Safety and Tolerability Subretinal OPGx-001 for LCA5-Associated Inherited Retinal Degeneration (LCA5-IRD)

Study Overview
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Brief Summary
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The goal of this clinical trial is to evaluate the safety and preliminary efficacy of subretinal gene therapy with OPGx-001 in patients with inherited retinal degeneration due to biallelic mutations in the LCA5 gene.

Detailed Description
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This is a non-randomized, open-label, phase 1/2 dose-escalation study evaluating two doses of OPGx-001 for the treatment of LCA5-IRD. Enrollment will begin with a low-dose of OPGx-001 delivered via single, unilateral subretinal injection (Cohort 1) and proceed to an intermediate dose (Cohort 2) and subsequent high dose (Cohort 3). Escalation to each next cohort will proceed only after review of all data and upon recommendation by an independent data monitoring committee (IDMC).

Official Title
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An Open Label, Dose Exploration, Safety and Tolerability Study of a Subretinal Injection of an OPGx-001 Gene Vector to Participants With LCA5-Associated Inherited Retinal Degeneration (LCA5-IRD)

Conditions
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LCA5

Intervention / Treatment
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* Biological: AAV8.hLCA5


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are willing and able to provide written informed consent (ICF) and, where appropriate, willing to sign an assent prior to any study procedures. Are willing to adhere to the clinical protocol and able to perform testing procedures. Participants must be at least 18 years of age at consent. Carry disease-causing biallelic LCA5 gene mutations determined by a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Visual acuity: BCVA < 20/80 on the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity chart (modified for low vision participants) in the eye to be treated Show evidence of detectable photoreceptors by Spectral Domain Optical Coherence Tomography (SD-OCT) Participant is a good candidate for surgery per investigator judgement Participant agrees to follow direction of investigator regarding restrictions post-surgery. Exclusion Criteria: Individuals of childbearing potential (male and female) who are pregnant or unwilling to use effective contraception for the duration of the study, including barrier methods for the first year after investigational product (IP) administration. Pre-existing eye conditions or complicating systemic diseases that would preclude the planned surgery. This includes individuals who are immunocompromised. History of intraocular surgery for either eye within 6 months prior to planned IP administration. Have previously received gene therapy. Have used any investigational drug or device within 90 days or 5 estimated half-lives of treatment, whichever is longer or plan to participate in another study of drug or device during the study period. History of disease which may preclude the participant from participation, or which may interfere with outcome measure testing or test results. Incapable of performing visual function testing (e.g., FST testing) for reasons other than poor vision. Any absolute contraindication to a course of oral steroids. Any other condition that would not allow the potential participant to complete follow-up examinations during the study and, in the opinion of the Investigator, makes the potential participant unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Group 1<br>Single, unilateral subretinal administration of a low dose of OPGx-001 to adult participants at least 18 years of age | Biological: AAV8.hLCA5<br>* Adeno-associated virus vector expressing human LCA5 gene<br>|
| Experimental: Dose Group 2<br>Single, unilateral subretinal administration of an intermediate dose of OPGx-001 to adult participants at least 18 years of age | Biological: AAV8.hLCA5<br>* Adeno-associated virus vector expressing human LCA5 gene<br>|
| Experimental: Dose Group 3<br>Single, unilateral subretinal administration of a high dose of OPGx-001 to adult participants at least 18 years of age | Biological: AAV8.hLCA5<br>* Adeno-associated virus vector expressing human LCA5 gene<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities |  | 1 year | 
| Number of adverse events related to OPGx-001 |  | 1 year | 
| Number of procedure-related adverse events |  | 1 year | 
| Change in retinal thickness (as measured by OCT) | Changes from baseline in total retinal thickness and outer retinal thickness (in microns) | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to month 12 in retinal sensitivity as measured by full-field stimulus testing (FST) |  | 1 year | 
| Change from baseline to month 12 in best corrected visual acuity (BCVA) |  | 1 year | 
| Change from baseline to month 12 in oculomotor control and fixation stability |  | 1 year | 
| Change from baseline to month 12 in dark-adapted transient pupillary light reflexes (TPLR) |  | 1 year | 
| Change from baseline to month 12 in visual functioning questionnaire |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LCA, Retinal Degeneration, IRD, adeno associated virus, gene therapy, LCA5