Randomized Clinical Trial Jeffrey G. Gross, M.D. for the DRCR Network Protocol S Five-Year Outcomes of Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: Randomized Clinical Trial Jeffrey G. Gross, M.D. for the DRCR Network DRCR.net

Financial Disclosures Funding/Support: Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services. Additional Contributions: Genentech Inc. provided the ranibizumab and clinical site funding. A complete list of all DRCR.net investigator financial disclosures can be found at www.drcr.net.

Randomized, multi-center clinical trial (55 Sites) Study Design Randomized, multi-center clinical trial (55 Sites) Study eye(s) meeting all of the following criteria (a participant can have 2 study eyes): PDR No history of PRP Best corrected visual acuity letter score ≥24 (~Snellen equivalent 20/320 or better) Eyes with or without central-involved DME were eligible Primary Objective: Compare the efficacy and safety of PRP with that of intravitreous ranibizumab (0.5-mg in 0.05 mL) for proliferative diabetic retinopathy (PDR)

Published Two-Year Outcomes Primary outcome: mean change in VA with ranibizumab no worse than (non-inferior to) PRP at 2 years Secondary outcomes: Favored ranibizumab: Superior mean VA over course of 2 years (AUC) Less peripheral visual field loss 3-fold decrease in vitrectomies Decreased development of central-involved DME with vision impairment Cost effective when DME IS present and causing vision impairment Favored PRP: Fewer visits Fewer injections Cost effective when DME causing vision impairment IS NOT present initially

Visit Completion 394 Eyes Randomized (305 Participants) Ranibizumab Group N = 191 PRP Group N = 203 Baseline 2-Years Excluding Deaths 88% 86% 5-Years Excluding Deaths 69% 65% 5-Years Overall 61% 61%

Ocular Baseline Characteristics at Enrollment All Eyes Had PDR Per Investigator Determination Prior to Randomization Ranibizumab Group (N = 191) PRP (N = 203) DR Severity Confirmation by Reading Center* NPDR 10% 13% Mild to moderate PDR 52% 49% High risk PDR to advanced PDR 38% 37% Presence of CI-DME with VA loss**, % 22% 23% Required ranibizumab at baseline *Diabetic retinopathy level data were missing for 2 in the ranibizumab group and 4 in the PRP group. ***Eyes with VA letter score ≤ 78 (20/32 or worse) AND OCT CST ≥ machine and gender specific thresholds

Mean Number of Injections 5-Year Completers Only Ranibizumab Group (N = 117) PRP Group (N = 123) Year 1  7.1 2.3  Year 2 3.3 1.1

Mean Number of Injections 5-Year Completers Only Ranibizumab Group (N = 117) PRP Group (N = 123) Year 1  7.1 2.3  Year 2 3.3 1.1 Year 3 3.0 0.9 Year 4 2.9 0.6 Year 5 0.4 Cumulative Through 5 Years 19.2 5.4

Number of Intravitreous Injections by Year Ranibizumab Group, 5-Year Completers Only

Panretinal Photocoagulation Ranibizumab Group (N = 191) PRP Group (N = 203) Received PRP During Follow-up, N (%) 26 (14%) 103 (51%) Received PRP prior to 104 Weeks, N 6% 45% Received PRP after 104 Weeks, N 8% 15% Received PRP during Vitrectomy, N 9% 14% Received PRP outside of Vitrectomy, N 5% 44%

Mean Changes in VA From Baseline Over Time - Overall Cohort Adjusted Mean Difference at 5 Years: +0.6 letters 95% Confidence Interval: (-2.3, +3.5), P = .68 +3.1 +3.0 N = 191 N = 117 N = 203 N = 123

Mean Changes in VA From Baseline Over Time for 5-Year Completers Only 5-Year AUC Difference: +1.6 letters 95% Confidence Interval: (0, 3.2), P = .05 +3.3 +1.5 N = 117 of 191 N = 123 of 203 Outlying values were truncated to 3 SD from the mean

Visual Acuity at 5-Years Ranibizumab (N = 117) PRP (N = 123) Visual Acuity Mean letter score 80 81 ~Snellen Equivalent, Mean 20/25 Median letter score (25th, 75th percentile) 84 (89, 78) (89, 77) ~Snellen Equivalent, Median 20/20 (20/16, 20/32)

Change in VA Letter Score at 5-Years Ranibizumab (N = 117) PRP (N = 123) Adjusted Difference (95% CI) ≥ 15 letters improvement, % 26% 23% 1% (-12%, 15%) ≥ 10 letters improvement, % 52% 41% 6% (-10%, 21%) ≥ 10 letters worsening, % 9% -3% (-11%, 5%) ≥ 15 letters worsening, % -1% (-7%, 5%)

Mean Change in Cumulative Visual Field Total Point Score (30-2 + 60-4) - Overall Cohort Outlying values were truncated to 3 SD from the mean

Mean Change in Cumulative Visual Field Total Point Score (30-2 + 60-4) - Overall Cohort -330 -527 5-Year Adjusted Mean Difference: 208 dB 95% Confidence Interval (-9, 408), P = .04 N = 81 N = 41 N = 86 N = 38 Outlying values were truncated to 3 SD from the mean

Diabetic Retinopathy on Fundus Photographs at 5 Years* Ranibizumab (N = 90) PRP (N = 93) Without PDR (≤ level 60), % 43% 37% With Regressed NV (level 61A), % 28% 33% With Active NV (≥ level 61B), % 29% 30% Improved from PDR (≥ level 61) to NPDR (≤level 53)**, % N/A Without DR (≤ level 20)*, % 10% Improved ≥2 steps in DR severity on fundus photos at 5 years**, % 46% *Observed data only, only include eyes with active NV at baseline as graded by reading center. **Not applicable or cannot determine for PRP group.

DR Adverse Events: Over 5 Years Ranibizumab (N = 117) PRP (N = 123) Adjusted Difference (95% CI) Any Retinal detachment, % 6% 15% -9% (-14%, -4%) Retinal Detachment involving Center of the Macula, % 1% 4% -3% (-7%, 0%) Neovascular Glaucoma, % 3% -2% (-6%, 2%) Neovascularization of the Iris, % (-1%, 3%) Vitreous Hemorrhage, % 48% 46% 2% (-6%, 11%) Vitrectomy, % 11% 19% -7% (-14%, -1%)

Ocular Adverse Events Ranibizumab (N = 191) PRP (N = 203) P-Value Number of Injections 3132 981 Endophthalmitis, % 0.03% Inflammation, % 2% 5% .05 Retinal Tear, % <1% Cataract Surgery, % 16% 19% .62 Elevated IOP, % 18% .58 Event defined as occurring at least once through 5 years.

Systemic Adverse Events 2 Study Eyes (N = 89) Ranibizumab (N = 102) PRP (N = 114) Global P-Value Nonfatal Myocardial Infarction 3% 6% 4% .64 Nonfatal Stroke .65 Death due to potential vascular cause or unknown cause 7% 2% .13 Any APTC Event* 13% 18% 11% .31 Event defined as occurring at least once through 5 years. *Anti-platelet Trialists’ Collaboration Arterial Thromboembolic Events.

Summary: 5-Year Results Visits, Injections, Safety 66% of participants (excluding death) completing 5-year visit Ranibizumab = 117 PRP = 123 Median number of visits* Ranibizumab = 43 PRP = 21 Mean number of injections Ranibizumab = 19 (Mean of 3 per year- Years two through five) PRP = 5 APTC events appeared similar between groups. No ocular safety concerns were identified. * Counting participants with one study eye only

Summary: 5-Year Results Central Visual Acuity Mean change in VA letter score at 5 years Ranibizumab = 3.1±14.3 letters PRP = 3.0±10.5 letters +3.1 +3.0 Difference = 0.6 (95% CI: -2.3 to 3.5; P = .68)

Summary: 5-Year Results Central Visual Acuity Mean change in VA letter score over 5 years Ranibizumab = 3.3±9.5 letters PRP = 1.5±7.5 letters +3.3 +1.5 Difference = 1.6 (95% CI: 0 to 3.2; P = .05)

Summary: 5-Year Results Peripheral Visual Field* Mean change in cumulative visual field total point score (HFA 30-2 + 60-4) Ranibizumab = -330 ± 645 dB (N = 41) PRP = -527 ± 635 dB (N = 38) Difference = 208 (95% CI: 9 to 408) In the subgroup of eyes that participated in this ancillary study -330 -527 Visual field loss present in both groups from years 2 - 5

Summary: 5-Year Results Complications Development of Vision-Impairing DME Among Eyes Without Vision-Impairing (better than 20/32) DME at Baseline Ranibizumab = 22% PRP = 38% Hazard Ratio = 0.4 (95% CI: 0.3 to 0.7) 22% 38% P < .001

Summary: 5-Year Results Complications Development of Retinal Detachment Ranibizumab = 7% PRP = 18% Hazard Ratio = 0.4 (95% CI: 0.2 to 0.8) 7% 18% P = .004

Conclusions: Five-Year Outcomes Mean change in VA with ranibizumab similar to PRP at 5 years Loss to follow-up was relatively high in both groups Other outcomes: Favored PRP: Fewer visits Fewer injections Favored ranibizumab: Decreased development of central-involved DME with vision impairment Decreased development of retinal detachments Both Groups: Substantial VA loss rare (6% in each group) Visual field loss progressed in both groups in years 2-5; difference between groups diminished Vitreous hemorrhage in almost 50% of both groups

Clinical Relevance of 5-Year Outcomes from DRCR Network Protocol S These findings support either ranibizumab or PRP as viable treatments for PDR Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for PDR. What’s in your toolbox?

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) Slide-Set Available at www.drcr.net A complete list of all DRCR.net investigator financial disclosures at www.drcr.net. Full protocol available on clinicalTrials.gov (NCT01489189)