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.

Novel Findings from High Res OCT Talk (Dr. Freund)

Dr. K. Bailey Freund presented a talk on “Novel Findings from Innovative High-Res and Wide-Field OCT Devices”. The background for this talk demonstrated correlation of in-vivo OCT findings in Age Related Macular Degeneration (AMD) with post-mortem histology to validate current imaging technology and showed longitudinal single patient imaging findings as AMD evolves over time. It was noted that retromode near-infrared (NIR) imaging may currently be the most sensitive technique for fully detecting the extent of sub-RPE deposits. The current most widely accepted understanding for the development of large soft drusen, is that small drusen will eventually grow over time, change composition, and merge with neighboring drusen to form the late-stage phenotype seen in AMD. Dr. Freund however, proposed an alternative mechanism for the development of large soft drusen. Considering that, other than AMD, pachy-choroid disease is one of the few pathologies that frequently manifests pigmented epithelial detachments, these patients may hold clues to the pathogenesis of RPE/Bruch’s membrane interface pathology. Dr. Freund speculates that in eyes with AMD, basilar laminar depositions and small drusen can eventually merge, and along with the RPE, separate from the inner collagenous layer of Bruch’s membrane as a continuous thickened layer. This may then allow for an accumulation of lipoprotein rich lipid pools in the sub-RPE space, resembling the clinical finding of soft drusen. This mechanism may be shared with patients who present with typical pachy-choroid disease findings on OCT as well. Dr. Freund showed multiple longitudinal and cross-sectional cases that lend credibility to this potential pathogenesis in vivo with high-resolution OCT. Careful scrutiny of in vivo clinical imaging, particularly over extended follow-up intervals and using more refined retinal techniques may inform efforts to fill gaps in knowledge of the understanding of AMD progression.

SubQ MGB Injections Phase 2 Study (Dr. Singer)

Dr. Michael Singer presented a discussion on “Subcutaneous Migaldendranib (MGB) for the Treatment of Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: 9 Month Results of Chronic Dose Phase 2 Study”. Subcutaneous (subQ) migaldrendrinib is a novel, first-in-class drug in clinical development for the potential at-home treatment of wet AMD and DME. This drug, MBG, is a VEGF receptor tyrosine kinase inhibitor covalently linked to a hydroxyl dendrimer (nanomedicine), that targets inflammation without systemic side effects. This medication is ideal for chronic bilateral disease as it has the potential to treat both eyes with a single subQ administration. Its subQ administration also provides an excellent ocular safety profile. Its lack of systemic side effects is secondary to its specificity and rapid clearance. It binds to and is uptaken by RPE cells, macrophages, and microglia in choroidal neovascular lesions, and is retained by these cells for 30 days despite being renally cleared in 2 days. This study involved 27 patients (16 wet AMD/11 DME) and evaluated the safety and tolerability of subQ MGB as its primary measures. Patients included in the study had to have been treated with intravitreal injections for at least twelve weeks, demonstrated a reduction in fluid and then re-accumulated this fluid after cessation of treatment before enrollment in the study. Ultimately, the phase 2 chronic dose clinical study interim results (at 24 weeks) demonstrated that this treatment was safe and well tolerated. The most common side effect was local injection site reactions, which were typically transient and mild. There were no treatment-related systemic serious adverse events. There was a greater than 69% reduction in the need for supplemental anti-VEGF IVT in wet AMD and DME subjects. The study also demonstrated maintenance of Mean Central Subfield Thickness (CST) and Best Corrected Visual Acuity (BCVA) in wet AMD subjects, as well as maintenance of CST with modest increases in BCVA in DME subjects. Finally, there was a similar efficacy manifested in the “fellow eyes” to those being monitored in the study. Full end-study results will be presented at an upcoming conference.

Dr. Giovanni Staurenghi delivered an insightful presentation on the Differential Diagnosis of Macular Atrophy. He emphasized the importance of distinguishing age-related macular degeneration (AMD) from other macular atrophies, noting that current treatments may slow disease progression in AMD, whereas other conditions may require different management strategies.

Dr. Staurenghi highlighted the critical role of multimodal imaging in differentiating these conditions, as early degenerative changes on OCT often overlap across multiple diseases. He emphasized that the integration of FAF, OCT angiography, and ICG angiography is essential for precise phenotyping.

Using illustrative examples, he demonstrated how mitochondrial disease and Malattia Leventinese share nasal changes on FAF but exhibit distinct deposit characteristics on OCT. He also discussed the utility of ICG angiography in differentiating Stargardt disease, characterized by a “dark atrophy” pattern, from AMD. Similarly, ICG angiography can reveal “dark atrophy” in central areolar choroidal dystrophy and subtle angioid streaks in pseudo-xanthoma elasticum.

Dr. Staurenghi pointed out that reticular pseudodrusen are visible on OCT in several disease states, and the extent of dark signal on FAF can provide clues to the underlying etiology. He concluded his excellent presentation by stressing the importance of a thorough medication review to address the possibility of toxic maculopathies.

Faricimab for PCV: SALWEEN trial

Dr. Gemmy Cheung Chui Min presented on the use of faricimab for polypoidal choroidal vasculopathy (PCV), with a particular focus on the week 16 results from the Phase 3b/4 SALWEEN trial. She began by highlighting faricimab’s excellent safety and efficacy profile in age-related macular degeneration (AMD), while noting that PCV cases have been limited in pivotal studies of the drug, including the landmark TENAYA and LUCERNE trials.

The SALWEEN trial enrolled 135 patients aged >50 years across 38 study sites in nine countries in Asia. Participants had symptomatic PCV confirmed by ICG angiography, with evidence of macular exudation or hemorrhage and a baseline VA between 20/32 and 20/320. Key exclusion criteria included extensive fibrosis, foveal atrophy, and massive subfoveal hemorrhage.

The study design was adapted from the TENAYA/LUCERNE trials. Patients received four initial doses of faricimab 6.0 mg every four weeks, followed by disease activity assessments at weeks 20 and 24. Based on disease activity, treatment intervals were assigned (Q8W, Q12W, or Q16W) through primary endpoints at weeks 40, 44, and 48, with a subsequent treat-and-extend phase (Q8W–Q20W) extending up to 108 weeks.

At the week 16 interim analysis, the results were promising: patients demonstrated an average gain of 7.8 letters and a reduction in central subfield thickness (CST) of ~145 microns. Fluid reduction was notable, with absence of subretinal fluid (SRF), intraretinal fluid (IRF), or both in approximately 83%, 95%, and 80% of participants, respectively. Furthermore, ICG angiography showed complete regression of polypoidal lesions in 51% of subjects, while combined ICG and OCT imaging demonstrated polypoidal inactivity in 86%.

Dr. Cheung compared these findings to prior studies such as EVEREST II, PLANET, and the PULSAR PCV cohort, highlighting the similarities in outcomes. She also emphasized the favorable safety profile of faricimab in the trial, mentioning one case of retinal vasculitis that was later ruled out upon independent review of imaging.

Dr. Cheung concluded her excellent presentation with an illustrative case of a patient with PCV who received faricimab per the treatment protocol in the SALWEEN study, demonstrating a robust therapeutic response.