Interim results for the Phase 1/2 PRISM Trial evaluating 4D-150, a dual-transgene intravitreal genetic medicine in individuals with neovascular (wet) age-related macular degeneration

Abstract

Purpose : 4D-150 is a single-dose intravitreal (IVT) retinotropic AAV vector (R100) carrying two transgenes encoding aflibercept (AFLB) and an miRNA sequence targeting VEGF-C. Here we report first-time interim results from the dose exploration portion of the Phase 1/2 PRISM study evaluating the safety and activity of 4D-150 in individuals with neovascular (wet) age-related macular degeneration (wAMD) who require frequent anti-VEGF therapy.

Methods : PRISM is an ongoing, multicenter, open-label dose exploration and randomized expansion study (NCT05197270). In the dose exploration phase, individuals ≥50 years of age with study eye macular neovascularization secondary to AMD and best corrected visual acuity (BCVA) of 25-78 letters were enrolled in 3 dose cohorts: 3×10¹⁰, 1×10¹⁰, and 6×10⁹ vg/eye (n=5/cohort; Fig. 1). The primary objective was evaluation of 4D-150 safety and tolerability. Annualized number of supplemental AFLB injections post-4D-150 and changes in BCVA and central subfield thickness (CST) were also assessed.

Results : As of the data cutoff, enrollment in the exploration phase was complete (n=15; Table 1). 4D-150 was safe and well tolerated, with no reported dose-limiting toxicities or 4D-150–related serious adverse events, and no clinically significant intraocular inflammation, endophthalmitis, retinal vasculitis, retinal artery occlusion, choroidal effusions, or hypotony. Follow-up was longest for the 3×10¹⁰ vg/eye cohort (12-40 weeks), which had a mean annualized anti-VEGF injection rate of 10.8 before 4D-150. Following 4D-150 injection, a 96.7% overall reduction in mean annualized anti-VEGF injection rate was observed, and 4 of 5 eyes were supplemental AFLB injection-free. Aqueous humor samples from the 3 eyes evaluated to date had detectable AFLB. New data from this ongoing first-in-human study will be presented, including complete follow-up data for all participants (≥6 months).

Conclusions : 4D-150 was safe and well tolerated at doses ranging from 6×10⁹ to 3×10¹⁰ vg/eye. Encouraging evidence of clinical activity was observed. These preliminary data suggest that in individuals with wAMD requiring frequent anti-VEGF treatment, a single, routine, in-office IVT injection of 4D-150 may potentially provide sustained AFLB expression and reduce treatment burden.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.