Safety and Tolerability of Subretinal OPGx-RDH12-1001 for LCA-Associated Inherited Retinal Degeneration (LCA-IRD)

A Phase 1b/2a Open-Label, Dose-Exploration Study to Investigate the Safety and Tolerability of Subretinally Injected OPGx-RDH12 Administered in Participants With Leber Congenital Amaurosis With Autosomal-Recessive Retinol Dehydrogenase 12 Mutations

This study is an early-stage clinical trial (Phase 1b/2a) testing a gene therapy called OPGx-RDH12 for people with Leber Congenital Amaurosis (LCA) caused by mutations in the RDH12 gene, a rare genetic eye disease that leads to severe vision loss. The treatment is delivered as a one-time injection (300 µL) into the retina (subretinal space) of the worse-seeing eye, using a method similar to approved gene therapies like Luxturna. The study is designed to evaluate safety and effectiveness at two dose levels (1E11 and 3E11 viral genomes per eye) in small groups of 5 participants. Each group begins cautiously with 2 adults (age ≥18), treated at least one month apart, followed by FDA review before allowing adolescents (ages 12-17) to participate. An independent monitoring committee (IDMC) oversees safety throughout. After 3 adolescents are treated and followed for 3 months, the committee reviews all data to decide whether to move to a higher dose. However, if the lower dose (1E11 vg/eye) shows strong effectiveness in the first group, the study may expand by treating more adolescents at that same dose instead of increasing it further.

This is a Phase 1b/2a multicenter, open-label, and non-randomized dose-escalation safety study of up to two vector doses of OPGx-RDH12 (300 µL) administered via unilateral injection in participants with Leber Congenital Amaurosis (LCA) with autosomal-recessive retinol dehydrogenase 12 (RDH12) gene mutation(s). Administration will occur via a cannula into the subretinal space, using the standard technique for delivery of other adeno-associated virus (AAV) therapies including Luxturna®, the first United States Food and Drug Administration (FDA)-approved ocular gene therapy.

Up to 2 OPGx-RDH12 dose cohorts will be studied: 1E11 vg/eye (Cohort 1) and 3E11 vg/eye (Cohort 2). The treatment eye will be the eye with the worst visual function (as determined by visual acuity, full-field sensitivity testing [FST] and kinetic perimetry) or the non-dominant eye in cases of bilateral symmetric disease. Toxicity related to the administration of OPGx-RDH12 will be monitored in the eye using a comprehensive clinical monitoring plan and an Independent Data Monitoring Committee (IDMC).

Each cohort will enroll 5 participants. The first 2 participants will be adults (≥18 years old), treated at least 1 month apart. One month after the second participant's treatment, safety and efficacy data from the adult participants will be submitted to FDA for review and approval to open the study to adolescent participants (12-17 years old). The IDMC will next determine whether adolescent participants may be enrolled in the same dose cohort.

Three months after the third adolescent participant's treatment, the IDMC will review all safety and efficacy data from the cohort and determine whether to recommend escalation to the next dose cohort. Efficacy signals in Cohort 1 may justify conversion to a larger cohort of adolescent participants at the 1E11 vg/eye dose, with no further dose escalation.

Inclusion Criteria:

• Age ≥18 years (adult participants) or 12-17 years (adolescent participants) at the time of consent/assent.
• Provide written informed consent and/or assent prior to any study procedures.
• Willing to adhere to the clinical protocol and follow directions of the Investigator regarding post-surgery restrictions.
• Are a good candidate for surgery, per the Investigator's judgment.
• Have LCA with autosomal-recessive RDH12 mutation(s), confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Historic testing, up to 15 years prior to date of consent, may be considered.
• Clinical diagnosis of LCA with RDH12 mutation(s), in the judgment of the Investigator.
• BCVA 20/200 (1.0 logarithm of the minimum angle of resolution [logMAR]) or worse for the sentinel adult in each cohort; BCVA 20/40 (0.5 logMAR) or worse for all subsequent participants in each cohort.

Exclusion Criteria:

• Women of childbearing potential (WOCBP) who are pregnant, lactating, and/or unwilling to use effective contraception from Screening through 1 year after IMP administration.
• Men who are unwilling to use effective contraception from Screening through 180 days after IMP administration.
• Have an ocular infection, a pre-existing eye condition, or a complicating systemic disease that could preclude the planned surgery or any future ocular surgery. This includes individuals who are immunocompromised and/or on continuous systemic immunosuppressive therapy.
• Have a past or current condition that may preclude participation in the study, interfere with outcome measure testing or test results, or otherwise make the potential participant unsuitable for the study.
• Have previously received gene therapy of any kind.
• In either eye, have undergone 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 device or investigational drug within 90 days (or 5 half-lives of the drug, whichever is longer) prior to planned IMP administration or intend to participate in another drug or device study during the same period as the current study.
• Have received or plan to receive a vaccination within 6 weeks prior to or 6 weeks after IMP administration. Note: For the influenza vaccine, the exclusionary period is shorter: 2 weeks prior to and 5 weeks after IMP administration (i.e., during steroid treatment).
• Have received anticoagulant therapy within 2 weeks prior to planned IMP administration.
• Currently use medications that are potentially neuroprotective/beneficial or retinotoxic.
• Are incapable of performing visual function testing (e.g., FST), with or without assistance, for reason other than poor vision.
• Have any contraindication to a course of oral steroids, in the opinion of the Investigator.
• Have a known history of hypersensitivity to constituents or excipients in the pharmaceutical formulation of the IMP.
• Have a known or active infection of human immunodeficiency virus (HIV) or hepatitis B or C virus.
• Have a known or active infection of herpes simplex virus with ocular manifestations.
• Are an employee of the Sponsor or a relative of the Investigator or investigative site staff.