulotomy within 2 mo prior to enrollment  IOP ≥25 mmHg or history of open angle glaucoma  History of herpetic ocular infection  Sutured PC-IOL with ruptured post. capsule  Exam evidence of toxoplasmosis or pseudoexfoliation 18

19. Non-Study Eye Criteria  In subjects with only one study eye, the following must be met in the fellow non-study eye: IOP <25 mm Hg No history of open-angle glaucoma No history of steroid-induced IOP elevation that required IOP-lowering treatment No exam evidence of pseudoexfoliation 19

20. Enrollment Testing Procedures  E-ETDRS visual acuity testing at 3 meters in each eye within 8 days prior to enrollment Includes protocol refraction prior to VA testing  OCT on study eye within 8 days prior to enrollment and at least 21 days after any prior intravitreal anti-VEGF treatment  Ocular examination on each eye including slit lamp, measurement of intraocular pressure, lens assessment, and dilated ophthalmoscopy (within 8 days prior to enrollment)  Measurement of blood pressure 20

21. Run-In Phase  Overview All enrolled eyes are required to complete a 12-week run- in phase, where they receive 3 additional anti-VEGF injections  Objective To ensure that enrolled eyes truly have “persistent DME” despite prior anti-VEGF therapy when given up to 3 injections within the controlled environment of a study  Visit Schedule 4 weeks (±1 week) 8 weeks (±1 week) 12 weeks (±1 week) – Randomization visit  A minimum of 21 days required between visits 21

22. Run-in Phase Visits (4 and 8-week visit) Procedures  E-ETDRS visual acuity testing in each eye, including protocol refraction in the study eye  OCT on study eye  Ocular examination on study eye including slit lamp, measurement of intraocular pressure, lens assessment, and dilated ophthalmoscopy 22

23. Treatment During Run-in Phase  All study eyes will receive an injection of ranibizumab 0.3 mg at enrollment, 4 weeks, and 8 weeks.  Injections must be at least 21 days apart.  If an eye experienced adverse effects from a prior injection during the run-in phase precluding future injections or additional injections are otherwise contraindicated according to the investigator (e.g. DME is no longer present), the eye will not continue in the study 23

24. Randomization  At end of run-in phase, study eye(s) are randomized if: All 3 run-in visits and injections completed within ±10 days of the target visit date owebsite will force completion of final status form if, at any run-in visit, the participant comes in past the allowable window or the injection is missed Randomization visit is no more than 5 weeks from 8- week visit Has been ≥21 days since prior study injection VA letter score ≤78 and ≥24 (20/32 to 20/320) Definite central-involved DME on clinical exam Definition of “persistent DME” is met Confirmation that no exclusion criteria for enrollment have developed/occurred during run-in phase  If above are not met, study eyes exit the study 24

25. Persistent DME at End of Run-in Phase  CSF thickness on OCT meeting either one of the following two criteria: 1) ≥ 440 µm Zeiss Cirrus OR ≥ 460 µm on Heidelberg Spectralis1) ≥ 440 µm Zeiss Cirrus OR ≥ 460 µm on Heidelberg SpectralisOR 2) Zeiss Cirrus [340 - 439 μm] or2) Zeiss Cirrus [340 - 439 μm] or Heidelberg Spectralis [360 - 459 μm] Heidelberg Spectralis [360 - 459 μm] AND has not decreased from the prior AND has not decreased from the prior (8-week) visit by 10% or more (8-week) visit by 10% or more 25

26. Randomization Visit Procedures  E-ETDRS visual acuity (including protocol refraction) in each eye on day of randomization  OCT on study eye (on day of randomization)  Ocular examination on each eye including slit lamp, measurement of intraocular pressure, lens assessment, and dilated ophthalmoscopy (on day of randomization)  HbA1c  Measurement of blood pressure 26

27. Study Treatment Groups  Participants with one study eye Group A: Sham + intravitreal ranibizumab Group B: Intravitreal dexamethasone + intravitreal ranibizumab  Participants with two study eyes ( both eyes are eligible at the time of randomization ): One eye randomly receives Group A, and the other eye receives Group B  Randomization will be stratified by VA and OCT CSF thickness improvement during run-in phase 27

28. Treatment On Day of Randomization  The ranibizumab injection must be given on the day of randomization.  The sham or dexamethasone injection will be given within 0-8 days of the ranibizumab injection.  If the injections are given consecutively on the same day, Group A: Give Sham injection first Group B: Give Ranibizumab injection first  Dexamethasone injection is NEVER given first 28

29. Post-Randomization Treatment 29 Evaluate VA and OCT at each protocol visit VA ≥84 (20/20 or Better) AND OCT CSF thickness < Cirrus: 290 ♀ / 305 ♂ Spectralis: 305 ♀ / 320 ♂ VA <84 (worse than 20/20) OR OCT CSF thickness ≥ Cirrus: 290 ♀ / 305 ♂ Spectralis: 305 ♀ / 320 ♂ NO Protocol Injection(s) Give Protocol Injection(s) * Retreatment at investigator’s discretion if AE occurs from prior injection * Non-protocol treatment for DME should not be given

30. Injections 30 Rand Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Rand Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 SHM VGF SHM VGF Dex VGF Dex VGF Group A: Sham + Ranibizumab Group B: Dexamethasone + Ranibizumab Within 0- 8 days of each other Within 0- 8 days of each other

31. About Treatment….  If combination injections were not given at the 12-week (post random.) for any reason, combination injections should be given at the first visit at which retreatment criteria for injections are met (16- or 20-week visit)  Treatment at the 24 week visit is at investigator discretion.  The Protocol Chair’s approval must be obtained before treating the study eye with any DME treatment that is different from the treatment detailed in the protocol. 31

32. Order of Combination Injections 32 Group A (Ranibizumab alone) SHAM FIRST RANIBIZUMAB Group B (Combination) RANIBIZUMAB DEXAMETHASONE Group A (Ranibizumab alone) Random. day: RANIBIZUMAB Day 1-8: SHAM Group B (Combination) Random. day: RANIBIZUMAB Day 1-8: DEXAMETHASONE If the participant returns after a protocol visit specifically to receive a study injection, testing prior to the injection is at investigator discretion. Must be Given 0 to 8 Days of Each Other

33. OCT Machines  Only the following spectral domain machines are permitted Zeiss Cirrus Heidelberg Spectralis  Time domain machines are not permitted  Same machine as baseline (randomization) should be used in follow-up visits 33

34. Efficacy Outcomes at 24 Weeks  Primary: Mean change in visual acuity letter score adjusted for baseline (randomization)  Secondary: Visual Acuity o% of eyes with ≥10 and ≥15 letter increase or decrease oArea under the curve (AUC) from baseline OCT oChange in CSF thickness adjusted for baseline o% ≥2 logOCT step gain or loss in CSF oCSF thickness < spectral-domain value equivalent to 250 microns on Zeiss Stratus oAUC from baseline Diabetic Retinopathy worsening or improvement on clinical exam 34

35. Safety Outcomes Ocular Drug-Related  Increased IOP  IOP-lowering treatment  Migration of Ozurdex to anterior chamber 35 Injected Related  Increased IOP  Endophthalmitis  Retinal Detachment  Intraocular Hemorrhage  Wound problems Systemic Drug-Related  Cardiovascular  Cerebrovascular

36. Study Challenges  Recruitment 25% of all protocol T eyes were pseudophakic at baseline About 40% of ranibizumab eyes still have macular edema (≥300 µm) after 7 injections Projected 7 participants recruited/month oRecruitment: 18 months  Safety Combination injection in one or two eyes 36

37. The Diabetic Retinopathy Clinical Research Network Thank you 3737