J1 - Gene Therapy Trials - In-Vivo Modification
917: Longitudinal Analysis of BCVA and Near-Field Object Recognition in Low- or High-Dose MCO-010 Mutation Agnostic Optogenetic Therapy for Retinitis Pigmentosa: 12-Month Results from a Phase 2b/3 Randomized, Sham-Controlled, Patient- and Assessor-Masked Clinical Trial (RESTORE)
Type: Poster Session
Poster Board Number: 917
Presentation Details
Session Title: Wednesday Posters: Gene Therapy Trials - In Vivo Modification
Purpose MCO-010 is a gene mutation agnostic optogenetic therapy being evaluated in an ongoing Phase 2b/3 RESTORE clinical trial in individuals with advanced retinitis pigmentosa (RP). We performed an analysis of 52-week longitudinal data to evaluate the safety and efficacy of a single administration of 2 different doses of MCO-010 therapy vs sham. MCO-010 is an AAV2-delivered multi-characteristic opsin (MCO) transgene administered by intravitreal injection. MCO-010 transduces bipolar cells to express a photosensitive opsin protein, restoring light sensitivity to the retina in patients with RP.
Methods Subjects had an advanced RP clinical diagnosis and baseline visual acuity worse than 1.9 logMAR (CF, 20/1600 equivalent) in the study eye and no better than 1.6 logMAR in the fellow eye. Subjects (n = 27) were randomized 1:1:1 to receive a single dose of 0.9E11 gc/eye (low-dose), 1.2E11 gc/eye (high-dose) MCO-010, or sham IVT in the study eye at day 0. Visual function was assessed systematically through week 52 by best-corrected visual acuity (BCVA) using Freiburg visual acuity and a multi-luminance shape discrimination test (MLSDT). BCVA data were analyzed comparing the low- or high-dose MCO-010-treated individuals vs sham using a mixed-effects model for repeated measures with treatment, visit, and treatment-by-visit interaction as factors in the model, using the baseline score as a covariate. MLSDT data were analyzed by comparing the baseline scores of the low-dose, high-dose or sham vs Week 52 scores using a paired samples t-test.
Results MCO-010 patients had mean baseline BCVA scores of 2.207 ± 0.105 and 2.250 ± 0.00 logMAR (low- and high-dose, respectively), and the sham patients had a mean baseline BCVA of 2.172 ± 0.1342 logMAR. The following BCVA results are reported from weeks 16, 24, 36, and 52. Compared to sham, low-dose MCO-010 patients had a mean improvement of 0.160, 0.192, 0.431, and 0.336 logMAR (P = 0.2780, 0.1958, 0.0060 and 0.0300 respectively). High-dose MCO-010 patients had a mean improvement of 0.022, 0.197, 0.214, and 0.287 logMAR (vs sham; P = 0.8392, 0.0765, 0.0544 and 0.0103, respectively). MCO-010 patients had mean baseline MLSDT scores of 1.44 ± 0.67 and 0.22 ± 0.15 (low- and high-dose, respectively), and the sham patients had a mean baseline MLSDT score of 1.67 ± 0.62. The following MLSDT results are reported as the mean change from baseline for weeks 16, 24, 36 and 52. The low-dose MCO-010 patients had mean scores of 0.22, 0.00, 1.22, and 1.33 (P = 0.8337, 1.000, 0.2489, and 0.2721, respectively). High-dose MCO-010 patients had mean scores of 1.57, 0.78, 1.00, and 1.89 (P = 0.0914, 0.2594, 0.1599, 0.0265, respectively). Sham patients had mean scores of -0.25, 0.33, -0.11, and 0.22 (P = 0.7486, 0.6666, 0.5943, and 0.8032, respectively). MCO-010 was well tolerated with no serious adverse effects observed through week 52.
Conclusion BCVA assessed with Freiburg visual acuity can objectively quantify visual acuity for low-vision patients on a logMAR scale and has been recommended for clinical trials in individuals with low vision, including optogenetics, by the International HOVER Taskforce (Harmonization of Outcomes and Vision Endpoints in Vision Restoration Trials). The RESTORE data further support the validity of using Freiburg visual acuity for low-vision patients as an efficacy endpoint. RESTORE data demonstrate MCO-010-treated patients improved in BCVA in both dose groups, compared to sham-treated patients, where statistically significant improvements in visual acuity were observed at week 36 and was maintained through the 52-week study. Furthermore, a dose-dependent improvement in near-field object recognition was observed in the MCO-010-treated patients; the high-dose patients statistically improved in MLSDT at week 52 compared to baseline.
Plain Language Summary
MCO-010 is a gene therapy used to restore vision in patients with retinitis pigmentosa (RP) by targeting retinal bipolar cells to become sensitive to light—supplementing the need for functional photoreceptors. Twenty-Seven patients with RP were enrolled in the RESTORE Phase 2b/3 clinical study, where 18 patients were treated with a single dose of MCO-010 and 9 patients were treated with sham. Patients were subjected to a visual acuity test and a near-field object recognition test. MCO-010-treated patients made statistically significant improvements in visual acuity, a finding reported at week 36 that was maintained through week 52. Additionally, we found MCO-010-treated patients experienced modest improvements in object recognition. Furthermore, MCO-010 was well tolerated with no serious adverse effects. This suggests a promising step forward in treating vision loss for patients with RP.
Samuel Barone
Nanoscope Therapeutics, Dallas, TX"
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