Safety and efficacy of MCO-010 optogenetic therapy in patients with Stargardt disease in USA (STARLIGHT): an open-label multi-center Ph2 trial.

Background: Stargardt disease (SD) is an inherited degenerative retinal disease affecting rod and cone photoreceptors and retinal pigment epithelial (RPE) cells, leading to severe and irreversible vision loss. Optogenetics is a promising approach to restoring vision by photosensitizing spared healthy retinal neurons. Methods: The STARLIGHT phase 2 open-label study (NCT05417126) was conducted over 48-weeks at two US sites to assess the safety and efficacy of MCO-010 administered via a single intravitreal injection in the worse-seeing eye of SD patients. The study began on July 5, 2022, and was completed on September 28, 2023. MCO-010 targets bipolar cells rather than retinal ganglion cells (RGCs) to utilize more abundant cells that respond to ambient light while preserving natural visual processing pathways after treatment. Six adults (mean age 50 years, range 32-71 years, four males and two females) received 1.2E11 genome copies (gc)/eye of MCO-010. The primary outcome was the incidence, nature, severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), intraocular inflammation, retinal thickness, best-corrected visual acuity (BCVA), and lesion size. Secondary endpoints included change in BCVA, vision-guided mobility, and shape determination accuracy. Visual field perimetry and Michigan Retinal Degeneration Questionnaire (MRDQ) were exploratory endpoints. Findings: All six participants had at least one ocular TEAE; non-ocular TEAEs occurred in three participants. The most common TEAEs were conjunctival hemorrhage, ocular hypertension, and vitreous cells (two subjects). There were no deaths, hospitalization, loss of eye, retinal detachment, endophthalmitis, or TEAEs leading to study discontinuation. The BCVA (mean ± SD) of the six treated eyes at baseline and 48-week follow-up was 22.8 ± 9.87 (range 9-35), and 28.3 ± 13.28 (range 4-42) ETDRS letters, respectively. The BCVA change from baseline was 7.2 ± 11.74, 4.2 ± 14.81, and 5.5 ± 12.29 at 12, 24, and 48 weeks, respectively. With a wearable magnifier (low-vision glasses), the BCVA change was 17.8 ± 13.35, 15.7 ± 17.37, 13.3 ± 21.37 at 12, 24, and 48 weeks, respectively. The improvement in mean defect in visual field perimetry was 1.02 ± 3.54, 2.47 ± 5.00, and 2.63 ± 5.26 dB at 12, 24, and 48 weeks, respectively. Specific improvements were noted in reading, and color, and contrast domains of the MRDQ. Interpretation: MCO-010 optogenetic phase 2 results support further investigation for treatment SD. To our knowledge, this is the first report of improving on(eye)-chart vision of SD participants utilizing optogenetics. Funding: Nanoscope Therapeutics Inc.