Gene Therapy in Neovascular Age-related Macular Degeneration: Three Year Follow-up of a Phase 1 Randomised Dose Escalation Trial

Purpose To assess the safety of rAAV.sFlt-1 subretinal injection in neovascular age-related macular degeneration (wet AMD) over 36 months. Design Phase 1 dose escalation trial. Methods Eight subjects with advanced, treatment-experienced wet AMD were randomly assigned (3:1) to treatment and non-gene therapy control groups. Eligible subjects were ≥65 years, had wet AMD and best corrected visual acuity (BCVA) 10/200 -20/80 in the study eye and 20/200 or better in the other eye. Three of the treatment group subjects received low dose (1X1010 vector genomes) and three high dose (1X1011 vector genomes) rAAV.sFLT-1 via subretinal injection. Study monitoring was monthly to the primary endpoint at month 12 and then protocol-driven follow-up study visits were conducted at months18 and 36. All subjects received intravitreal ranibizumab at baseline and week 4, and retreatment injections at subsequent visits based on pre-specified criteria for active wet AMD. The primary end-point was ocular and systemic safety but exploratory data including BCVA, retinal centre point thickness and the number of ranibizumab retreatments at and between study visits were also analyzed. Results Six (75%) of the 8 subjects completed the 36 month study. Subretinal injection with pars plana vitrectomy was well tolerated in this cohort. No ocular or systemic safety signals were observed during the long-term follow-up period. Exploratory data analysis suggests stability of wet AMD over the 36-month period. Conclusions Subretinal delivery of rAAV.sFLT-1 was well tolerated and demonstrated a favorable safety profile through month 36. Thus, rAAV.sFLT-1 could be safely considered for future evaluation in the treatment of wet AMD.