The Diabetic Retinopathy Clinical Research Network Change in Diabetic Retinopathy (DR) Through 2 Years Secondary Analysis of a Randomized Clinical Trial Comparing Aflibercept, Bevacizumab, and Ranibizumab JAMA Ophthalmol. 2017 Jun 1;135(6):558-568. doi: 10.1001/jamaophthalmol.2017.0821.

Background Exploratory analyses of changes in diabetic retinopathy level during treatment periods of up to 3 years have shown that eyes randomly assigned to ranibizumab or aflibercept to manage DME, as compared to eyes treated with focal/grid photocoagulation are*: less likely to experience retinopathy worsening and more likely to realize retinopathy improvement. While more limited data is available on the effect of bevacizumab on retinopathy level, similar trends have been suggested.** * VISTA&VIVID, DRCR.net Protocol I, RISE&RIDE. ** BOLT

Cumulative Probability of DR Worsening: Protocol I* NPDR group 1 Year 2 Years 3 Years *JAMA Ophthalmology 2013

Cumulative Probability of DR Worsening: Protocol I* PDR group 1 Year 2 Years 3 Years *JAMA Ophthalmology 2013

What we Learned from Protocol I Ranibizumab was associated with a reduced probability of retinopathy worsening relative to laser, in eyes with or without PDR, through 3 years. Improvement of retinopathy occurred between baseline and 1 year in: 25% of eyes with moderately severe NPDR or better (N = 182), and 28% of eyes with severe NPDR or worse (N = 121) Beneficial changes in retinopathy worsening occurred despite decreasing number of injections in years 2 and 3.

Purpose of Exploratory Analysis Protocol T Evaluate the effect of intravitreous: aflibercept bevacizumab ranibizumab administered to manage DME, on the risk of worsening or improvement of DR, during a treatment period of up to 2 years. Purpose of Exploratory Analysis Protocol T

Worsening of DR During follow-up on annual photos Worsening of Diabetic Retinopathy Received PRP Received vitrectomy or injections for PDR Developed vitreous hemorrhage retinal detachment NVI or NVA or NVG Worsened 2 or more levels on the ETDRS retinopathy scale* Progressed from No PDR to PDR* Progressed from ≤HRPDR to advanced PDR* Between baseline and follow-up

Worsening of DR During follow-up on annual photos Worsening of Diabetic Retinopathy Received PRP Received vitrectomy or injections for PDR Developed vitreous hemorrhage retinal detachment NVI or NVA or NVG Worsened 2 or more levels on the ETDRS retinopathy scale* Progressed from No PDR to PDR* Progressed from ≤HRPDR to advanced PDR* Between baseline and follow-up Only applies to eyes with the potential to worsen 2 or more levels* Only applies to eyes without PDR at baseline Only applies to eyes with inactive PDR to HRPDR *Based on Reading Center grading of annual fundus photos, excludes eyes with level >81 (advanced PDR)

Improvement of DR Between baseline and annual follow-up Improvement of Diabetic Retinopathy Did NOT receive PRP Did NOT receive vitrectomy or injections for PDR Did NOT develop vitreous hemorrhage Did NOT develop retinal detachment NVI or NVA or NVG Improvement on annual fundus photos* Between baseline and annual follow-up During follow-up on annual photos *Based on Reading Center grading of annual fundus photos, excludes <20 (MA)

Improvement of DR Between baseline and annual follow-up Improvement of Diabetic Retinopathy Did NOT receive PRP Did NOT receive vitrectomy or injections for PDR Did NOT develop vitreous hemorrhage Did NOT develop retinal detachment NVI or NVA or NVG Improvement on annual fundus photos* Improved from active PDR to Inactive (if PRP at baseline) or No PDR (if no PRP at baseline)* Between baseline and annual follow-up During follow-up on annual photos OR improved 2 or more levels on the ETDRS retinopathy scale* (applies to eyes with NPDR or PDR with potential to improve 2 or more levels) *Based on Reading Center grading of annual fundus photos, excludes <20 (MA)

Methods Evaluated within each of the 2 DR severity subgroups*: NPDR group Moderate NPDR or better, includes levels 10, 12, 14, 15, 20, 35, and 43 Moderately severe to very severe NPDR, includes levels 47, 53, and 53E PDR group PRP without NV (Inactive PDR), includes level 60 Mild or moderate PDR, includes level 61 and 65 High-risk PDR, includes levels 71 and 75 Advanced PDR, includes levels 81 and 85 *Based on Reading Center grading of baseline fundus photos

Worsening of DR between Baseline and 2 Years*

Cumulative Probability* of DR Worsening NPDR at Entry Weeks 0 52 104 P values for pairwise comparison†: A vs. B: 0.99 A vs. R: 0.54 R vs. B: 0.54 * Calculated using the life-table method, adjusted for baseline DR severity † Hochberg-adjusted P values for multiple treatment-group comparisons to account for an overall type I error rate of 0.05 13

Cumulative Probability Cumulative Probability* of DR Worsening (level 47/53 subgroup- mod-severe to severe NPDR) Weeks 0 52 104 P values for pairwise comparison †: A vs. B: 0.47 A vs. R: 0.13 R vs. B: 0.42 * Calculated using the life-table method, adjusted for baseline DR severity † Hochberg-adjusted P values for multiple treatment-group comparisons to account for an overall type I error rate of 0.05 14

Cumulative Probability* of DR Worsening PDR at Entry Weeks 0 52 104 P values for pairwise comparison†: A vs. B: 0.70 A vs. R: 0.70 R vs. B: 0.62 * Calculated using the life-table method, adjusted for baseline DR severity † Hochberg-adjusted P values for multiple treatment-group comparisons to account for an overall type I error rate of 0.05 15

Improvement of DR Level between Baseline and Annual Visits*

Proportion with Improvement of DR Level* (NPDR at entry) P values for pairwise comparison at 1 year†: A vs. B: 0.004 A vs. R: 0.51 R vs. B: 0.01 P values for pairwise comparison at 2 years†: A vs. B: 0.85 A vs. R: 0.85 R vs. B: 0.85 1 Year 2 Years (N = 141, 131, 151) (N = 133, 113, 129) *Adjusted for baseline DR severity † Hochberg-adjusted P values for multiple treatment-group comparisons to account for an overall type I error rate of 0.05 17

Proportion with Improvement of DR Level NPDR subgroup (level 47/53) P values for pairwise comparison at 1 year†: A vs. B: 0.62 A vs. R: 0.62 R vs. B: 0.53 P values for pairwise comparison at 2 years†: A vs. B: 0.97 A vs. R: 0.97 R vs. B: 0.97 1 Year 2 Years (N = 55, 54, 79) (N = 55, 46, 68) *Adjusted for baseline DR severity † Hochberg-adjusted P values for multiple treatment-group comparisons to account for an overall type I error rate of 0.05 18

Proportion with Improvement of DR Level (PDR at entry) P values for pairwise comparison at 1 year†: A vs. B: <0.001 A vs. R: 0.02 R vs. B: 0.09 P values for pairwise comparison at 2 years†: A vs. B: 0.01 A vs. R: 0.06 R vs. B: 0.73 1 Year 2 Years (N = 29, 35, 29) (N = 27, 33, 24) *Adjusted for baseline DR severity † Hochberg-adjusted P values for multiple treatment-group comparisons to account for an overall type I error rate of 0.05 19

Improvement of DR Level Sustained Improvement at 2 years Aflibercept Bevacizumab Ranibizumab NPDR (N = 111) 20 (50%) 16 (73%) 30 (61%) PDR (N = 40) 14 (70%) 7 (78%) 7 (64%)

Improvement of DR Level Sustained Improvement at 2 years* Aflibercept Bevacizumab Ranibizumab NPDR (N = 111) 20 (50%) 16 (73%) 30 (61%) PDR (N = 40) 14 (70%) 7 (78%) 7 (64%) Initial Improvement at 2 years* NPDR (N = 253) 11 (13%) 9 (10%) 10 (13%) PDR (N = 42) 4 (67%) 3 (13%) 2 (15%) *No treatment group differences

Summary Potential limitations: Finite follow-up period of 2 years and higher than ideal numbers of missed visits and annual visits without gradable photographs Limited number PDR patients and baseline DR severity was not a stratification factor for randomization Slight treatment group imbalances on baseline factors: NPDR: bevacizumab group was slightly older; aflibercept group had more participants with type 1 diabetes PDR: Ranibizumab group had more prior PRP, more severe retinopathy; aflibercept group had more severe DME No evidence that the improvement in retinopathy changes the timeline to actual VA loss or need for intervention of any type. Hypothesis to be tested by Protocol W

Retinopathy Worsening: Summary Retinopathy Worsening: In eyes with NPDR at baseline approximately 10% or less, in each group, experienced retinopathy worsening by 2 years. In the small group of eyes with PDR at baseline, 17%, 26%, 18% of eyes had worsening retinopathy in the aflibercept, bevacizumab, and ranibizumab groups. No treatment group differences between the 3 anti-VEGF groups were identified within either of the baseline retinopathy subgroups. Rates are consistent with Protocol I findings Eyes Receiving Anti-VEGF for DME still need to be Monitored for Worsening of Retinopathy

Summary Retinopathy Improvement: NPDR group: PDR group: # of Eyes in Each Group is Small Retinopathy Improvement: NPDR group: Aflibercept and ranibizumab both appeared to be superior to bevacizumab at 1 year. No treatment group differences between the 3 anti-VEGF groups were identified at 2 years. PDR group: Aflibercept appeared superior to bevacizumab or ranibizumab at 1 or 2 years No difference was identified between bevacizumab and ranibizumab at 1 or 2 years. Consistent with the superiority of aflibercept to manage DME in eyes with worse VA or thicker CST.