At AAO 2025’s Retina Subspecialty Day, a pair of presentations delivered compelling new data on emerging strategies for diabetic retinopathy. Dr. Victor H. Gonzalez, from the University of Texas San Antonio, presented U.S. data for the first time from the pivotal NEW DAY trial. This prospective, randomized study compared the fluocinolone acetonide 0.19 mg intravitreal implant (Iluvien) to aflibercept in patients with center-involved diabetic macular edema (DME).

The study’s primary endpoint was the mean number of supplemental aflibercept injections required by participants through the study’s 18 month follow up period. The study found comparable supplemental injections between the two arms, with 2.4 injections needed in the fluocinolone group versus 2.5 in the aflibercept group. However, when the total injection burden was examined, the fluocinolone arm required just 3.4 total injections compared to 7.5 in the aflibercept arm, demonstrating a nearly 50% reduction during the trial period. While visual acuity gains favored aflibercept (5.5 letters versus 1.8 letters), this was largely attributed to cataract development in phakic patients receiving the steroid implant as evidenced by a subanalysis which showed similar visual outcomes across both treatment arms in pseudophakic patients.

Aflibercept produced a robust drying effect during the induction phase, but patients experienced rebound thickening of the CST in the maintenance phase. In contrast, the fluocinolone group showed steady and continued CST reduction, ending with a 50-micron advantage at month 18. Safety results aligned with known drug profiles: cataracts and IOP-related events were more common with the steroid implant. Dr. Gonzalez concluded that this prospective dataset informs the use of the fluocinolone implant, in combination with anti-VEGF bolus therapy, in the management of diabetic macular edema.

Following Dr. Gonzalez’s presentation, Dr. Charles C. Wykoff of Retina Consultants of Texas and the Blanton Eye Institute presented two-year results from the ALTITUDE trial, a phase 2 study evaluating suprachoroidal delivery of surabgene lomparvovec (Suravec, ABBV-RGX-314), an investigational anti-VEGF gene therapy, for NPDR without DME. The therapy, delivered via a single, in-office suprachoroidal injection, is designed to act as a localized biofactory producing an anti-VEGF Fab.

Two or more DRSS step improvements were observed in 50% of eyes at two years that received the treatment, compared to just 8% in historical controls, similar to Protocol W. Notably, no patients in this group showed worsening of DRSS scores. Rates of vision-threatening events (either PDR or DME) were also significantly reduced, just 14% in dose level 3, compared to 50% in standard-of-care trials, suggesting a ~70% relative risk reduction.

Safety signals were encouraging. While earlier dose levels without steroid prophylaxis saw episcleritis and mild inflammation, with the addition of a seven-week prophylactic topical steroid course for dose level 3, there were no cases of intraocular inflammation.

A thoughtful panel discussion followed, focusing on the clinical implications of early intervention in diabetic eye disease. The experts generally agreed that waiting for patients to develop DME or PDR before initiating treatment mirrors waiting for a heart attack before managing hypertension. Yet real-world barriers, including injection burden, compliance, and procedural risk, limit widespread anti-VEGF use in early NPDR which can also be managed with moderate systemic therapy as well without risking ocular complications.

Panelists also weighed in on practice patterns. While most still opt for a second anti-VEGF agent or Ozurdex before considering Iluvien, the NEW DAY trial may shift that paradigm, especially in pseudophakic eyes with high treatment burden. Focal laser also remains an option in select cases with extrafoveal microaneurysms, but not a primary tool in most practices.

Late-breaking data presented at AAO 2025 highlighted emerging gene-independent treatment strategies for inherited retinal diseases.

Allen C. Ho, MD (Wills Eye Hospital, Philadelphia) presented the three-year extension results from the RESTORE trial evaluating MCO-010, an investigational intravitreal optogenetic therapy for severe retinitis pigmentosa. The treatment delivers a light-sensitive protein to surviving retinal bipolar cells, aiming to restore light responsiveness even in the absence of functional photoreceptors. In long-term follow-up, a meaningful proportion of treated eyes demonstrated sustained functional improvement over the three year follow up period. There was a good safety profile and no serious inflammatory events. As a mutation-agnostic approach, MCO-010 may hold a potential across a broad range of retinal degenerations.

In a complementary strategy targeting Stargardt disease, Michel Michaelides, MD (Moorfields Eye Hospital, London) presented the interim analysis of the Phase 3 DRAGON trial investigating Tinlarebant, an oral RBP4 antagonist designed to reduce accumulation of toxic bisretinoids associated with ABCA4 dysfunction. Visual function remained stable through the first treatment year, and treatment-related effects such as delayed dark adaptation were consistent with the drug’s mechanism and generally manageable. Tinlarebant has received FDA Breakthrough Therapy designation, and global regulatory discussions are ongoing.

While long-term outcomes and real-world applicability will require further study, both presentations sought to advance the broader goal of developing mutation-independent therapies for patients who currently have limited or no treatment options.

The Retina Society 58^th Annual Scientific Meeting featured two Late Breaking Sessions. On Friday September 12^th, the late breaking session involved early-phase results for novel therapeutics for neovascular age-related macular degeneration (nAMD) and central retinal occlusion (CRAO).

Dr. Arshad Khanani of Sierra Eye Associates presented the first talk, discussing first time results from the Phase I/IIa Everest Trial. The multicenter trial investigated the safety and efficacy of EXG102-031, a novel adeno-associated virus (AAV)-based gene therapeutic vector, for treating nAMD. The therapeutic vector expresses a fusion protein ABD-VEGFR, which binds to angiopoietin 2 as well as all subtypes of VEGF.

The study had a dose-escalation (Phase1) and extension (Phase IIa) design and involved assessing a single subretinal injection of EXG102-031 in patients with nAMD. The primary safety outcomes were the incidence of adverse and serious adverse events. The primary efficacy outcomes were the annualized number of supplemental anti-VEGF injections and change in best corrected visual acuity (BCVA) as well as central subfield thickness (CRT).

In phase I, cohort follow up ranged from 4 to 52 weeks to date; there were no drug related serious adverse events or dose-limiting toxicity. There was dose-dependent reduction in annualized anti-VEGF injection rates (57-96%) across cohorts 1-4 and patients had improved or stable CRT and BCVA.

In summary, the results of the Phase I/IIa Everest Trial demonstrated a favorable safety and efficacy profile of a novel subretinal injection for nAMD. The anti-VEGF injection rate reductions were of particular interest. The durability of the injection rate reduction and long-term safety profile of this new subretinal therapy will be important factors to assess in later phase trials.

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The second late breaking presentation was delivered by Dr. Richard Rosen of New York Eye and Ear Infirmary of Mount Sinai. The study evaluated a novel intravitreal therapeutic (KUS121) for patients with non-arteritic CRAO. KUS121 is a cytoprotective compound, aimed to reduce metabolic stress from ischemia. The study was a multicenter phase 2 trial.

There were 17 patients with non-arteritic CRAO presenting 3 to 48 hours from time of symptom onset were included. Patients received an intravitreal injection for three days (two dosage groups and a control sham group). Outcomes included proportion of eyes improving 15 or more ETDRS letters from presentation at Week 12 and safety measures.

There were no statistically significant differences between proportion of eyes achieving the visual acuity outcome between the experimental and control arms. Dr. Rosen did highlight that there was a numerical trend towards improved visual recovery in the patients receiving KUS121 compared to control. The study’s small sample size may be underpowered to detect differences for now. There were no concerning safety signals.

Overall, the authors recommended further evaluation of the drug in later phase trials given the favorable safety profile and trend towards visual improvements. Larger sample sizes and evaluation of patient selection (consider time to symptom onset) may be needed to better understand this novel therapeutic.