ASRS Day 3: Subretinal gene therapy for neovascular AMD

Raziyeh Mahmoudzadeh, MD
Retina Research Fellow
The Retina Service of Wills Eye Hospital

On the third day of ASRS 2021 meeting, Dr. Lejla Vajzovic, presented the end of phase I/IIa study results of the subretinal delivery of RGX-314 for neovascular age related macular degeneration (nAMD).

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RGX-314 uses a novel AAV8 vector to deliver an anti-vascular endothelial growth factor (VEGF) Fab. This vector has a high transfection rate and potent transduction rate that can create an ocular biofactory. The RGX-314 phase I/IIa trial involved 42 patients across eight sites in the USA, and all these patients were previously treated with frequent injections. This was a dose-escalating trial and consisted of five cohorts. Each patient received ranibizumab with a documented positive response on optical coherence tomography (OCT) imaging prior to enrollment. The retreatment threshold was set very low, and any fluid or any disease activity retreated. The typical enrolled patient was an eighty-year-old patient requiring injections for the last four to five years, receiving about 33 injections and about 9-10 injections in the year prior to enrollment.

Regarding safety, RX-314 continues to be generally well-tolerated across all doses. There were no reports of clinically determined immune responses, drug-related ocular inflammation (such as retinal vasculitis and occlusive vasculitis), or post-surgical inflammation beyond what is expected following routine vitrectomy. The only significant finding was retinal pigmentary change in about 70% of patients, especially in higher dose cohorts, and two patients had severe vision loss in higher dose cohorts.

Regarding the efficacy, the mean best-corrected visual acuity (BCVA) was stable to improved in the study cohorts across the two years, and the higher dose cohorts gained more vision. The placebo cohort, though, had a vision loss of eight letters and received about 10 re-injections during the study period.

There was a significant reduction in the retreatment rate, roughly 60% reduction in the lower dose cohorts and 80% in the higher dose cohorts. Notably, the two-year data showed that the RGX-314 protein production level was maintained throughout the study, which is an important achievement in gene therapy delivery. These exciting findings have fueled the design of the first pivotal clinical trial called ATMOSPHERE. This clinical trial aims to enroll 300 patients across 60 sites in the USA.

In conclusion, RGX-314 remains generally well-tolerated in patients with nAMD. In addition, a long-term, durable treatment effect demonstrated stable to improved visual acuity, retinal thickness, and meaningful reduction in intravitreal anti-VEGF injection burden over a two-year follow-up.