Safety and Tolerability of Subretinally Injected OPGx-BEST1 in Patients With Best Vitelliform Macular Dystrophy (BVMD) or Autosomal-Recessive Bestrophinopathy (ARB)

This is a Phase 1b/2a, open-label, dose-exploring, safety and tolerability basket study of a single subretinal injection of OPGx-BEST1 in one eye of adult participants with ARB or BVMD due to BEST1 mutations. OPGx-BEST1 has been bioengineered to include a transgene expression cassette with a codon-optimized, full-length hBEST1 gene under the control of an RPE-specific promoter. The vector genome contains inverted terminal repeats flanking an expression cassette containing the VMD2 promoter, full-length BEST1 ORF followed by SV 40 and bGH polyadenylation signal sequences, and lastly includes a kanamycin resistance gene. The Kozak sequence (upstream of the start codon) enhances the translation from the correct initiation codon. Selection of the VMD2 promoter was done to restrict the expression to the target cell type and drive expression levels comparable to those in photoreceptors. This intervention is a one-time injection. Two vector doses are proposed for evaluation: 1.5E9 vg/eye (Cohort 1) and 4.5E9 vg/eye (Cohort 2). A minimum of 5 evaluable participants will be treated at each dose level, starting with a sentinel participant in Cohort 1. An Independent Data Monitoring Committee (IDMC) will evaluate safety 30 days after treatment of the sentinel participant before the remaining 4 participants in Cohort 1 are eligible for treatment. After the last participant has completed the Month 3 visit, the IDMC will review all Cohort 1 data and determine whether to initiate enrollment in Cohort 2 or adjust the dose escalation scheme. Each participant will have a Screening visit and two-part Baseline visit. On Day 1 (Visit 4), participants will undergo vitrectomy with subretinal injection of OPGx-BEST1 at the preassigned dose. Participants will return for follow-up on Day 2, Day 7, Day 14, Day 30, and Day 45 following IMP administration (Visits 5-9). Participants will also return 3 and 6 months following IMP administration (Visits 10-11) and 1, 1.5, 2, 3, 4, and 5 years following IMP administration (Visits 12-17). Post-IMP administration, safety and efficacy outcomes will be evaluated for 5 years. In addition to the primary objectives of establishing IMP safety and tolerability and identifying the most appropriate dose strength, the study will evaluate the preliminary efficacy of OPGx-BEST1 and characterize the immunogenic effects of administration. A central reading center will provide standardized evaluation of select imaging data. Analysis of results will include treatment-eye comparisons of visual function post-administration of OPGx-BEST1 to baseline visual function.