For retina specialists managing patients with neovascular age-related macular degeneration (nAMD), the question is no longer whether anti-VEGF therapy can preserve vision, but whether treatment can be delivered with fewer injections over longer periods of time. Durability has become a central focus of drug development, particularly for intravitreal gene therapy programs designed to provide sustained intraocular anti-VEGF expression after a single treatment.
At the 2026 Retina World Congress meeting in Fort Lauderdale, David A. Eichenbaum, MD, of Retina Vitreous Associates of Florida, reviewed emerging data from a pair of phase 3 intravitreal gene therapy programs, focusing on whether these approaches may finally deliver what he called the “truly durable injection.”
“If you look at the ASRS Preferences and Trends Survey, retina specialists agree that the largest unmet need in macular degeneration treatment is durability,” Dr. Eichenbaum said (Figure 1). “About half of retina specialists identified gene therapy as the most exciting way to address that.”
Figure 1. There is broad consensus among retina specialists on the need for more durable treatments, and many believe in the transformative potential of gene therapy for patients with neovascular age-related macular degeneration.
The ixoberogene soroparvovec (Ixo-vec; Adverum Biotechnologies) program currently has the longest-duration clinical follow-up among intravitreal gene therapies in nAMD. The phase 1 OPTIC study enrolled heavily treatment-burdened patients and has now generated follow-up extending out to 5 years in some participants. According to Dr. Eichenbaum, aqueous aflibercept expression has remained detectable throughout long-term follow-up, while visual acuity has remained stable with continued reductions in supplemental injection burden over time. The subsequent phase 2 LUNA study evaluated lower doses after inflammation observed in earlier development raised safety concerns, particularly in diabetic macular edema studies. Dr. Eichenbaum noted that the lower-dose cohorts have shown encouraging 2-year anatomic and visual stability with reduced inflammation, and the 6×10^10 vg dose has advanced into phase 3 development in the ARTEMIS trial.
Another late-stage program, 4D-150 (4D Molecular Therapeutics), is an intravitreal dual-transgene vector designed to express an aflibercept-like anti-VEGF protein along with a VEGF-C inhibitor. The therapy has progressed through phase 1/2 development and is also approaching phase 3 testing. Dr. Eichenbaum described how the program gradually expanded from refractory nAMD populations into broader patient cohorts with less advanced treatment histories.
“In the severe and recalcitrant patients in the phase 1 and 2a portions of the program, there was maintenance of vision and anatomy and a durable, dose-dependent reduction in supplemental injection requirements,” he said. “When they broadened the population and looked at the 1×10^10 vg and 3×10^10 vg doses, they observed even greater reductions in injection requirement in a dose-dependent fashion, likely because the broader population included more recently diagnosed patients than the severe recalcitrant cohort.”
Dr. Eichenbaum suggested that patients with less entrenched disease activity may ultimately derive greater durability benefits from gene therapy than heavily pretreated eyes. He also noted that early diabetic macular edema (DME) data with 4D-150 have shown sustained visual acuity gains and reduced central subfield thickness through 1 year at the planned phase 3 dose.
Safety, however, remains central to the broader discussion surrounding intravitreal gene therapy. Prior inflammatory events observed across retinal gene therapy programs have heightened attention to intraocular inflammation, vasculitis, and long-term tolerability. According to Dr. Eichenbaum, the safety profiles observed with both lower-dose Ixo-vec and 4D-150 have become increasingly encouraging as dose selection and steroid prophylaxis strategies have evolved.
Even if safety and sustained protein expression continue to hold up in phase 3 trials, Dr. Eichenbaum said the practical definition of “durability” may ultimately depend on physician behavior in real-world practice (Figure 2).
“The caveat is that all of these programs tolerate some fluid and all do require some level of supplementation,” he said. “The question is whether the dose that eventually comes to market will be strong enough to discourage doctors from doing more supplemental injections in real-world practice than are given in the clinical trials. We’ll have to see whether physicians become more comfortable tolerating small amounts of persistent or fluctuating fluid, or whether supplementation rates increase in practice. We will also have to see how comfortable physicians are managing the inflammation associated with intravitreal gene therapy, although it looks like we are decreasing the incidence of that as we optimize the dosing and prophylaxis in the registration trials. The large phase 3 trials in AMD—and hopefully DME as well—will help answer that question, and real-world data will be important as these drugs come to market.
“It’s exciting because there’s a lot of directional evidence that we now have durable protein production and durable clinical effect with these drugs.” RP
Figure 2. At Retina World Congress, David A. Eichenbaum, MD, discussed target vector characteristics needed to achieve truly durable intravitreal therapy.