Diabetic Retinopathy Clinical Research Network Study Update

The Diabetic Retinopathy Clinical Research Network Expanded 2-year Follow-up of Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services 1

Changes to Protocol I To Initiate After Primary Results Published Study extended to 5 years from randomization All study participants given opportunity to receive ranibizumab injections if edema present or develops Triamcinolone+prompt laser (Group D) participants can continue to receive triamcinolone injections instead of ranibizumab at investigator discretion 2

Availability of 2-Year Data Completed prior to implementation of protocol change: N=642 (75%) Unavailable: N=212 (25%) death (35) withdrawals from the study (47) lost to follow (28) unavailable for the 2-year visit (3) completed after the protocol change implemented (99) 3

Treatments 4

Injections Prior to 2 Year * Ranibizumab + Prompt Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Deferred Laser N=141 Maximal possible # of injections prior to 2- year visit Median number of study drug injections from baseline to (prior to) 1-year visit Median number of study drug injections from 1-year to (prior to) 2- year visit 26 26 8 8 9 3 2 3 1 5 * Restrict to eyes that completed 2 year visit

Injections Prior to 2 Year (continued)* Ranibizumab + Prompt Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Deferred Laser N=141 Number (%) of eyes that met success at 16 weeks and then received injection by 1-year visit Number (%) of eyes that met success at 1-year visit and then received injection by 2-year visit 58 (87%) of 67 46 (84%) of 55 47 (85%) of 55 47 (56%) of 84 41 (59%) of 69 43 (56%) of 77 * Restrict to eyes that completed 2 year visit 6

Focal/Grid Laser Prior to 2 Years * Ranibizumab + Prompt Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Deferred Laser N=141 Maximal possible number of focal/grid laser treatments prior to 2-year visit Median number of focal/grid laser treatments from baseline to (prior to) 1-year visit % of eyes that received focal/grid laser treatments from 1-year to (prior to) 2-year visit 8 6 8 2 0 2 40% 29% 52% 7 * Restrict to eyes that completed 2 year visit

Visual Acuity (includes all data up to and including the first visit when all investigators are unmasked to primary outcome results) 8

Change in Visual Acuity (LOCF) at 1 Year* Sham + Immediate Laser N=211 N=136 Ranibizumab + Immediate Laser Ranibizumab + Deferred Laser N=139 Triamcinolone + Immediate Laser N=142 Change in Visual Acuity (letters) Mean +3 +8 +9 +3 Difference in mean change from Sham + Laser [P -Value]** +5.2 +6.1 +0.6 [P=0.61] [P <0.001] [P <0.001] *Visits occurring between 308 and 420 days from randomization were included as 1 year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1 year target date were used. For other eyes w/o any 1 year data (1 eye in the sham+immediate laser group and 1 eye in the triamcinolone+immediate laser group) the last observation carried forward method was used to impute data for the primary analysis. **Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity 9

Change in Visual Acuity at 2 Years* Sham + Immediate Laser N=211 Ranibizumab + Immediate Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Immediate Laser N=142 Change in Visual Acuity (letters) +3 +7 +9 +2 Mean Difference in mean change from Sham + Laser [P-Value]** +3.7 [P=0.03] +5.8 -1.5 [P<0.001] [P=0.35] *Visits occurring between 616 and 840 days from randomization were included as 2 year visits **Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity 10

Mean Change in Visual Acuity* at Follow-up Visits Change in Visual Acuity from Baseline (letter score) Sham+Prompt Laser Ranibizumab+Prompt Laser Ranibizumab+Deferred Laser Triamcinolone+Prompt Laser 11 10 9 8 7 N = 626 (52 weeks) N = 600 (68 weeks) N = 600 (84 weeks) N = 628 (104 weeks) 6 5 4 3 2 1 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96100104 Visit Week *Truncated to 30 letters P-values for difference in mean change in VA from sham+prompt laser at the 104 week visit: ranibizumab+prompt laser =0.03; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.35. 11

Visual Acuity Gain at 2 Years Proportion of Visual Acuity Improvement N=126 N=129 N=187 N=122 12

Visual Acuity Loss at 2 Years Proportion of Visual Acuity Worsening N=126 N=122 N=129 N=187 13

Mean Change in Visual Acuity* at Follow-up Visits: Pseudophakic Eyes at Baseline Sham+Prompt Laser Ranibizumab+Prompt Laser Ranibizumab+Deferred Laser Triamcinolone+Prompt Laser Change in Visual Acuity from Baseline (letter score) 11 10 9 N = 205 (52 weeks) N = 199 (68 weeks) N = 196 (84 weeks) N = 206 (104 weeks) 8 7 6 5 4 3 2 1 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96100104 Visit Week 14 *Truncated 30 letters

Retinal Thickening (includes all data up to and including the first visit when all investigators are unmasked to primary outcome results) 15

Change in Retinal Thickening at 2 Years* Sham + Immediate Laser N=211 N=136 Ranibizumab + Immediate Laser Ranibizumab + Deferred Laser N=139 Triamcinolone + Immediate Laser N=142 Change in OCT CSFa Mean change from baseline ( m) -138 -141 -150 -107 Difference in mean change from Sham + Laser [P Value]** -31 -28 -10 [P=0.003] [P=0.01] [P=0.37] Thickness <250 microns with at least a 25 m decrease from baseline 39% 54% 56% 45% *Visits occurring between 616 and 840 days from randomization were included as 2-year visits. When more than 1 visit occurred in this window,data from the visit closest to the 2-year target date were used. ** Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes Excluding missing or ungradable data for 3 eyes in the Sham +Immediate Laser group, 5 eyes in the Ranibizumab +Immediate Laser group, 4 in the Ranibizumab +deferred Laser, and 10 eyes in the Triamcinolone +Immediate Laser group 16

Mean Change in CSF Thickening at Follow-up Visits Sham+Prompt Laser Ranibizumab+Prompt Laser Ranibizumab+Deferred Laser Triamcinolone+Prompt Laser Mean Change in OCT Central Subfield Thickness 0 -20 -40 from Baseline (microns) -60 -80 -100 N = 617 (52 weeks) N = 581 (68 weeks) N = 568 (84 weeks) N = 606 (104 weeks) -120 -140 -160 -180 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96100104 Visit Week 17 *P values are for the difference in mean change in OCT CSF retinal thickness from Sham + Immediate Laser at the 52 week visit: ranibizumab+prompt laser =0.003, ranibizumab+deferred laser =0.01, and triamcinolone+prompt laser =0.37.

Mean Change in CSF Thickening at Follow-up Visits among eyes that were Pseudophakic at baseline Sham+Prompt Laser Ranibizumab+Prompt Laser Ranibizumab+Deferred Laser Triamcinolone+Prompt Laser Mean Change in OCT Central Subfield Thickness 0 -20 N = 202 (52 weeks) N = 192 (68 weeks) N = 188 (84 weeks) N = 200 (104 weeks) -40 from Baseline (microns) -60 -80 -100 -120 -140 -160 -180 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96100104 Visit Week 18 *Truncated 30 letters

Safety (all available data) 19

Cardiovascular Events According to Antiplatelet Trialists Collaboration Shama N*=130 Ranibizumab N*=375 Triamcinoloneb N*=186 3% 1% 3% Non-fatal myocardial infarction Non-fatal cerebrovascular accident-ischemic or hemorrhagic (or unknown) 6% 2% 2% Vascular death (from any potential vascular or unknown cause) 6% 3% 4% 13% 7% 8% Any ATC cardiovascular event * N=Number of Study Participants. Study participants with 2 study eyes are assigned to the non- sham group. Multiple events within a study participant are only counted once per event. aone participant began receiving ranibizumab prior to nonfatal stroke bone participant began receiving ranibizumab prior to nonfatal stroke 20 20

Major Ocular Adverse Events During Follow-up Sham + Prompt Laser N=293 Ranibizumab + Prompt Laser N=187 Ranibizumab + Deferred Laser N=188 Triamcinolone + Prompt Laser N=186 Number of injections* (91) 1759 2046 646 (53) Endophthalmitis 1 (<1%) 2 (1%) 2 (1%) 0 Pseudoendophthalmitis 1 (<1%) 0 0 1 (1%) 2 (1%) 2 (1%) 1 (%) 3 (2%) Ocular vascular event Retinal detachment 1 (<1%) 0 1 (1%) 0 *Numbers in parenthesis indicate # ranibizumab injections No major ocular adverse events for eyes with ranibizumab injections 21 21

Cumulative Probability of Cataract Surgery Over 2-Years 100% 90% Sham (N = 192) Ranibizumab (N = 265) Triamcinolone (N = 124) 80% 70% 74% 60% 50% 40% 30% 18% 16% 20% 10% 0% 0 0 120 4 240 8 360 12 480 16 600 20 720 24 22 Month

Summary Expanded 2-year results are similar to results published previously and reinforce conclusions with respect to: Visual acuity outcomes OCT outcomes Pseudophakic subgroup analyses Injections given Lasers given Safety results 23