Outcomes of Aflibercept, Bevacizumab, or Ranibizumab for DME: 5-Year Study Results

DRCR Retina Network 5 Year Outcomes after Aflibercept, Bevacizumab, or Ranibizumab for DME: Protocol T Extension Study 1

Protocol T - Study Design Randomized Multi-center Clinical Trial (N = 660) 18 years old with type 1 or type 2 diabetes Center-involved DME on OCT VA letter score 20/32 to 20/320 No or minimal prior treatment for DME Aflibercept Bevacizumab Ranibizumab 2

Mean Change in VA Over 2 Years Baseline Visual Acuity 20/50 or Worse ~50% of Cohort Baseline Visual Acuity 20/32 to 20/40 20 20 ~50% of Cohort Mean Change in Visual Acuity Letter Score 18 18 16 16 14 14 12 12 10 10 8 8 6 6 4 4 2 2 0 0 Baseline 1-Year 2-Year 2-Year Baseline 1-Year Visit Visit Aflibercept Bevacizumab Ranibizumab 3

T Extension - Methods Protocol T participants return for 5-year visit (3 years after Protocol T ended) DME and diabetic retinopathy management at clinician discretion (not part of a study) between years 2 and 5 At 5 year visit: Ocular and medical history was solicited Medical records were reviewed Visual acuity, eye exam, OCT, color photos obtained 4

T Extension - Objectives Primary Objective: For the 3 years after Protocol T was stopped, provide information on: Treatment Course Visual Acuity DME Main objectives do NOT include comparing treatment groups after 2 years Management at clinician discretion Did participants continue care with a Retina Specialist? and how often? baseline and between the 2 year visit and 5-years? the 2 year visit and 5-years? What treatments have been given How did participant VA change from How did participant CST change from Baseline and between How many eyes still have DME at 5 years? Data may be confounded by clinicians and patients awareness of treatment group and Protocol T results 5

Eligibility and Participation Eligible for T Extension N Patients = 558 Participant N Patients = 317 68%* Non-Participant N Patients = 146 32%* Died after Protocol T N Patients = 95 * Excluding deaths

Ocular Characteristics Participants vs. Non- Participants Non- Participant Participant* Baseline Randomized Treatment Group Aflibercept Bevacizumab Ranibizumab Mean VA Letter Score Mean OCT CST, m 2-Year Mean VA Letter Score Mean OCT CST, m N = 158 N = 317 34% 33% 34% 36% 30% 33% P=0.81 62 (20/63) 419 N = 124 74 (20/32) 256 66 (20/50) 413 N = 312 78 (20/32) 252 P<.001 P=0.53 P=.03 P=0.86 7 * Excludes deaths

1 Retinal Exam Since Protocol T 100% ~98% of Visits Occurred at Protocol T Clinical Site Overall Aflibercept Bevacizumab Ranibizumab 50% 97% 96% 95% 92% Mean Number of Visits Per Participant (between 2-5 years): ~14 0% Overall N = 317 Aflibercept Bevacizumab Ranibizumab N = 115 N = 96 N = 106 8

Treatments Since Protocol T 100% 80% 60% 40% 70% 20% 38% 32% 19% 10% 10% 8% 0% Aflibercept Bevacizumab Ranibizumab Corticosteroid Focal/Grid Laser PRP 1 Treatment for DME or DR At Least One Treatment 9

Anti-VEGF Treatments Since Protocol T 100% 17% 16% 19% 25% 6% 80% 11% 51% 45% 10% 17% 12% Multiple anti-VEGF Agents Ranibizumab Only Bevacizumab Only Aflibercept Only None 19% 18% 60% 18% 31% 22% 22% 40% 12% 61% 20% 33% 32% 32% 30% 0% All Aflibercept N = 115 Bevacizumab Ranibizumab N = 96 N = 317 N = 106 10 Percentage not receiving alternative anti-VEGF

Distribution of Anti-VEGF Injections Received After 2-Years Median Number of Injections: 4 35% 2% 30% 25% 32% Participants (%) 1% 20% 15% 0% 10% 20 21 22 23 24 25 26 27 28 29 30 31 32 5% 0% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Injections After Last Trial Visit (No.) N = 317 11

Visual Acuity

Mean Change in VA Over 5 Years Overall 25 Mean Change in Visual Acuity Letter Score Observational Study Randomized Trial 20 15 5-Year Mean Change: 7.4 letters 95% CI: (5.9, 9.0) +12.2 10 +7.4 Mean Change between 2 and 5 Years: -4.7 letters 95% CI: (-6.0, -3.3) 5 0 Baseline N = 317 2- Year N = 312 1- Year N = 315 5- Year N = 312 13

Mean Change in VA Over 5 Years Full Cohort 25 Mean Change in Visual Acuity Letter Score Observational Study Randomized Trial 20 Overall Aflibercept Bevacizumab Ranibizumab +14.0 15 +7.6 +8.0 +12.4 +10.0 10 5 +6.6 0 1- Year 2- Year 5- Year N = 112 N = 96 N = 104 N = 115 N = 96 N = 106 N = 112 N = 94 N = 106

Mean Change in VA Over 5 Years Baseline VA 20/32 to 20/40 Baseline VA 20/50 or Worse 25 25 Mean Change in Visual Acuity Letter Score 20 20 15 15 10 10 5 5 0 0 Baseline 2-Year Baseline 2-Year 5-Year 5-Year Visit Visit 15 Overall Aflibercept Bevacizumab Ranibizumab

Baseline, 1, 2 and 5 Year VA 100% 80% 47% 51% 52% 57% Participants (%) 60% 20/25 or better 20/32 - 20/40 20/50 - 20/160 20/200 or worse 40% 27% 32% 27% 45% 20% 21% 14% 15% 0% Baseline N = 317 1-year N = 315 2-year N = 312 5-year N = 312 Visit Year

Central Subfield Thickness

Mean Change in OCT CST Over 5 Years 25 Full Cohort Observational Study Randomized Trial -25 Mean Change in OCT CST (m ) 5-Year Mean Change: -154 m 95% CI: (-166 to -142) -75 -125 -156 m -154 m Mean Change between 2 and 5 Years: - 1 m, 95% CI: (-12 to 9) -175 -225 1- Year N = 313 2- Year N = 310 5- Year N = 313 Baseline N = 313 22

Mean Change in OCT CST Over 5 Years Full Cohort 25 Observational Study Randomized Trial -25 Mean Change in OCT CST (m ) Overall Aflibercept Bevacizumab Ranibizumab -75 -131 -150 -125 -150 -153 -175 -161 -181 -225 5- Year N = 113 N = 95 N = 105 Baseline 2- Year N = 111 N = 93 N = 106 1- Year N = 113 N = 95 N = 105

Baseline, 1, 2 and 5 Year OCT CST* 100% Percent of Participants 80% 53% 52% 59% 62% 60% <250 m 250 to 400 m 400 m 40% 37% 34% 46% 30% 20% 11% 8% 7% 0% Baseline N = 313 1 Year N = 313 2 Year N = 310 5 Year N = 313 *Stratus Equivalent 24

Limitations Only 2/3 of eligible participants completed 5-year visit Baseline visual acuity and 2-year visual acuity better for participants who completed 5-years than those who didn t Treatment from 2-5 years at investigator discretion Cannot compare treatment groups after 2 years Treatment data collection after 2 years was retrospective 25

Conclusion After Protocol T ended and patients had standard care: 95% of patients received retinal care and 68% received at least 1 anti-VEGF injection On average patients demonstrated visual gains from baseline, but mean visual acuity worsened between 2 and 5 years No significant changes in central subfield thickness were seen between 2 and 5 years Results differ from prior clinical trials in DME that have demonstrated better maintenance of VA gains (e.g. Protocol I) Strategies to improve long-term visual outcomes in clinical care among eyes with DME are needed 26

Thank you! 27