Gene Therapy Delivers Sustained Retinal Protection

The investigational gene therapy ixoberogene soroparvovec (Ixo-vec) helped patients maintain vision and left active levels of the therapeutic protein in the eye 5 years after an initial injection, according to results of an extension trial presented at the American Society of Retina Specialists (ASRS) 2026 Annual Meeting in Montreal.The drug, a long-term treatment for neovascular age-related macular degeneration (AMD), also significantly reduced the need for supplemental injections.“For a first-in-human program in a chronic, vision-threatening disease, the 5-year data are extremely encouraging,” said Szilard Kiss, MD, professor of ophthalmology and genetic medicine at Weill Cornell Medicine in New York City.Gene therapy holds significant promise for reducing the number of intravitreal injections people with retinal disease need, said Sunir Garg, MD, chief of the retina service at Wills Eye Hospital in Philadelphia, who was not involved with the research. Patients on anti-VEGF therapy can also lose vision over time due to disease progression, macular atrophy, or even undertreatment, he said.“Gene therapy has the potential to mitigate some of this loss by providing more sustained drug delivery over time,” Garg said. “When I speak with my patients who have had ongoing injections for neovascular AMD, I explain that my goal is to help them maintain their vision while reducing how often they need injections.”Kiss and colleagues presented results from an extension trial of 15 patients treated with Ixo-vec at a dose of 200 billion vector genes per eye. The patients had a high treatment burden before they enrolled in the trial, averaging nearly 10 injections a year.The patients had “durable” aqueous levels of the anti-VEGF protein aflibercept following a single injection of Ixo-vec for up to 5 years, Kiss said.‘Durable’ Anti-VEGF LevelsPatients showed a sustained improvement in central subfield thickness, an anatomic biomarker of fluid in the retina, with an average reduction of 131.6 µm at 5 years.Overall, low-dose patients also needed fewer supplemental, rescue anti-VEGF injections after receiving the Ixo-vec injection than they did before, dropping from 1.9 injections in the second year to 1.3 injections in the fifth year.After excluding two patients with progressive disease, the remaining 13 patients on the low dose showed a mean gain of 0.9 Early Treatment Diabetic Retinopathy Study letters after 5 years, Kiss said. With the excluded patients, overall letters dropped by 6.1.That compares favorably with long-term outcomes on existing therapies, he said.“On average on current treatments after 5 years, patients lose 12-17 letters,” Kiss said.No new treatment-related serious adverse events, hypotony, vasculitis, choroiditis, or vascular occlusion events were reported. Intraocular pressure remained stable, and all patients remained inflammation-free through 5 years, excluding one patient who had complex cataract surgery.“The expectation for this approach was not that every patient would never need another injection, but that a single intravitreal gene therapy could provide sustained intraocular anti-VEGF expression, markedly reduce the need for repeated injections, maintain anatomic disease control, and do so with an acceptable long-term safety profile,” Kiss told Medscape Medical News.Garg said he was surprised by the loss of vision that low-dose patients experienced.“I look forward to understanding why that occurred — whether due to persistent disease activity, development of outer retinal atrophy, or some other reason,” he said.Two phase 3 trials evaluating a higher dose of 600 billion vector genes of Ixo-vec are ongoing and include patients who have and have not been treated for their disease, Kiss said.“These studies are designed to determine whether a single intravitreal injection of Ixo-vec can provide comparable visual outcomes to standard aflibercept therapy while substantially reducing treatment burden,” he said.Long-term safety data on gene therapy in AMD are needed, particularly with regard to risks for inflammation, changes to the retinal pigment epithelium, and preservation of vision, Garg said.Kiss was a consultant and a member of the board of directors of Adverum Biotechnologies and is a consultant to Eli Lilly and Company. Garg reported financial relationships with Regeneron Pharmaceuticals and Genentech. Richard Mark Kirkner is a medical journalist based in the Philadelphia area.