Jimmy Chen, MD
Mass Eye and Ear, Boston, MA
The Clinical Trial Updates Part I session at AAO 2026 Retina Subspecialty Day in New Orleans covered durable treatment for neovascular age-related macular degeneration (nAMD), slowing geographic atrophy (GA), and restoring central vision. Mark Humayun, MD, PhD, moderated, with panelists Michael Ip, MD, Andreas Lauer, MD, Joan Miller, MD, Joel Pearlman, MD, and Jay Stewart, MD.
LUGANO and sustained delivery of EYP-1901
Carl Regillo, MD, presented the phase 3 LUGANO results from EyePoint Pharmaceuticals evaluating EYP-1901, a bioerodible intravitreal insert delivering the tyrosine kinase inhibitor Vorolanib. The trial compared six-month dosing of EYP-1901 with on-label aflibercept 2 mg, with a primary endpoint of change in best-corrected visual acuity (BCVA), averaged at weeks 52 and 56.
Unfortunately, LUGANO did not meet its primary noninferiority endpoint. Mean visual gains were approximately two letters with EYP-1901 versus six with aflibercept, despite similar central subfield thickness (CST) outcomes. Dr. Regillo described an imbalance in eyes losing at least three lines of vision, including losses attributed to GA, retinal detachment, and other ocular conditions. A post hoc analysis excluding substantial vision loss attributed to causes other than wet AMD produced more favorable results, but did not change the trial’s primary outcome.
Secondary outcomes showed a 42% reduction in injection burden, with 79% of EYP-1901-treated eyes receiving zero or one supplemental injection over the first year. Repeat dosing had a favorable safety profile, without severe intraocular inflammation, free-floating drug particles, or implant migration. Dr. Regillo emphasized reduced treatment burden with persistent good anatomic controls, with results from the second pivotal trial, LUCIA, forthcoming.
SOL-1 and the durability of OTX-TKI
Darius Moshfeghi, MD, then discussed the phase 3 SOL-1 trial of OTX-TKI (Ocular Therapeutix), an axitinib-containing intravitreal hydrogel. Following an aflibercept loading phase, selected responders were randomized to a single OTX-TKI injection or a single aflibercept 2 mg injection, with protocol-directed rescue treatment. This design tested durability against a single comparator dose rather than against continued aflibercept dosing at regular intervals.
SOL-1 met its primary endpoint of maintaining vision, defined as losing fewer than 15 ETDRS letters, at week 36. The proportion maintaining vision was 74.1% with OTX-TKI versus 55.8% with aflibercept. At week 52, the corresponding proportions were 65.9% and 44.2%. Nearly 75% of OTX-TKI-treated patients remained rescue-free at week 36, and approximately 69% remained rescue-free at week 52.
Dr. Moshfeghi also presented quantitative OCT fluid analyses, suggesting that early drying may help identify eyes with a durable response. He emphasized the hydrogel’s role in sustained drug delivery. Floaters were the most notable adverse event, and reported intraocular inflammation was mild to moderate, without cases of endophthalmitis or retinal vasculitis.
DAYBREAK and novel antibody biopolymer conjugates
Charles Wykoff, MD, PhD, presented the phase 3 DAYBREAK trial, which enrolled 667 treatment-naive patients and evaluated two investigational therapies against a shared aflibercept control: Tarcocimab tedromer, which targets VEGF, and Tabirafusp alfa tedromer, which targets both VEGF and interleukin-6. Both use a novel antibody biopolymer conjugate platform designed to extend intraocular exposure and half-life.
DAYBREAK used AI-based OCT fluid quantification to guide retreatment. Both investigational arms received four monthly loading doses. Tarcocimab was then administered as needed at intervals of four to 24 weeks; Tabirafusp received fixed dosing every eight weeks, with additional treatment up to monthly when indicated. The control received on-label aflibercept 2 mg. Additional treatment in the investigational arms was triggered by retinal fluid rather than vision loss or a specified CST increase.
Both investigational arms met their independent primary BCVA noninferiority endpoints. Mean visual gains were 7.2 letters with tarcocimab, 6.3 with tabirafusp, and 7.6 with aflibercept. More than half of tarcocimab-treated patients achieved a 24-week interval despite strict retreatment criteria. Tabirafusp also met its prespecified anatomic endpoint. Dr. Wykoff reported low rates of inflammation and cataract.
Discussion of nAMD trials
The LUGANO post hoc analysis drew particular scrutiny. A panelist questioned whether excluding eyes with vision loss attributed to GA or glaucoma could obscure a treatment effect. Dr. Regillo agreed that the analysis was exploratory and intended to investigate the unexpected discrepancy between visual and anatomic outcomes. Additional analyses and the LUCIA results would be needed to clarify those findings.
For SOL-1, panelists questioned whether results in good anti-VEGF responders with relatively good vision would generalize to patients with persistent fluid, poorer vision, or less predictable responses. Dr. Moshfeghi acknowledged this uncertainty and suggested that early quantitative fluid assessment could help guide patient selection.
For DAYBREAK, panelists questioned whether durability could be fairly compared with fixed-dose aflibercept, which was not allowed to extend. Dr. Wykoff acknowledged that the comparator could not establish how individualized aflibercept dosing would perform, but described on-label treatment as an established benchmark. He emphasized that durability beyond the first year remained to be assessed. Panelists also discussed DAYBREAK’s shared-control design and fluid-based retreatment in context of deviations from prior trial designs. Dr. Wykoff cautiously shared optimism regarding using anatomy to guide treatment before patients lose vision, while acknowledging the need for standardized trial criteria.
K8 and inflammasome inhibition for GA
Liangbo Shen, MD, presented a phase 2 study of kamuvudine K8, an investigational inflammasome inhibitor delivered through a bioerodible intravitreal implant. Thirty participants with bilateral GA received treatment in one eye at baseline and month three, while their untreated fellow eyes served as controls. Three dose cohorts were studied over six months.
The 0.7-mg cohort showed a 54% reduction in the mean rate of GA growth compared with pooled control eyes. A prespecified analysis of extrafoveal lesions showed a four-letter adjusted BCVA advantage in treated eyes. Dr. Shen also described analyses suggesting a greater treatment effect during the second three-month interval, while emphasizing the need for longer follow-up.
The preloaded implant was administered using a 24-gauge injector and did not require refrigeration. No drug-related serious adverse events or dose-limiting toxicities were reported.
OCU410 and modifier gene therapy for GA
Raj Maturi, MD, presented 12-month phase 2 ArMaDa results for OCU410, an AAV5-based modifier gene therapy delivering the human RORA gene through a single subretinal administration. RORA encodes retinoic acid receptor-related orphan receptor alpha, a nuclear receptor regulating gene expression involved in retinal inflammation, oxidative stress, complement activity, and lipid metabolism. Fifty-one participants were randomized to medium-dose treatment, high-dose treatment, or untreated control.
The medium-dose group showed approximately one-third less GA lesion growth than controls at 12 months. Prespecified exploratory OCT analyses also suggested slower ellipsoid zone loss, supporting further investigation of photoreceptor preservation. Dr. Maturi reported no treatment-related serious adverse events or adverse events of special interest and noted that a phase 3 study was underway.
PRIMA and restoration of central vision in GA
Ehsan Rahimy, MD, presented 36-month safety and functional outcomes for the photovoltaic retinal implant microarray (PRIMA). The system combines a subretinal implant with camera-equipped glasses and a pocket processor. Near-infrared light projected onto the implant is converted into electrical stimulation of surviving retinal neurons, providing prosthetic central vision within the atrophic region.
In the PRIMAvera study, 38 patients underwent implantation. Results for 27 patients were evaluable for safety and 18 for efficacy at 36 months. With the system activated, assessed patients demonstrated a mean improvement of approximately 29 ETDRS letters, while natural vision remained relatively stable. Dr. Rahimy described patients using the device to recognize letters, numbers, and words and, in some cases, perform daily activities such as reading or completing crossword puzzles.
PRIMAvera safety findings reflected the risks of subretinal surgery. Most serious adverse events occurred within six months, including pressure elevation, retinal tears, hemorrhage, macular holes, retinal detachment, and neovascularization. However, no new long-term safety signal emerged. Dr. Rahimy emphasized that an adverse event did not necessarily prevent meaningful prosthetic visual gain.
Discussion of GA trials
For the phase 2 K8 trial, panelists questioned the small sample, six-month follow-up, fellow-eye controls, and incomplete dose-response relationship. Dr. Shen agreed that the findings required confirmation in a larger study.
For ArMaDa, the OCU410 trial, panelists asked about loss to follow-up, inflammation, and the less favorable high-dose response. Dr. Maturi proposed a possible non-linear response to nuclear receptor modulation and described localized postoperative inflammation as manageable.
For PRIMAvera, the PRIMA implant study, panelists asked about attrition, patient-reported outcomes, and postoperative training. Dr. Rahimy explained that implantation was followed by substantial rehabilitation. Benefit varied across patients, highlighting the importance of assessing daily function alongside device-assisted acuity gains.
Overall, these studies highlight an exciting frontier in age-related macular degeneration treatment, focusing on sustained control of exudation, preservation of retinal tissue, and restoration of central vision. Further assessment of these therapies is needed, and their clinical value will depend on more rigorous long-term evaluation across diverse patient settings.
