1. The Diabetic Retinopathy Clinical Research Network 5-Year Follow-up of a Randomized Trial Evaluating Ranibizumab Plus Prompt versus Deferred Laser for Diabetic Macular Edema

2. Background: Protocol I  Previously reported intravitreous ranibizumab with prompt or deferred laser more effective through at least 2 years compared with laser  3-year comparison of ranibizumab groups concluded prompt laser was no better and possibly worse than deferred laser  Study extended to 5 years to assess longer- term course of DME treated with ranibizumab  To report the comparison of ranibizumab groups through 5 years 2

3. 3 Completion of 5 Year Visit Ranibizumab + Prompt Laser Ranibizumab + Deferred Laser Eyes originally randomized N = 180N = 181 Completed 5 Year (excl deaths)69% (76%)61% (74%) Death prior to 5 Year9%17% Discontinued/Dropped prior to 5 Year Includes pts who did not consent to extension 21%22% Eyes in the extension study N = 132N = 136 Completed 5 Year (excl deaths)94% (97%)82% (92%) Death prior to 5 Year3%11% Dropped prior to 5 Year3%7%

4. Ranibizumab + prompt laser Ranibizumab + deferred laser Completers Non- completersCompleters Non- completers N = 124N = 56N = 111N = 70 Median Age63656365 Prior PRP33%11%21%20% Lens Status Phakic73%61% 75%63% Median VA (letter score) 65 6762 Median CST (µm)375372394378 Mild/Moderate/HR PDR34%27%24%37% 4 Baseline Characteristics of Completers vs Non-Completers

5. 5 Visits Prior to 5 Year * Ranibizumab + Prompt Laser N=124 Ranibizumab + Deferred Laser N=111 Median # of visits in year 1 13 Median # of visits in year 2 810 Median # of visits in year 3 78 Median # of visits in year 4 56 Median # of visits in year 5 45 Median # of visits prior to 5 year visit 3840 * Only eyes that completed 5 year visit

6. Treatments 6

7. 7 Injections Prior to 5 Year * *Only eyes that completed 5 year visit Ranibizumab + Prompt Laser N=124 Ranibizumab + Deferred Laser N=111 Median # of injections in year 1 89 Median # of injections in year 2 23 Median # of injections in year 3 12 Median # of injections in year 4 01 Median # of injections in year 5 00 Median # of injections prior to 5 year visit 1317 % of eyes that received >1 injection in year 4 46%55% % of eyes that received >1 injection in year 5 38%48%

8. 8 Focal/Grid Laser Prior to 5 Years * Ranibizumab + Prompt Laser N = 124 Ranibizumab + Deferred Laser N = 111 % of eyes that did NOT receive laser treatments prior to the 5 year visit 056% Median # laser treatments prior to the 5 year visit 30 * Only eyes that completed 5 year visit

9. Visual Acuity 9

10. Mean Change in Visual Acuity * at Follow-up Visits 10 +7.2 +9.8

11. 11 Change in Visual Acuity at 5 Years Change in Visual Acuity (letters) Ranibizumab + Prompt Laser N = 124 Ranibizumab + Deferred Laser N = 111 Estimated Means*+7.2+9.8 Estimated Diff* (95% CI)* [P-Value]* [adjusted P-Value]† -2.6 (-5.5 to +0.4) [P = 0.09] [P = 0.15] *truncated to ± 30 letters, based on longitudinal analyses adjusting for baseline VA †Additional adjustment for potential confounders (baseline lens status, CSF, DR severity, prior PRP, age)

12. Distribution of VA Change at 5 Years 12 Change in Visual Acuity (letters) Ranibizumab + Prompt N = 124 Ranibizumab + Deferred N = 111 >15 letter gain27%38% RR (95%CI) P value 1.47 (1.04, 2.09) 0.03 >10 letter gain46%58% RR (95%CI) P value 1.27 (1.01, 1.60) 0.04 >15 letter loss6%5% RR (95%CI) P value 0.96 (0.34, 2.72) 0.94 >10 letter loss9%8% RR (95%CI) P value 0.91 (0.40, 2.10) 0.83

13. Change in VA Over 5 Years Stratified by Baseline VA 13 Test for interaction at 5 Year time point: P = 0.001 Test for interaction from longitudinal model: P = 0.004

14. 14 Percent of Eyes with VA 20/40 (Letter Score 69) or Better

15. 15 Percent of Eyes with VA 20/200 (Letter score 38) or Worse

16. Retinal Thickening 16

17. Mean Change in CSF Thickening at Follow-up Visits 17

18. 18 Change in Retinal Thickness at 5 Years* *Based on a longitudinal model adjusting for baseline CSF and VA †Additional adjustment for potential confounders (baseline lens status, DR severity, prior PRP, age) Ranibizumab + Prompt Laser N = 124 Ranibizumab + Deferred Laser N = 111 Estimated Mean change*-167-165 Estimated Difference* (95% CI) [P-Value] [adjusted P-Value]† -8 (-30 to +15) [P = 0.48] [P = 0.53]

19. 19 Reduced VA and Thickened at 5 Years Ranibizumab + Prompt Laser N = 124 Ranibizumab + Deferred Laser N = 111 VA 20/32 or worse and CSF >250 µm 23%24%

20. Endophthalmitis Ranibizumab + Prompt Laser treatment Ranibizumab + Deferred Laser treatment N = 187 eyesN = 188 eyes Number (%) cases 1 (1%)2 (1%) N=2557 injectionsN=3176 injections Rate per injection0.04%0.06% 20 N’s include ALL randomized eyes

21. Summary  VA gain at 1 year was maintained to 5 years concomitant with diminishing need for treatment over time  Adding laser at initiation of ranibizumab was no better than deferring laser at least 24 weeks  Deferring laser may be associated with more VA gain through 5 years, especially in eyes with worse VA at baseline 21

22. Summary  Over half assigned to deferral never received laser through 5 years  Eyes assigned to prompt laser needed fewer injections over 5 years  Few eyes in either group had substantial VA loss  About 1/3 still thickened  more work to be done 22

23. Discussion – Observed Difference in VA in Favor of Deferred Laser  May be related to greater number of ranibizumab injections during follow-up in the deferred group  May be related to potentially destructive effect of laser at baseline in the prompt group (subsequently given to fewer than half in deferred group)  Similar results noted in RESTORE through 1 year 23

24. Discussion - Limitations (Incomplete Data)  Excluding deaths, about a quarter of all randomized eyes did not complete the 5-year visit, in both ranibizumab groups. Mostly pts choosing not to continue in the extension study  Model adjusted for imbalances in baseline completer characteristics that could be related to VA outcome  If dropout is related to what was observed prior to loss to follow-up (last VA), then the longitudinal model accounts for this (estimates are based on projected trajectories)  It is not possible to know whether incomplete data were related to unobserved factors and could have affected the results in either direction 24

25. Conclusions  Differences in VA may be real, in particular for eyes with worse baseline VA, but deferral may require more injections over 5 years to achieve results seen in this report, and thus may entail greater costs (cost effectiveness analysis is beyond scope of study)  Results apply to patients similar to those enrolled in this trial and following same retreatment criteria.  Eyes initiating ranibizumab (with prompt or deferred laser) can maintain vision gains obtained by first year through 5 years with minimal treatment after 3 years 25

26. The Diabetic Retinopathy Clinical Research Network Thank You