The Diabetic Retinopathy Clinical Research Network Repeated Intravitreous Ranibizumab Injections for DME and Risk of Sustained IOP Elevation or Need for Ocular Hypotensive Treatment 1

Background   Multiple reports suggest a small risk of sustained elevation of IOP with repeated injections of ranibizumab in eyes with AMD. Bakri, 2008: Graefes Ach; Adelman, 2010: J Ocu. Phar; Good, 2010 BJO; Choi, 2011:Retina   Recent post hoc analysis of ANCHOR and MARINA data showed 11% of ranibizumab treated eyes had sustained IOP rise vs 5% in control eyes. Bakri et al, 2014: Ophthalmology   RISE and RIDE, RESTORE did not identify difference in IOP-related adverse events in ranibizumab vs macular laser treatment groups. 2

Did not identify any differences in IOP ocular adverse events between ranibizumab and sham arms. 3 Ranibizumab 0.5 mg + Prompt Laser Ranibizumab 0.5 mg + Prompt Laser Ranibizumab 0.5 mg + Deferred Laser Ranibizumab 0.5 mg + Deferred Laser Sham + Prompt Laser Sham + Prompt Laser Triamcinolone + Prompt Laser Triamcinolone + Prompt Laser DRCR.net Protocol I: Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination with Laser Photocoagulation for Diabetic Macular Edema Trial (LRT-DME)

Purpose   To explore DRCR.net Protocol I data for evidence of IOP concerns, including sustained elevation of IOP or need for IOP therapy, in ranibizumab groups in comparison with the prompt laser + sham injections group 4 Ranibizumab 0.5 mg + Prompt Laser Ranibizumab 0.5 mg + Prompt Laser Ranibizumab 0.5 mg + Deferred Laser Ranibizumab 0.5 mg + Deferred Laser Sham + Prompt Laser Sham + Prompt Laser Triamcinolone + Prompt Laser Triamcinolone + Prompt Laser Vs

Primary Outcome Cumulative probability of “Persistent Elevation of IOP” through 3 years Persistent elevation of IOP definition: Any of the following: IOP ≥22 mm Hg with at least 6 mm Hg increase from baseline, at 2 consecutive visits, or Initiation of IOP-lowering medicine or procedure to lower IOP  was based on:  Threshold selection criteria was based on: “usual" IOP range of 10 mm Hg to 21 mm Hg “usual" IOP range of 10 mm Hg to 21 mm Hg “usual" IOP fluctuation typically less than 6 mm Hg “usual" IOP fluctuation typically less than 6 mm Hg Similar criteria used in prior studies of intravitreous injections Similar criteria used in prior studies of intravitreous injections 5

Visits   Through the 52-week visit (1 year), protocol visits occurred every 4 weeks   After year 1, visits varied from 4 to 16 weeks depending on response to treatment; analysis done only on every 16 th -week visit (mandatory visits). 6

Data Exclusion / Censoring  Exclude baseline IOP obtained post-dilation (10%)  Exposure to corticosteroids of any source – censored at date receiving steroid (29%)  Sham eyes receiving anti-VEGF: eyes censored at date received anti-VEGF (12%)  Eyes missing consecutive visits (5%)  Vitrectomy– censored at date of surgery (3%)  NVG or ghost cell glaucoma (1%) 7

8 Subjects Baseline Characteristics Sham N = 260 eyes Ranibizumab N = 322* eyes Age (yr), mean63 Gender, Women, %43% Race, % White72%74% African American18%16% Hispanic7% Other2% Diabetes Duration (yr), mean1718 * and Ranibizumab + Deferred Laser Ranibizumab + Prompt Laser

Ocular Baseline Characteristics 9 Sham N = 260 Ranibizumab N = 322 IOP (mm Hg), mean16 IOP 22 to 24 mm Hg*, %4%5% IOP Device, % Goldmann82% Tonopen18% History of OHT/on IOP- lowering medicines 3% *Eligibility permitted IOP ≤24 mmHg

Primary Outcome Through 1 year Sham N = 260 Ranibizumab N = 322 Primary Outcome* Persistent IOP elevation/ Initiation of glaucoma med/surgery 5 (2.0%)15 (5.7%) Persistent IOP elevation only0.7%2.4% IOP-lowering medicine only0.9%1.5% Persistent IOP and IOP Med0.41.9% Any glaucoma procedure00 *from Time-To-Event analysis

Outcome Through 3 years Sham N = 260 Ranibizumab N = 322 Hazard Ratio (99%CI) Primary Outcome* Persistent IOP elevation/ Initiation of glaucoma med/surgery 6 (3.4%)22 (9.5%) 2.9 (1.0 – 7.9) Persistent IOP elevation only1.1%3.8% IOP-lowering medicine only1.9%3.2% Persistent IOP and IOP Med0.5%2.4% Any glaucoma procedure00 Cumulative number of injections at meeting primary outcome, mean, mean±SD 7±4** *from Time-To-Event analysis ** Average cumulative # injections through 3 years 15±8

Outcome Through 3 years In Participants with Bilateral Study Eyes Sham N = 96 Ranibizumab N = 96 Hazard Ratio (99%CI) Primary Outcome* Persistent IOP elevation/ Initiation of glaucoma med/surgery 5 (8.3%)10 (15.0%) 1.9 (0.7 to 5.1) Persistent IOP elevation only IOP-lowering medicine only Persistent IOP and IOP Med Any glaucoma procedure00 *from Time-To-Event analysis

IOP Cumulative Data – 3 Years 13 Sham N = 260 Ranibizumab N = 322 Proportion of eyes with IOP ≥30mmHg at any visit* 3%2% Proportion of eyes with IOP change ≥10mmHg at any visit** 9%6% *every 4 wks through 1 year, then every 16 wks through 3 years

Weaknesses   Ad hoc review   IOP may have been subject to diurnal fluctuations   Different definitions of persistent DME may lead to different event rates   Treating physicians unmasked to treatment groups – potential bias May be more likely to treat eyes in the active injection groups   Other risk factors for glaucoma, such as central corneal thickness and family history of glaucoma were not evaluated 14

Strengths   Subgroup of participants with 2 eyes in study 1 eye ranibizumab treated - 1 prompt laser Endogenous factors should be same Intravitreous injection eyes behave similar to overall cohort o oHR 1.9 (8.5% sham vs 14.7% injection group)   Carefully censored data to eliminate other causes of IOP effects. 15

Conclusion DRCR.net Protocol I data suggest that:   In eyes with center-involved diabetic macular edema and no prior open angle glaucoma, repeated intravitreous injections of ranibizumab may increase the risk of sustained IOP elevation or the need for ocular hypotensive treatment   Data support recommendation to monitor IOP in similarly-treated eyes   Unknown whether these data are similar for other anti-VEGFs used to treat DME 16

The Diabetic Retinopathy Clinical Research Network (drcr.net) Thank you 17