Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 study

**Background:** Neovascular age-related macular degeneration (nAMD) is a leading cause of irreversible vision loss, driven by VEGF-mediated choroidal neovascularization. Standard treatment requires frequent intravitreal anti-VEGF injections, often monthly, leading to high treatment burden and real-world undertreatment. Gene therapy offers a potential durable solution. Ixoberogene soroparvovec (ixo-vec) is a single-dose intravitreal gene therapy using an AAV2.7m8 capsid encoding aflibercept, designed to provide sustained endogenous anti-VEGF production.

**Methods:** This two-year, open-label, prospective, multicentre phase 1 study (OPTIC) enrolled 30 patients with nAMD who had responded to anti-VEGF therapy. Participants were sequentially assigned to four cohorts: cohorts 1 and 4 received high dose (6×10^11 vg/eye) with oral prednisone or topical difluprednate prophylaxis, respectively; cohorts 2 and 3 received low dose (2×10^11 vg/eye) with the same respective prophylaxis. The primary endpoint was safety (type, severity, incidence of ocular and systemic adverse events). Secondary endpoints included mean change in best-corrected visual acuity (BCVA) and central subfield thickness (CST), and number of supplemental aflibercept injections compared to the prior year's annualized rate.

**Key Results:** Thirty patients (mean age ~79 years, 50% female) were enrolled. Baseline mean annualized anti-VEGF injections were 9.6-10.5. No systemic ixo-vec-related adverse events occurred. The most common ocular adverse event was anterior chamber cell (11/15 in high-dose, 7/15 in low-dose). Inflammation was dose-dependent, mild-to-moderate, and responsive to topical corticosteroids. At study end, no low-dose patients had ≥1+ anterior chamber or vitreous cells; 47% of high-dose patients still required topical corticosteroids. Serious ocular adverse events included cataract (2), dry AMD (1), retinal detachment (1), and recurrent uveitis (1). Two deaths (lung malignancy, cardiopulmonary arrest) were unrelated to ixo-vec. BCVA was maintained: mean change +0.2 letters (low dose) and -0.2 letters (high dose). CST decreased: mean change -92.9 μm (low dose) and -60.2 μm (high dose). Annualized anti-VEGF injections were reduced by 80% (from 10.0 to 1.9) in the low-dose group and 98% (from 9.8 to 0.2) in the high-dose group. At week 104, 53% (8/15) of low-dose and 80% (12/15) of high-dose participants required no supplemental injections. Aqueous aflibercept levels remained stable; levels >300 ng/mL correlated with no need for rescue.

**Clinical Implications:** Ixo-vec demonstrates a favorable safety profile and substantial efficacy in reducing anti-VEGF injection burden while maintaining vision and improving anatomical outcomes in nAMD. The 2×10^11 vg/eye dose showed a superior safety profile with comparable efficacy, supporting its further investigation in larger trials (e.g., phase 2 LUNA study). This intravitreal gene therapy approach could transform nAMD management by offering durable disease control with a single injection, potentially reducing the lifelong treatment burden and improving real-world outcomes. Limitations include small sample size, open-label design, lack of comparator arm, and potential bias in rescue injection decisions.