PurposeTo report long-term results from a Phase 1/2a clinical trial assessment of a scaffold-based human embryonic stem cell-derived retinal pigmented epithelium (RPE) implant in subjects with advanced geographic atrophy (GA). DesignThe study was a US Food and Drug Administration (FDA)-approved single-arm, open-label Phase 1/2a clinical trial. SubjectsSubjects were between the ages of 69 and 85 at the time of enrollment and were legally blind in the treated eye (best corrected visual acuity (BCVA) of ≤ 20/200) as a result of GA involving the fovea. InterventionThe clinical trial enrolled 16 subjects, 15 of whom were successfully implanted. The implant was administered to the worse-seeing eye with the use of a custom subretinal insertion device. The companion non-implanted eye served as the control. The primary endpoint was at 1 year; thereafter subjects were followed at least yearly. Main Outcome MeasuresSafety was the primary endpoint of the study. The occurrence and frequency of adverse events were determined by scheduled eye exams, including measurement of BCVA, intraocular pressure, and multimodal imaging (fundus photography, optical coherence tomography, and fluorescein angiography). In addition, serum antibody titers were collected to monitor systemic humoral immune responses to the implant cells. ResultsAt a median follow-up of three years, fundus photography revealed no migration of the implant. There were no unanticipated, severe, implant-related adverse events throughout the follow-up period, and the most common anticipated severe adverse event (severe retinal hemorrhage) was eliminated in the second cohort (9 subjects) through the use of improved intraoperative hemostasis. Non-severe, transient retinal hemorrhages were noted either intra-op or post-op in all subjects as anticipated for a subretinal surgical procedure. Throughout the median 3-year follow-up, the results show that implanted eyes were more likely to improve by >5 letters BCVA, and less likely to decrease by >5 letters compared to non-implanted eyes. ConclusionsThis report details the long-term follow-up of the largest study of subjects with GA to receive a scaffold-based stem cell-derived bioengineered RPE implant. Results show that the implant, at a median 3-year follow-up, is safe and well-tolerated in subjects with advanced dry AMD. The safety profile, along with the early indication of efficacy, warrants further clinical evaluation of this novel approach for the treatment of GA.