Short-Term Evaluation of Combination Protocol U Short-Term Evaluation of Combination Dexamethasone + Ranibizumab vs. Ranibizumab Alone in Eyes with Persistent DME and VA Impairment Despite Previous Anti-VEGF Treatment DRCR.net

Financial Disclosures Funding/Support: Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services. Additional Contributions: Genentech provided the Ranibizumab and Allergan, Inc. provided the Dexamethasone for the study. In addition, Allergan provided some funds to the DRCR.net to defray the study’s clinical site costs. A complete list of all DRCR.net investigator financial disclosures can be found at www.drcr.net. Personal Disclosures Raj K. Maturi, MD receives financial support for clinical trials from Allergan, Genentech-Roche, Allegro Pharmaceuticals, Boehringer-Ingelheim, and Aerpio Therapeutics, LLC.

Background After at least 6 monthly injections of anti-VEGF for DME, some eyes still have unresolved DME and reduced VA Protocol I Protocol T

Background Corticosteroids have been considered as an alternative treatment for DME Known to decrease inflammation, reduce breakdown of the blood-retinal barrier, and have anti-angiogenic properties Shown to result in superior visual acuity to sham treatment but worse than laser or anti-VEGF in phakic patients May be similar to anti-VEGF in pseudophakic patients, at least for two years Reduce retinal thickening

Run-in Phase: 236 Eyes Enrolled* Persistent Edema VA letter score ≤78 and ≥24 (20/32 to 20/320), & Central-involved DME on clinical exam and OCT Despite at least 3 anti-VEGF tx prior to enrollment (in 20 wks) 3 injections of study Ranibizumab, given every 4 weeks 78 subjects (33%) did not meet criteria for persistent edema at the end of this 12 week period. Run-in Phase: 236 Eyes Enrolled* 9 additional subjects were either lost to follow-up (2), died (1), requested to withdraw (1), were withdrawn by the site (2), or were believed to no longer need Injections by the investigator (3) †Dropped = 2 eyes

Eligible for Randomization? Randomization (6 months) Week 0 4 8 12 16 20 24 65 eyes Study Overview DEX DEX RAN RAN RAN RAN RAN RAN Week 0 4 8 12 Enrolled (236 eyes) Week 0 4 8 12 16 20 24 RAN RAN RAN Eligible for Randomization? RAN RAN RAN RAN RAN RAN SHAM SHAM 64 eyes Run-In (3 months) Randomization (6 months)

Excellent Follow-up Combination Group Eyes Randomized N = 65 24-Week Completers† N = 63 (97%) Ranibizumab Group Eyes Randomized N = 64 24-Week Completers N = 64 (100%) *Run-in Phase: 78 participants were not eligible for randomization because they did not meet the criteria for persistent DME; 9 were either lost to follow-up (2), died (1), requested to withdraw (1), were withdrawn by the site (2), or were believed to no longer need Injections by the investigator (3) †Dropped = 2 eyes

+ Continued Ranibizumab + Continued Ranibizumab Study Design Randomized Multi-center Clinical Trial (Enrolled = 236 eyes, N = 129 Eyes randomized) ≥18 years old with Type 1 or Type 2 diabetes ≥3 injections of any anti-VEGF within the prior 20 weeks VA letter score ≤78 and ≥24 (20/32 to 20/320) Central-involved DME on clinical exam and OCT Outcomes Primary Mean Visual Acuity Change at 24 Weeks Secondary Mean OCT CST Change at 24 Weeks Dexamethasone + Continued Ranibizumab “Combination” VS Sham + Continued Ranibizumab “Ranibizumab”

Ocular Baseline Characteristics Combination Group (N = 65) Ranibizumab (N = 64) Mean Randomization VA letter score (Snellen Equivalent) 63 (20/63) Mean VA change during run-in +3 Mean OCT Randomization CST* 375 396 < 350 µm 52% 50% 350 to 449 µm 26% 23% ≥ 450 µm 22% 27% Mean OCT Change during run-in (µm) -58 -50 *Stratus equivalent

DME Treatment Combination Group (N = 65) Ranibizumab (N = 64) No. of ranibizumab injections through 24 weeks (max possible = 6)* 5.6 5.7 No. of eyes received second combination injection (sham or dexamethasone) through 20 weeks† 97% 98% No. of eyes received non-protocol treatment for DME * Including participants who completed 24-week visit † Including participants who completed at least one follow-up visit at 12, 16, or 20 weeks

Visual Acuity (VA)

What Happened in the Run-in Phase? Randomization 129 eyes remained eligible for randomization Mean (SD) visual acuity improvement: +3 (7) letters Mean (SD) CST decrease: 54 (93) microns 80 eyes (34%) no longer had “inadequate response” – i.e., either 20/25 or better, or OCT (central subfield thickness) no longer thickened, or both

Enrollment to Run-in Phase Randomization Only 17 pseudophakic eyes enrolled between February 2014 and July 2015 Starting July 2015, phakic patients allowed to enroll

Change in VA and OCT CST During Run-in Phase Randomization Mean (SD) visual acuity improvement: +3 (7) letters

Mean Randomization Letter Score (~Snellen Equivalent) VA Mean Change Run-In Randomization 63 (20/63) Mean Randomization Letter Score (~Snellen Equivalent) + 3.0

VA Mean Change Adjusted Mean Difference: -0.5 letters Run-In Randomization Adjusted Mean Difference: -0.5 letters 95% Confidence Interval: (-3.6, +2.5), P = 0.73 + 3.0 + 2.7 N = 65 N = 63

Pre-Planned Subgroups VA Mean Change Pre-Planned Subgroups

VA Mean Change: Baseline Lens Status Pseudophakic +5.1 +2.0 N = 32 N = 26 N = 25 N = 32 * P-value for interaction = 0.08

Change in VA (Letter Score) from Randomization at 24 Weeks Mean SD: 2.7 (9.8) Mean SD: 3.0 (7.1) Percent Change in VA (Letter Score) at 24 Weeks

Binary VA Outcomes* Combination Group (N = 63) Ranibizumab (N = 64) P-value VA at 24 Weeks 20/20 or better 6% 5% 0.70 20/40 or better 51% 52% 0.80 20/200 or worse Changes at 24 Weeks ≥15 letters improvement 11% 2% 0.03 ≥10 letters improvement 22% 14% 0.34 ≥15 letters worsening 0.62 ≥10 letters worsening 13% 0.09 * Pre-planned secondary outcomes

Central Subfield Thickness (CST)

OCT CST Mean Change -62 N = 64 N = 64 Randomization Run-In *Outlying values were truncated to 3 SD from the mean. One image was non-gradable due to low resolution.

OCT CST Mean Change Adjusted Mean Difference: -52 µm 95% Confidence Interval: (-82,-22), P < 0.001 -62 -110 N = 65 N = 62 N = 64 N = 64 *Outlying values were truncated to 3 SD from the mean. One image was nongradable due to low resolution.

Binary OCT Outcome* CST at 24 Weeks Below gender-machine Combination Group (N = 62) Ranibizumab (N = 64) P-value CST at 24 Weeks Below gender-machine specific values 52% 31% 0.02 * Pre-planned secondary outcome

Safety

Ocular Adverse Events Combination Group (N = 65) Ranibizumab (N = 64) P-value Eyes with at least one ocular adverse event 63% 31% <0.001 Increased IOP at any visit 29% Increased ≥10 mmHg from randomization 23% IOP ≥30 mmHg 15% Received ocular anti-hypertensives 20%

Conclusion Mean VA improvement by 6 months was no better in the dexamethasone + ranibizumab group than in the sham + ranibizumab group On average, there was a greater reduction in retinal thickness in the dexamethasone + ranibizumab group Study was not sufficiently sized to determine whether treatment response might differ by lens status

Conclusion Lens status Very few pseudophakic patients likely could be enrolled in a reasonable time to warrant pursuit of a Phase 3 trial in pseudophakic patients Protocol I and Protocol T data do not suggest that persistent DME following the DRCR Network treatment regimen is a substantial public health issue for visual acuity 30% (aflibercept) to 65% (bevacizumab) of participants in Protocol T had persistent DME at 6 months, and only about half of those are 20/32 or worse Half of those with persistent DME at 6 months have resolved by 2 years Most eyes with persistent DME through 2 years are better than 20/32 or gained at least 10 letters from baseline