The Diabetic Retinopathy Clinical Research Network ShortTerm Evaluation

The Diabetic Retinopathy Clinical Research Network Short-Term Evaluation of Combination Corticosteroid+Anti-VEGF Treatment for Persistent Central-Involved DME Following Anti-VEGF Therapy Protocol Chair: Raj Maturi, MD 1

Background: Persistent DME ØExperience from DRCR. net Protocol I • 52% of ranibizumab eyes didn’t achieve ≥ 2 vision-line improvement • ≥ 40% did not have resolution of retinal thickening (<250 µm) at year 2 • Eyes that remain edematous at 6 months and 1 year following ranibizumab treatment have been consistently thickened throughout the treatment 2 period.

Evidence from Clinical Trials of Beneficial Effects of Intravitreal Corticosteroids for DME Ø DRCR. net Protocol I • pseudophakic subgroup had a visual gain similar to the Ranibizumab groups Ø FAME study • Fluocinolone Acetonide demonstrated benefits over 3 years Ø MEAD study • benefit of dexamethasone intravitreal implant over three year treatment period Cataract and IOP rise are issues

Rationale Ø There is a need for alternative or additional treatments due to incomplete response to ranibizumab in about ½ the eyes. Ø 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. 4

Why This Study? Ø To assess short-term effects of combination corticosteroid+anti-VEGF therapy on OCT retinal thickness and visual acuity in comparison with that of continued anti-VEGF therapy alone in eyes with persistent DME and visual acuity impairment despite previous anti-VEGF treatment. Ø To provide more information needed for future conduct of a definitive phase III clinical trial. 5

Study Drugs Dexamethasone (OZURDEX®) Ranibizumab 0. 3 mg (LUCENTIS®) Ø Sustained-release polymer that provides 700 μg of dexamethasone Ø FDA-approved for uveitis and macular edema due to RVO, and for DME that have had (or will imminently have) cataract surgery Ø Provided by Allergan Inc. Ø Anti-human VEGF monoclonal antibody Ø FDA-approved for treatment of wet AMD, macular edema following RVO, and DME Ø Provided by Genentech Inc. 6

Dexamethasone Applicator 7

Dexamethasone Video 8

Dexamethasone Video 9

METHODS 10

Study Overview SHM VGF Week 0 VGF Week 4 VGF Week 8 VGF Week 12 VGF Week 16 Week 20 Week 24 Group A: Sham + Ranibizumab VGF Week 0 Week 4 VGF Week 8 Week 12 Group B: Dexamethasone+ Ranibizumab Enrollment Week 0 VGF Dex Run-In Phase (3 months) Assess Eligibility For Randomization Week 4 VGF Week 8 VGF Week 12 VGF Week 16 VGF Week 20 Week 24 VGF Dex Randomization Phase (6 months) 11

Study Eye Ø Both eyes can be enrolled if eligible for the run-in phase Ø Both eyes can be randomized if criteria met for randomization Ø Two eyes from the same participant will be randomized to different treatment arms 12

Study Sample Size A minimum of 75 study eyes in each group (from approximately 62 participants) 13

Major Eligibility Criteria Ø Age ≥ 18 years Ø Type 1 or type 2 diabetes Ø At least 1 eye meeting study eye eligibility criteria Ø No history of chronic renal failure requiring dialysis or kidney transplant Ø BP <180/110 Ø No history of cardiac event or stroke within 1 month prior to enrollment 14

Major Study Eye Eligibility Criteria Ø At least 3 injections of anti-VEGF drugs (aflibercept, bevacizumab, or ranibizumab) within the prior 20 weeks (5 months) Ø Visual acuity letter score ≤ 78 and ≥ 24 (20/32 to 20/320) Ø Central-involved DME on clinical exam Ø OCT CSF thickness within 8 days of enrollment § Zeiss Cirrus: ≥ 290 in women; ≥ 305 in men § Heidelberg Spectralis: ≥ 305 in women; ≥ 320 in men Ø No macular laser or PRP within 4 months or anticipated need for PRP in next 6 months Ø No previous history of glaucoma or steroid intraocular pressure response in either eye 15

Other Important Study Eye Exclusion Criteria Ø History of cataract extraction within 6 months prior to enrollment or anticipated need for cataract extraction within the study follow-up period Ø IOP ≥ 25 mm. Hg or history of open angle glaucoma Ø Sutured PC-IOL with ruptured post. Capsule Ø Pseudoexfoliation, zonular dehiscence or lens instability Ø Aphakia 16

Non-Study Eye Criteria Ø 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 17

Visit Schedule and Procedures Enrollment Run-In Randomization 4 w-24 w Visits (± 1 w) Window BCVA a ü ü ü Blood pressure ü ü Hb. A 1 cd OCT b Eye exam c ü ü ü ü a. both eyes at each visit; includes protocol refraction in study eye at each visit and the non-study eye at the randomization visit and 24 week visit b. study eye c. both eyes at enrollment and randomization and study eye only at each follow-up visit 18 d. does not need to be repeated if Hb. A 1 c is available from within the prior 3 months

Ø Overview Run-In Phase • All enrolled eyes are required to complete a 12 -week runin phase, where they receive 3 additional anti-VEGF injections Ø 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 Ø Visit Schedule • 4 weeks (± 1 week) • 8 weeks (± 1 week) • 12 weeks (± 1 week) – Randomization visit Ø A minimum of 21 days required between visits 19

Treatment During Run-in Phase Ø All study eyes will receive an injection of ranibizumab 0. 3 mg at enrollment, 4 weeks, and 8 weeks. Ø Injections must be at least 21 days apart. Ø If each injection is not given within window for any reason (e. g. AE, DME resolution), the eye will not continue in the study 20

Randomization Ø 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 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 Ø If above are not met, study eyes exit the study 21

Persistent DME at End of Run-in Phase ØCSF thickness on OCT meeting either one of the following two gender- and OCT machine-specific criteria: • Zeiss Cirrus o ≥ 290 in women o ≥ 305 in men • Heidelberg Spectralis o ≥ 305 in women o ≥ 320 in men 22

Study Treatment Groups Ø Participants with one study eye • Group A: Sham + intravitreal ranibizumab • Group B: Intravitreal dexamethasone + intravitreal ranibizumab Ø 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 23

Treatment On Day of Randomization Ø The ranibizumab injection must be given on the day of randomization. Ø The sham or dexamethasone injection will be given within 0 -8 days of the ranibizumab injection. Ø If the injections are given consecutively on the same day, • Group A: Give Sham injection first • Group B: Give Ranibizumab injection first Ø Dexamethasone injection is NEVER given first 24

Post-Randomization Treatment Evaluate VA and OCT at each protocol visit VA ≥ 84 (20/20 or Better) AND OCT CSF thickness < Cirrus: 290 ♀/ 305 ♂ Spectralis: 305 ♀/ 320 ♂ NO Protocol Injection(s) VA <84 (worse than 20/20) OR OCT CSF thickness ≥ Cirrus: 290 ♀/ 305 ♂ Spectralis: 305 ♀/ 320 ♂ Give Protocol Injection(s) * Retreatment at investigator’s discretion if AE occurs from prior injection * Non-protocol treatment for DME should not be given 25

About Treatment…. Ø If combination injections were not given at the 12 -week for any reason, combination injections should be given at the first visit at which retreatment criteria for injections are met (16 - or 20 -week visits). Ø Treatment at the 24 week visit is at investigator discretion. Ø The Protocol Chair’s approval must be obtained before treating the study eye with any DME treatment that is different from 26 the treatment detailed in the protocol.

Order of Combination Injections Must be Given 0 to 8 Days of Each Other 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. 27

OCT Machines ØOnly the following spectral domain machines are permitted • Zeiss Cirrus • Heidelberg Spectralis ØTime domain machines are not permitted ØSame machine as baseline (randomization) should be used in follow-up visits 28

Efficacy Outcomes at 24 Weeks Ø Primary: • Mean change in visual acuity letter score adjusted for baseline (randomization) Ø Secondary: • Visual Acuity o % of eyes with ≥ 10 and ≥ 15 letter increase or decrease o Area under the curve (AUC) from baseline • OCT o Change in CSF thickness adjusted for baseline o % ≥ 2 log. OCT step gain or loss in CSF o CSF thickness < spectral-domain value equivalent to 250 microns on Zeiss Stratus o AUC from baseline • Diabetic Retinopathy worsening or improvement on clinical exam 29

Safety Outcomes Injected Related Ø Ø Increased IOP Endophthalmitis Cataract Retinal Detachment Ø Intraocular Hemorrhage Ø Wound problems Ocular Drug-Related Ø Increased IOP Ø IOP-lowering treatment Ø Cataract Ø Migration of Ozurdex to anterior chamber Systemic Drug-Related Ø Cardiovascular Ø Cerebrovascular 30

The Diabetic Retinopathy Clinical Research Network Thank you 31