DRCRnet Rationale and Clinical Application of the DRCR.net Anti-VEGF Treatment Algorithm for Proliferative Diabetic Retinopathy Jennifer K. Sun, MD, MPH Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817  1

Purpose Review DRCRnet anti-VEGF treatment algorithm for PDR Discuss Protocol S data that might provide guidance on managing PDR with anti-VEGF Frequency of injections given in relation to retinal neovascular status of the treated eye Time course of neovascularization response

Retinal Neovascularization NV of the iris, NV of the disc, and NV elsewhere*† Resolved (or Success) Improved (compared with prior visit) Stable Recurrent/Worsened (compared with previous visit, vitreous or preretinal hemorrhage) Failure: NV growing and worse than baseline after 4 consecutive injections OR NVA Futility: Persistent NV after 18 months with at least 5 injections over prior 6 months *Assessment of the angle was required only if NVI was present or the eye met criteria for increased IOP, but was otherwise left to investigator discretion. †Methods for evaluation of NV status were left to investigators’ discretion based on usual clinical practice

Retreatment and Follow-up Start With 6 Monthly Injections Exception: all NV resolved after 4 to 5 injections Then.. Continue unless NV is resolved or shows “sustained stability” (stable NV compared with last 2 injection visits) Resume anti-VEGF IF NV worsens after withholding injections

Procedures Used to Assess NV* Exams: N = 3,410 N % Extended ophthalmoscopy 2595 76% Undilated examination of the iris 904 27% Fundus Photography 471 14% Fluorescein angiography 80 2% Ultrasound 3 <1% *Participants also received slit-lamp and dilated fundus examinations at each visit.

Treatment: Number of Injections Ranibizumab Group Overall N = 191 Without Vision Impairing DME N = 147 With Vision Impairing DME N = 42 Median (IQR) Number of Injections 1st 6 Months 5 (4-6) 2nd 6 Months 2 (1-4) 4 (2-6) 2nd Year 3 (1-6) 3 (1-5) 5 (2-7) Total 10 (7-14) 10 (6-13) 14 (10-17) *Note – 2 eyes were missing OCT at baseline and are not included in the DME columns. Compliance with treatment guidelines for PDR was 97%

Neovascularization Status by Visit At PRIOR visit: Injections required 2% Worsened 33% Stable 16% Improved 49% Resolved % of Eyes Receiving Injections at PRIOR Visit R 99 98

Neovascularization Status by Visit Required unless resolved At PRIOR visit: Injections required 8% Worsened 37% Stable 3% Improved 52% Resolved % of Eyes Receiving Injections at PRIOR Visit R 99 98 56 54

Neovascularization Status by Visit Required unless resolved At PRIOR visit: Injections required Required unless resolved or sustained stability 2% Failure/Futility 27% Worsened 23% Stable 5% Improved 43% Resolved % of Eyes Receiving Injections at PRIOR Visit R 99 98 56 54 44 42 39 35 41 40 36 34 29

Injections After NV Resolution Starting at 6 Months: When NV was resolved, investigators chose to inject at 23% of the visits Median (interquartile range) number of injections between 6 months and 2 years in eyes with resolved NV at 6 months was 4 (1-7) compared with 7 (4-11) for eyes without resolved NV at 6 months (P < .001)

Number of Injections After Stability Stability criteria could only be met after the 6 month visit: N = 153 eyes At 6 months 37% met stability criteria 22% achieved sustained stability Investigators chose to administer treatment 15% of the time when sustained stability was met

Neovascularization Stability Status by Visit

Consecutive Visits With Injection Deferral After Sustained Stability

Summary When using the DRCR.net anti-VEGF treatment algorithm for PDR: The number of injections given is reduced in the second year Median 7 in the first year vs 3 in the second year After the first 6 months of treatment, approximately 50% of eyes will achieve NV resolution >30% will achieve stability >20% will achieve sustained stability Most eyes (~90%) in which injections are withheld will need re-injection within 1 year

Conclusions Overall Protocol S results suggest that ranibizumab treatment for PDR following the DRCR.net algorithm is a viable alternative to PRP Using this algorithm, there is a decreasing treatment burden over the first 2 years of therapy Longer term Protocol S results are needed to determine whether stabilization of NV can be maintained chronically in eyes with PDR when anti- VEGF therapy is withheld Eyes in which injections are withheld should be watched closely for possible PDR worsening and need for re-treatment.