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.

Inclusion criteria

Individuals who meet all the following criteria will be eligible to participate in the study:

• Provide informed consent to study assessments.
• Able and willing to comply with all study assessments for the duration of the study.
• ≥18 years old.
• ETDRS BCVA measured with standard testing distances:

• For the sentinel participant in each cohort, ≤20 letters (Snellen equivalent of 20/200 [1.30 logMAR] or worse)
• For subsequent participants in the same cohort, 65 to 20 letters inclusive (Snellen equivalent of 20/50 [0.40 logMAR] to 20/200 [1.30 logMAR]).
• Genetic confirmation on chromosome 11q12-q13.1 of BVMD or ARB with a BEST1 genetic test or IRD panel test including a BEST1 variant test, by a Clinical Laboratory Improvement Amendments (CLIA) or European certified laboratory. If available test result is more than 15 years old, confirmation testing will be performed at Visit 1, with results needed by Visit 3.
• Confirmation of one disease-causing (pathogenic or likely pathogenic, autosomal-dominant) variant in the BEST1 gene for BVMD, as listed in the IB, or two variants for ARB per American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation.
• BVMD: Clinical phenotype and diagnosis consistent with advanced BVMD with active subretinal fluid or vitelliform material.
• ARB: Clinical phenotype and diagnosis consistent with ARB.

Exclusion criteria

Individuals who meet any of the following criteria will not be eligible to participate in the study.

• Women of childbearing potential (WOCBP) who are pregnant, lactating, and/or unwilling to use effective contraception from Screening through 1 year after IMP administration. See Section 13.3 (Appendix 3) for contraception guidelines.
• Men who are unwilling to use adequate contraception from Screening through 180 days after IMP administration. See Section 13.3 (Appendix 3) for contraception guidelines.
• Have a pre-existing eye condition or complicating systemic disease that could preclude the planned surgery (e.g., individuals who are immunocompromised, on continuous systemic immunosuppressive treatment or anticipate a need to initiate it for non-study reasons, or unable to take the concomitant immuno-suppressive regimen necessary for IMP administration).
• Have a history of disease that may preclude the individual from study participation (e.g., other bestrophinopathy, such as AOFVD or ADVIRC) or that may interfere with or preclude outcome measure testing as described in the protocol.
• Have previously received gene therapy of any kind.
• Presence of active choroidal neovascularization (CNV) that, in the opinion of the Investigator, affects vision or may require treatment.
• Presence of subretinal fibrosis that may significantly limit improvement in visual acuity.
• Have an epiretinal membrane that may require surgical intervention.
• Have undergone tube surgery for glaucoma at any time or have glaucoma that has been unstable within the past 4 years. Note: Prior incisional surgery (e.g., trabeculectomy and iridotomy) is not exclusionary.
• Had intraocular surgery within 90 days prior to planned IMP administration or have active inflammation at Screening resulting from prior ocular surgery.
• Have used any investigational drug or device within 90 days prior to planned IMP administration or plan to participate in another drug or device study during the same period as the current study.
• Have received a vaccination within 6 weeks prior to planned IMP administration or plan to be vaccinated within 6 months after IMP administration.
• Have received anticoagulant therapy within 2 weeks prior to planned IMP administration.
• Have active macular neovascularization as determined by OCT-A.
• Are incapable of performing visual function testing for reasons other than poor vision.
• Have any contraindication to the concomitant steroid regiment proscribed in the protocol.
• Have any other condition (ocular, medical, or psychological) that would not allow the individual to complete follow-up examinations during the study and/or, in the opinion of the Investigator, makes it hazardous or unsuitable for the individual to participate in the study.
• Have a known history of hypersensitivity to constituents or excipients in the pharmaceutical formulation of the IMP.
• Have a known infection of human immunodeficiency virus (HIV), hepatitis B or C virus, or herpes simplex virus.
• Are an employee of the Sponsor or a relative of the Investigator or investigative site staff.