Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema: Potential impact of Clinically Relevant Subgroups from DRCR.net Treatments of DME Scott M. Friedman, MD 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, EY

Disclosures   Presenter Financial Disclosures: I am a clinical investigator working on trials supported by Genentech, Allergan, Neovista, Thrombogenics, and Glaxo-Smith- Kline. I receive no income from these companies other than through the participation in these clinical trials.   Data from human research is presented   Genentech (provided the ranibizumab) and Allergan, Inc. (provided the triamcinolone) for the study and collaborated in a manner consistent with the DRCR.net Industry Collaboration Guidelines, the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol. 2

3 Subgroup Analyses   To examine potential differences in treatment group effects among baseline subgroups, the following were analyzed: Prior treatment for DME Baseline visual acuity Baseline OCT-measured central subfield thickening Baseline level of diabetic retinopathy on photos Description of edema by ophthalmologist as predominantly focal or predominantly diffuse Pseudophakic at baseline

Change in Visual Acuity at 1 Year Stratified by Baseline Visual Acuity 4 N=146

Change in Visual Acuity at 1 Year Stratified by Baseline CST 5

Change in Visual Acuity at 1 Year Stratified by Prior DME Treatment 6

Change in Visual Acuity at 1 Year Stratified by Eyes with Diffuse vs. Focal Edema at Baseline as Graded by Study Ophthalmologist 7

Change in Visual Acuity at 1 Year Stratified by Retinopathy Severity at Baseline 8

Change in Visual Acuity at 1 Year Stratified by Pseudophakic at Baseline 9

Mean Change in Visual Acuity at Follow-up Visits among Eyes that were Pseudophakic at Baseline* 10 Visit Week * Values that were ±30 letters were assigned a value of 30

≥10 Letter Visual Acuity Improvement/Worsening among Eyes Not Pseudophakic and Eyes that were Pseudophakic at Baseline 11 Eyes not Pseudophakic at Baseline Eyes Pseudophakic at Baseline

Discussion 12

13 Subgroup Analyses Summary   No obvious clinically important difference in results at 1-year primary outcome visit for any of the following subgroups: Prior treatment for DME Baseline visual acuity Baseline OCT-measured central subfield thickening Baseline level of diabetic retinopathy on photos Description of edema by ophthalmologist as predominantly focal or predominantly diffuse   In the subset of pseudophakic eyes at baseline (n = 273), visual acuity improvement in the triamcinolone+prompt laser group appeared comparable to the ranibizumab groups

 intravitreal triamcinolone with prompt focal/grid laser seems more effective than laser alone  In pseudophakic eyes, intravitreal triamcinolone with prompt focal/grid laser seems more effective than laser alone  These results are in contrast with a similar group of eyes treated with intravitreal triamcinolone without prompt focal/grid laser (DRCR.net Protocol B: Laser vs. Intravitreal Triamcinolone for DME) Pseudophakic eyes at baseline were not superior using intravitreal triamcinolone compared to focal/grid laserPseudophakic eyes at baseline were not superior using intravitreal triamcinolone compared to focal/grid laser Differences in outcome may be due to differences in characteristics of eyes between these 2 studiesDifferences in outcome may be due to differences in characteristics of eyes between these 2 studies Logical to assume that combination of 2 monotherapies (focal/grid laser & intravitreal triamcinolone) for DME in pseudophakic eyes is superior to focal/grid laser alone, although this was not true for entire cohort which included phakic eyesLogical to assume that combination of 2 monotherapies (focal/grid laser & intravitreal triamcinolone) for DME in pseudophakic eyes is superior to focal/grid laser alone, although this was not true for entire cohort which included phakic eyes Subgroup Analysis Summary

Protocol B and Protocol I comparison  Protocol B Pseudophakic eyes at baseline treated with intravitreal triamcinolone compared to focal/grid laser did not have superior outcomesPseudophakic eyes at baseline treated with intravitreal triamcinolone compared to focal/grid laser did not have superior outcomes  Protocol I subgroup analysis In pseudophakic eyes, intravitreal triamcinolone with prompt focal/grid laser seems more effective than laser aloneIn pseudophakic eyes, intravitreal triamcinolone with prompt focal/grid laser seems more effective than laser alone

16 Subgroup Analysis Conclusion  intravitreal triamcinolone with prompt focal/grid laser may be equally effective as ranibizumab at improving visual acuity and reducing retinal thickening, and associated with fewer injections, but also associated with an increased risk of intraocular pressure elevation.  In pseudophakic eyes, intravitreal triamcinolone with prompt focal/grid laser may be equally effective as ranibizumab at improving visual acuity and reducing retinal thickening, and associated with fewer injections, but also associated with an increased risk of intraocular pressure elevation. 16

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) 17  52 clinical study sites  Study participants who volunteered to participate in this trial  DRCR.net Data and Safety Monitoring Committee  Genentech (provided the ranibizumab) and Allergan, Inc. (provided the triamcinolone) for the study and collaborated in a manner consistent with the DRCR.net Industry Collaboration Guidelines, the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol.  DRCR.net investigators and staff (