OPGx-BEST1 subretinal gene therapy for Best vitelliform macular dystrophy and autosomal-recessive bestrophinopathy

A Phase 1b/2a, Open-Label, Dose-Exploration Basket Study to Investigate the Safety and Tolerability of Subretinally Injected OPGx-BEST1 Administered in Patients With Either Autosomal-Dominant BEST1 Disease (Best Vitelliform Macular Dystrophy [BVMD]) or Autosomal-Recessive Bestrophinopathy (ARB)

This trial will test whether a one-time subretinal gene therapy called OPGx-BEST1 is safe and can improve or stabilize vision in adults with Best vitelliform macular dystrophy (BVMD) or autosomal-recessive bestrophinopathy (ARB) in one eye.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 10 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Opus Genetics, Inc (Industry-sponsored)
• Locations: 4 sites (Los Angeles, California and 3 other locations)
• Trial ID: NCT07185256 on ClinicalTrials.gov

What this trial studies

This is a Phase 1b/2a, open-label, dose-escalation study delivering a single subretinal injection of OPGx-BEST1 to one eye of adults with genetically confirmed BEST1-related BVMD or ARB. Two vector dose levels (1.5 x 10^9 vg/eye and 4.5 x 10^9 vg/eye) will be tested, beginning with a sentinel participant and reviewed by an independent data monitoring committee before dosing the remainder of the cohort. Study participants will be followed for safety, tolerability, and exploratory efficacy measures for up to five years after injection. Enrollment requires genetic confirmation of BEST1 variants and prespecified visual acuity criteria, and procedures are performed at specialized ophthalmic centers.

Who should consider this trial

Good fit: Adults (≥18 years) with genetically confirmed BEST1-related BVMD or ARB who meet the study's visual acuity criteria and can attend long-term follow-up visits are the intended participants.

Not a fit: People without a confirmed BEST1 mutation, those whose vision loss is due to other retinal diseases, or those with advanced, irreversible retinal damage are unlikely to benefit from this intervention.

Why it matters

Potential benefit: If successful, a single gene-replacement injection could preserve or improve retinal function in the treated eye and slow vision loss from BEST1-related disease.

How similar studies have performed: Gene-replacement treatments have produced durable benefit in other inherited retinal disorders (for example, RPE65 disease), but human data specific to BEST1 gene replacement are limited, so this approach is relatively novel.

Eligibility criteria

Inclusion Criteria:

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

1. Provide informed consent to study assessments.
2. Able and willing to comply with all study assessments for the duration of the study.
3. ≥18 years old.
4. ETDRS BCVA measured with standard testing distances:

   1. For the sentinel participant in each cohort, ≤20 letters (Snellen equivalent of 20/200 \[1.30 logMAR\] or worse)
   2. For subsequent participants in the same cohort, 65 to 20 letters inclusive (Snellen equivalent of 20/50 \[0.40 logMAR\] to 20/200 \[1.30 logMAR\]).
5. 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.
6. 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.
7. BVMD: Clinical phenotype and diagnosis consistent with advanced BVMD with active subretinal fluid or vitelliform material.
8. 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.

1. 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.
2. 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.
3. 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).
4. 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.
5. Have previously received gene therapy of any kind.
6. Presence of active choroidal neovascularization (CNV) that, in the opinion of the Investigator, affects vision or may require treatment.
7. Presence of subretinal fibrosis that may significantly limit improvement in visual acuity.
8. Have an epiretinal membrane that may require surgical intervention.
9. 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.
10. Had intraocular surgery within 90 days prior to planned IMP administration or have active inflammation at Screening resulting from prior ocular surgery.
11. 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.
12. Have received a vaccination within 6 weeks prior to planned IMP administration or plan to be vaccinated within 6 months after IMP administration.
13. Have received anticoagulant therapy within 2 weeks prior to planned IMP administration.
14. Have active macular neovascularization as determined by OCT-A.
15. Are incapable of performing visual function testing for reasons other than poor vision.
16. Have any contraindication to the concomitant steroid regiment proscribed in the protocol.
17. 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.
18. Have a known history of hypersensitivity to constituents or excipients in the pharmaceutical formulation of the IMP.
19. Have a known infection of human immunodeficiency virus (HIV), hepatitis B or C virus, or herpes simplex virus.
20. Are an employee of the Sponsor or a relative of the Investigator or investigative site staff.

Where this trial is running

Los Angeles, California and 3 other locations

• Children's Hospital Los Angeles — Los Angeles, California, United States (Recruiting)
• Vitreo Retinal Associates — Gainesville, Florida, United States (Not_yet_recruiting)
• Cincinnati Eye Institute — Cincinnati, Ohio, United States (Recruiting)
• Retina Foundation of the Southwest — Dallas, Texas, United States (Recruiting)

Study contacts

• Study coordinator: Study Director

Conditions ARB; BVMD; Autosomal-Dominant Bestrophinopathy; Best Vitelliform Macular Dystrophy; Bestrophinopathy; OPGx-BEST1; Best vitelliform macular dystrophy