The goal of this clinical trial is to learn if drug OPGx-BEST1 works to treat BVMD and ARB Bestrophinopathy. It will also learn about the safety of drug OPGx-BEST1. The main questions it aims to answer are: Evaluate the safety and tolerability of drug OPGx-BEST1 in one eye (the treatment eye), for 5 years post-injection, in participants with BVMD or ARB. A second question it aims to answer is identification of the most appropriate dose strength of OPGx-BEST1 for clinical development. Evaluate the efficacy of single injection of OPGx-BEST1 in one eye for 5 years post-injection. What medical problems do participants have when taking drug OPGx-BEST1?
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
10
Experimental Genetic Therapy
Children's Hospital Los Angeles
Los Angeles, California, United States
RECRUITINGRetina Foundation of the Southwest
Dallas, Texas, United States
RECRUITINGNumber of dose-limiting toxicity (DLT) events at the dose tested
Number of dose-limiting toxicity (DLT) events, defined as any ≥Grade 3 toxicity that occurs within 90 days after IMP administration based on the National Cancer Institute common toxicity criteria
Time frame: 5 years
Number and severity of procedure-related adverse events
Number and severity of adverse events related to the administration of OPGx-BEST1 involving pars plana vitrectomy and subretinal injection under general anesthesia
Time frame: 5 years
Number and severity of adverse events related to OPGx-BEST1
Number and severity of adverse events considered related to the study drug, OPGx-BEST1
Time frame: 5 years
Changes from baseline in retinal morphology assessed by spectral-domain optical coherence tomography
Changes from baseline in retinal morphology assessed by spectral-domain optical coherence tomography
Time frame: 5 years
Changes from baseline in retinal morphology assessed by 55 degree fundus autofluorescence (FAF)
Changes from baseline in retinal morphology assessed by 55 degree fundus autofluorescence (FAF)
Time frame: 5 years
Changes from baseline in retinal morphology assessed by ultra-wide angle autofluorescence (FAF)
Changes from baseline in retinal morphology assessed by ultra-wide angle autofluorescence (FAF)
Time frame: 5 years
Changes from baseline in neovascularization assessed by optical coherence tomography
Changes from baseline in neovascularization assessed by optical coherence tomography angiography
Time frame: 5 years
Changes from baseline in retinal sensitivity
Changes from baseline in retinal sensitivity assessed by microperimetry
Time frame: 5 years
Changes from baseline in best corrected visual acuity
Changes from baseline in best corrected visual acuity letter score as measured by Early Treatment Diabetic Retinopathy Stuidy (ETDRS) charts
Time frame: 5 years
Changes from baseline in low luminance visual acuity
Changes from baseline in low luminance visual acuity assessed by ETDRS charts
Time frame: 5 years
Changes from baseline in participant-reported outcomes
Changes from baseline in participant-reported outcomes assessed by the Michigan Retinal Degeneration Questionnaire
Time frame: 5 years
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