Phase I/IIa Study of an Intravitreal Optogenetic Therapy (AGN-151597) in Patients with Advanced Retinitis Pigmentosa

Objective: Retinitis pigmentosa is an incurable, inherited retinal disease that causes vision loss and blindness. We evaluated the safety and preliminary efficacy of AGN-151597, a mutation-independent optogenetic therapy encoding channelrhodopsin-2, in patients with advanced retinitis pigmentosa. Design: First-in-human, phase I/IIa, open-label, dose-escalation study (1 study eye/participant). Participants: Participants had advanced retinitis pigmentosa with severely impaired visual function. Methods: vg/eye; n = 7) AGN-151597 in the study eye. The study duration was 24 months followed by a 3-year safety extension. Main Outcome Measures: The primary safety endpoint was safety at 6 months as assessed by intraocular pressure and changes in visual acuity, full-field sensitivity, ambulation, and visual anatomical parameters. Efficacy measures included changes in visual acuity, full-field stimulus threshold (FST), ambulation, object detection/discrimination, visual evoked potentials, electroretinography, and visual function-related quality of life (questionnaire). Results: Fourteen patients (median age 62 years) were enrolled. AGN-151597 treatment resulted in no clinically significant changes in ocular safety assessments. Most treatment-emergent adverse events (TEAEs) were ocular; none were severe. The most common treatment-related TEAE was transient increased intraocular pressure (n = 3). No clinically significant efficacy was observed. Full-field stimulus threshold measurements in both eyes showed good agreement between the screening and baseline visits, with coefficients of repeatability of 6.2 for blue light, 2.7 for red light, and 5.3 for white light. Overall mean FST in study eyes at baseline was -13.5 dB for blue light, -1.0 dB for red light, and -5.2 dB for white light. Participants' mean FST changed similarly in both eyes over 24 months for each light stimulus. Conclusions: There was no evidence of AGN-151597 efficacy in slowing vision decline in patients with advanced retinitis pigmentosa. However, the absence of safety concerns over 5 years after intravitreal administration of an adeno-associated virus type 2 vector-delivered genetic medicine is encouraging and supports further gene therapy endeavors to enhance visual function in this devastating retinal disease. Full-field stimulus threshold is a reliable test in patients with poor vision. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.