Diabetic Retinopathy Clinical Research Network Persistent Macular Thickening Following Intravitreous Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema (Post-Hoc Analyses from Protocol T) 1

Background Objective of DRCR.net anti-VEGF treatment regimen is to try to maximize visual acuity improvement while minimizing number of injections and number of visits Principles of DRCR.net anti-VEGF regimen: 6 monthly injections unless 20/20 and OCT “normal” Thereafter, continue anti-VEGF only if VA or OCT CST improves compared with last 2 injections – i.e., no injection if no DME or persistent but stable DME Resume anti-VEGF if VA or OCT worsen

Objective – Anatomic Outcomes Compare rates of persistent DME across different anti-VEGF agents at 24 weeks after 6 monthly injections

Bressler EYLEA APAC Training December 7, 2016 Persistent Diabetic Macular Edema DRCR.net Protocol T – Aflibercept Group Participation by Dr. Neil Bressler in this activity does not constitute or imply endorsement by the Johns Hopkins University, the Johns Hopkins Hospital, or the Johns Hopkins Health System.

Persistent Diabetic Macular Edema DRCR.net Protocol T Bressler EYLEA APAC Training December 7, 2016 Persistent Diabetic Macular Edema DRCR.net Protocol T How does this group differ from the eyes in which DME resolved for at least 2 consecutive visits by 6 months? ***41% in ranibizumab group with persistent DME at 24 weeks is very close to the 40% seen in Protocol I *Aflibercept = 32%; Bevacizumab = 66%; Ranibizumab = 41% *A vs. B, P<0.001; A vs. R, P = 0.05; R vs. B, P<0.001 Participation by Dr. Neil Bressler in this activity does not constitute or imply endorsement by the Johns Hopkins University, the Johns Hopkins Hospital, or the Johns Hopkins Health System.

Persistent DME at 24-week Visit Visual Acuity & OCT CST at Baseline Visit among Eyes with/without Persistent DME at 24-week Visit Persistent DME at 24-week Visit Baseline Visit Data   Yes No Afl (N=60) Bev (N=118) Ran (N=73) (N=130) (N=62) Ran (N=103) Median Baseline VA letter score 68 69 70 Approximate Snellen equivalent 20/50 20/40 Median Baseline CST, µm 412 413 427 365 327 355 ***Baseline CST also higher among eyes with persistent DME at 24 weeks in Protocol I

Visual Acuity Outcomes at 24-week Visit among Eyes with/without Persistent DME   Persistent DME at 24 weeks Yes No Afl (N=60) Bev (N=118) Ran (N=73) (N=130) (N=62) (N=103) Mean change in visual acuity* 9.9 8.8 8.0 13.2 9.6 12.3 ≥10-letter gain 45% 47% 37% 63% 52% 60% ≥10-letter loss 3% 2% 1% 0% *With vs. without persistent DME: Afl, P = 0.01; Bev, P = 0.58; Ran, P = 0.002

Persistent Diabetic Macular Edema DRCR.net Protocol T Bressler EYLEA APAC Training December 7, 2016 Persistent Diabetic Macular Edema DRCR.net Protocol T What happens to this group when injections are withheld starting at 24 weeks when OCT and VA no longer are improving, even if DME persists, unless worsening occurs *Aflibercept = 32%; Bevacizumab = 66%; Ranibizumab = 41% *A vs. B, P<0.001; A vs. R, P = 0.05; R vs. B, P<0.001 Participation by Dr. Neil Bressler in this activity does not constitute or imply endorsement by the Johns Hopkins University, the Johns Hopkins Hospital, or the Johns Hopkins Health System.

Chronic Persistent DME Over 2 Years No longer persistently thickened at 1 year A vs. B, P = 0.03 A vs. R, P = 0.41 R vs. B, P = 0.16 N=60 N=118 N=73 No longer persistently thickened at 2 years ***54% of ranibizumab eyes have chronic persistent DME at 2 years – similar to Protocol I (56%) Through 6 months, eyes with persistent central-involved DME 2-Year Estimates Rate of chronic persistent DME resolution higher with aflibercept compared with bevacizumab

Objective – Vision Outcomes Is it safe to stop anti-VEGF treatment for persistent but stable DME starting at 6 months? Outcomes of persistent but stable DME in Protocol T show what happens if one stops anti-VEGF treatment after 6 months and doesn’t switch to corticosteroids; (Note: focal/grid laser was added to persistent but stable DME if treatable lesions) Among eyes with persistent DME at 6 months, compare vision outcomes among eyes in which DME never resolved through 2 years vs. resolved at least once for 2 consecutive visits by 2 years

Visual Acuity Outcomes at 2 Years by Among Eyes With/Without Chronic Persistent DME Among eyes with Persistent DME at 24 weeks   Chronic Persistent DME through 2 y Yes No Afl (N=29) Bev (N=70) Ran (N=38) (N=30) (N=31) Mean change in visual acuity from baseline* 14.8 10.3 9.3 10.2 10.7 14.7 ≥10-letter gain 62% 51% 45% 63% 55% 66% ≥10-letter loss 0% 3% *NOTE – aflibercept VA is actually trending BETTER WITH chronic persistent DME *With vs. without chronic persistent DME: Afl, P = 0.05; Bev, P = 0.86; Ran, P = 0.04

Chronic Persistent DME through 2 y Injections & Laser Treatments Through 2 Years Among Eyes with/without Chronic Persistent DME Among eyes with Persistent DME at 24 weeks   Chronic Persistent DME through 2 y Yes No Afl (N=29) Bev (N=70) Ran (N=38) Afl (N=30) Bev (N=31) Ran (N=29) Median injections prior to 2 y* 15 18 14 17 Focal/grid laser treatment prior to 2 y* 59% 74% 66% 57% 81% 86% *No differences identified within treatment groups by presence of chronic persistent DME

Summary: Secondary Analyses of Protocol T – Chronic Persistent DME Persistent DME at 24 weeks more common with bevacizumab (66%) than aflibercept (32%) or ranibizumab (41%) Approximately half of eyes with aflibercept or ranibizumab with persistent DME at 24 weeks had resolution of DME by 2 years Among eyes with persistent DME at 6 months, with or without resolution of persistent DME through 2 years, approximately 50%-60% have ≥10 letter gain, <3% have ≥10 letter loss

Summary: Secondary Analyses of Protocol T – Chronic Persistent DME In aflibercept and ranibizumab groups, data suggest vision outcomes slightly worse for eyes with persistent DME compared with eyes without persistent DME through 24 weeks When following DRCR.net DME treatment protocol through 2 years, even in presence of chronic persistent DME, visual acuity gain is the norm, ≥2-line loss is uncommon Rate of chronic persistent DME resolving by 2 years is higher with aflibercept than bevacizumab No evidence to suggest that greater resolution in aflibercept group due to more injections or focal/grid laser than bevacizumab group

Thank You on Behalf of the Diabetic Retinopathy Clinical Research Network (DRCR.net) 15