The Diabetic Retinopathy Clinical Research Network Prompt PRP vs Ranibizumab+Deferred PRP for PDR Study Jennifer K. Sun, MD for the Diabetic Retinopathy Clinical Research Network Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817 

Disclosures Dr. Sun has served as a consultant for Abbott Labs, EISAI, Genentech, and Novartis She receives research support from Boston Micromachines, Genentech, and Optovue This presentation will discuss off-label use of ranibizumab for proliferative diabetic retinopathy

Anti-VEGF Treatment and DR Severity Clinical trials of anti-VEGF treatment for DME have clearly demonstrated a beneficial effect of anti-VEGF on overall DR severity level DRCR.net Protocol I Change in DR severity from baseline to 1-year visit* Sham +Prompt Laser Ranibizumab Laser or Deferred Laser P value for comparison with Sham Baseline Severity: Severe NPDR or worse N = 83 N = 121 Improved by ≥2 levels 19% 28% 0.04 Worsened by ≥2 levels 8% 1% 0.03 *Photos were missing or ungradeable for 61 eyes in the sham+prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone+prompt laser group Change from baseline to 1-year visit* Sham +Prompt Laser Ranibizumab Laser or Deferred Laser P value for comparison with Sham Baseline Severity: Moderately Severe NPDR or Better N = 150 N = 182 Improved by ≥2 levels 4% 25% <.001 Worsened by ≥2 levels 7% 3% 0.08 3

Protocol I: PDR-related Outcomes During 1 Year of Follow-up Sham N = 293 Ranibizumab N = 375 Triamcinolone N = 186 Reported vitreous hemorrhage OR received PRP 8% 3% P Value for comparison with sham -- 0.002 0.02 Eyes assigned to the ranibizumab groups or the triamcinolone+prompt laser groups, respectively, appeared less likely to have a vitreous hemorrhage or receive panretinal photocoagulation than the sham+prompt laser group (3% [P=0.002] and 3% , [P=0.02] respectively vs. 8%) during the first year of follow up.

Cumulative Probability of Worsening of Retinopathy for Eyes with Non-PDR at Baseline 1-Year 2-Years 3-Years NMB: Edited title

Cumulative Probability of Worsening of Retinopathy for Eyes with PDR at Baseline 1-Year 2-Years 3-Years NMB: Edited title

Median (Quartile) # of Injections Eyes with Non-PDR at Baseline   Ranibizumab + prompt laser Ranibizumab + deferred laser Traimcinolone + prompt laser Non-Proliferative Diabetic Retinopathy at Baseline Year 1* 8 (6, 10) 3 (2, 3) Year 2† 2 (0, 3) 2 (0, 5) 1 (0, 2) Year 3§ 1 (0, 4) Total§ 12 (9, 14) 10 (8, 16) 5 (3, 8) *Only included eyes that completed 1-year visit †Only included eyes that completed 2-year visit prior to protocol change §Only included eyes that completed 3-year visit prior to protocol change NMB: Edited title; made font larger

Median (Quartile) # of Injections Eyes with PDR at Baseline   Ranibizumab + prompt laser Ranibizumab + deferred laser Traimcinolone + prompt laser Proliferative Diabetic Retinopathy at Baseline Year 1* 9 (6, 11) 10 (8, 11) 3 (2, 4) Year 2† 1 (0, 6) 5 (1, 8) 1 (0, 2) Year 3§ 0 (0, 2) 1 (0, 4) 0 (0, 1) Total§ 11 (7, 19) 17 (9, 22) 5 (3, 7) *Only included eyes that completed 1-year visit †Only included eyes that completed 2-year visit prior to protocol change §Only included eyes that completed 3-year visit prior to protocol change NMB: Edited and increased font

RISE/RIDE: Risk of PDR Outcomes in Sham vs Ranibizumab Groups Time to First Progression to PDR Outcome 3 fold higher risk in sham group Months Cumulative probabilities calculated using the Kaplan-Meier method. Progression was defined by (1) progression from NPDR (DR severity level < 60) at baseline to PDR (DR severity level  60) at a later time point, (2) need for PRP laser, (3) vitreous hemorrhage (AE or slit lamp grade 0 at baseline to > 0 at a later time point, (4) cases identified by ophthalmoscopy, (5) vitrectomy, (6) iris neovascularization AE, or (7) retinal neovascularization AE. 1 month = 30 days. AE, adverse event; PRP, panretinal photocoagulation.

How Often & How Long to Continue Anti-VEGF for PDR? Baseline 8 mo after Last Anti-VEGF 8 Days after Anti-VEGF

Safety of Anti-VEGF in Eyes with PDR Endophthalmitis Arevalo JF, Maia M, Flynn HW Jr, Saravia M, Avery RL, Wu L, Eid Farah M, Pieramici DJ, Berrocal MH, Sanchez JG. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol. 2008 Feb;92(2):213-6. Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012 Feb;153(2):204-208. 11 Bhavsar AR, et al. Arch Ophthalmol. 2012 Jun;130(6):809-10. From Goldberg RA, Am J Ophthalmol. 2012;153(2):204-208.

Safety of Anti-VEGF in Eyes with PDR Traction detachment In most eyes with PDR without traction threatening the macula, anti-VEGF appears safe and well-tolerated DRCR.net Protocol J Intravitreal Saline Intravitreal Ranibizumab Traction and/or Rhegmatogenous RD on Clinical Exam 6 (5%) 5 (4%) Traction and/or Rhegmatogenous RD on Ultrasonography 3 (2%) RD on Adverse Event Form 9 (7%) 7 (5%) Traction and/or Rhegmatogenous RD on Any of the 3 Above 10 (8%) 11 (8%) From Arevalo JF, et al. Br J Ophthalmol. 2008;92(2):213-6. Arevalo JF, Maia M, Flynn HW Jr, Saravia M, Avery RL, Wu L, Eid Farah M, Pieramici DJ, Berrocal MH, Sanchez JG. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol. 2008 Feb;92(2):213-6. Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012 Feb;153(2):204-208. 12

Background Current standard treatment for PDR is panretinal photocoagulation (PRP) 96% reduction in severe vision loss with timely therapy! BUT, PRP is Inherently destructive Adverse effects on visual function Would initial treatment of PDR with intravitreal anti-VEGF delay or prevent need for PRP? 13

Protocol S: Study Objective and Treatment Groups To determine if visual acuity outcomes at 2 years in eyes with PDR (with or without concurrent DME) that receive anti-VEGF therapy with deferred PRP are non-inferior to those in eyes that receive prompt PRP. Prompt PRP 0.5mg ranibizumab with deferred PRP 1414

Important Secondary Objectives (assuming visual acuity outcomes are non-inferior) Compare visual function outcomes (including Humphrey visual field testing and study participant self-reports of visual function) Determine percent of eyes not requiring PRP when intravitreal anti-VEGF is given in the absence of prompt PRP Compare safety outcomes Perform cost effectiveness analysis 15

Major Inclusion Criteria Age ≥ 18 years Type 1 or 2 diabetes PDR for which PRP is planned but in the investigator’s opinion can be deferred for at least 4 weeks if an intravitreal anti-VEGF injection is given Visual acuity (Snellen equivalent) 20/320 or better Note: eyes with or without DME may be enrolled 16

Major Exclusion Criteria Systemic Significant renal disease BP > 180/110 Cardiac event or stroke within 4 months Study eye Prior PRP Tractional retinal detachment involving the macula NV of the angle History of intravitreal anti-VEGF within past 2 months History of corticosteriod in the past 4 months

Follow-up Schedule Both groups: Visits every 16 weeks IVR+Deferred PRP group: Visits every 4 weeks to evaluate for ranibizumab…interval may only be extended if PRP is given Baseline to 1 Year Both groups: Visits every 16 weeks IVR+Deferred PRP group: Visit every 4-16w to evaluate for ranibizumab…interval is extended if injections for PDR continually deferred Primary outcome visit at 2 years 1 Year to 3 Years 4 to 5 Years Annual visits for data collection only Treatment as part of usual care

Treatment for DME If DME present at baseline causing VA loss, ranibizumab must be given If DME develops during follow-up, treatment is at investigator discretion using study ranibizumab and/or focal/grid laser with Protocol I retreatment criteria as guidelines Additional follow-up visits for DME retreatment are at the discretion of the investigator (not part of visit schedule) 19

First 2-Year (Primary Outcome) Visit Review of Primary Outcome Data Study Timeline First 2-Year (Primary Outcome) Visit Review of Primary Outcome Data Last 1-Year Visit Last 2-Year Visit Last 5-Year Visit Dec 2013 Feb 2014 Dec 2014 Feb 2015 Dec 2017

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) 21