Intravitreal photoswitch therapy in advanced retinitis pigmentosa: a phase 1 open-label trial.

A small azobenzene photoswitch molecule (KIO-301), designed to confer light responsiveness to retinal ganglion cells, was evaluated for safety and feasibility in a first-in-human, phase 1, gene-agnostic, open-label, dose-escalation clinical trial in individuals with advanced retinitis pigmentosa (RP). KIO-301 was administered by intravitreal injection to 12 eyes of 6 participants. The primary outcome was ocular and systemic safety over 30 days. Secondary and exploratory assessments included functional vision testing, visual acuity, kinetic visual field, functional magnetic resonance imaging and participant-reported outcomes. The primary safety outcome was met, with no serious adverse events or dose-limiting toxicities observed at any point. No drug-related intraocular inflammation occurred, and all ocular adverse events were mild and procedure-related. Exploratory assessments identified variation in light perception and functional vision measures in some participants. Light-evoked blood-oxygen-level-dependent signal changes in visual cortical regions were observed following dosing and showed a temporal pattern compatible with pharmacodynamic activity. Participant-reported quality-of-life scores varied over time. In this small, nonrandomized phase 1 study in individuals with late-stage RP, intravitreal KIO-301 demonstrated an acceptable safety and tolerability profile, supporting the feasibility of photoswitch therapy in advanced RP, and motivating further evaluation in larger trials. ClinicalTrials.gov identifier: NCT05282953.