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

Abstract

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.

Keywords: Multi-characteristic opsin; Optogenetics; Retinal degenerative disease; Stargardt macular degeneration; Vision restoration.

Fig. 1

Profile and design of phase 2 STARLIGHT study of MCO-010 in stargardt disease. BCVA: Best-corrected visual acuity; ITT: Intent-to-treat; MRDQ: Michigan Retinal Degeneration Questionnaire.

Fig. 2

Cross-sectional and Fundus imaging of the enrolled subjects at baseline. Left: B-scan OCT images of study eye at baseline, showing the presence of the target (inner nuclear) layer in the participants. Right: FAF images of the subjects at baseline and end of study visit. Two distinct phenotypes associated with Stargardt disease as shown in the representative fundus autofluorescence images: atrophy confined to macula, and panretinal atrophy with widespread scalloped pattern atrophy of the retinal pigment epithelium and disease involving the peripapillary region. The classification of the Group is based on Fundus Autofluorescence.

Fig. 3

Longitudinally-measured change in best-corrected visual acuity of study eye following MCO-010 treatment, assessed with ETDRS chart. Mean change in BCVA from baseline: assessed with ETDRS chart (A) Without wearable magnifier (not performed for Subject 04 Week 32), and (B) with wearable magnifier (not performed for Subject 02 at Week 48, and Subject 04 at Week 4, 24). Data show BCVA mean ± SEM, with LOCF of missing data. Change in ETDRS letter score from baseline of individual participants at Week 48: (C) Without wearable magnifier, and (D) with wearable magnifier (∗Subject 02 LOCF from Week 24). BCVA, best-corrected visual acuity; ETDRS, early treatment of diabetic retinopathy study; LOCF: Last Observation Carried Forward.

Fig. 4

Longitudinally measured change in best-corrected visual acuity of fellow eye following MCO-010 treatment, assessed with ETDRS chart. Mean change in BCVA from baseline: assessed with ETDRS chart (A) Without wearable magnifier, and (B) with wearable magnifier (not performed for Subject 02 at Week 48, and Subject 04 at Week 4, 24). Data show BCVA mean ± SEM, with LOCF of missing data. Change in ETDRS letter score from baseline of individual participants at Week 48: (C) Without wearable magnifier, and (D) with wearable magnifier. BCVA, best-corrected visual acuity; ETDRS, early treatment of diabetic retinopathy study; LOCF: Last Observation Carried Forward.

Fig. 5

Impact of MCO-010treatment on patient-reported outcomes and visual field of study and fellow eyes. Michigan Retinal Degeneration Questionnaire (MRDQ) Domain scores of individual participants at baseline and post-injection time points; (A) Reading score, (B) Color and contrast score. (C) Mean improvements at Week 48 in MRDQ domain scores from baseline. Data show mean ± SEM. (D) Longitudinally measured mean defect (MD) of visual field of individual participant’s study eye assessed using Octopus visual field perimetry (data not collected for Subject 01 at Week 48, and Subject 04 at Week 4, 24). (E) Mean MD ± SEM study eye, with LOCF of missing data. (F) Change from baseline (CFB) Mean defect of individual participants at Week 48. (G) Longitudinally measured MD of the visual field of the individual participant’s fellow eye (data not collected for Subject 04 at Week 4, and 24). (H) Mean MD ± SEM, with LOCF of missing data. LOCF: Last Observation Carried Forward.