Study to Assess the Safety and Efficacy of OCU410ST for Stargardt Disease

Study Overview
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Brief Summary
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This is a Phase 1/2 Study to Assess the Safety and Efficacy of OCU410ST for Stargardt Disease. This is a multicenter study, which will be conducted in two phases and will enroll up to a total of 42 subjects.

Detailed Description
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Name of Investigational Product: OCU410ST Name of Active Ingredient: Adeno-associated viral vector 5 human RORA (AAV5-hRORA) Title of Study: A Phase 1/2 Study to Assess the Safety and Efficacy of OCU410ST for Stargardt Disease. Study Center(s): Approximately five clinical study centers in the US. Background: Stargardt disease is an eye disease that causes vision loss in children and young adults. It is an inherited disease caused by faulty genes that cause buildup of fat deposits in the eye. Currently, there is no approved treatment available for Stargardt disease. OCU410ST Product Information: OCU410ST is an Adeno-Associated Virus serotype 5 containing human RORA for the treatment of Stargardt disease. Dysregulation in lipid metabolism, oxidative stress, and anti-inflammatory mechanisms are critical for pathogenesis and progression of Stargardt disease. The role of hRORA in regulating these gene pathways strongly suggests OCU410ST could restore homeostasis in the eye and thereby serve as a therapeutic candidate for Stargardt disease. This study will be conducted in two phases. enrolling up to 42. Phase 1 is a multicenter, open-label, dose-ranging/dose escalation study with a 3+3 design enrolling up to 18 subjects Phase 2 is a randomized, dose-expansion cohort in which 24 subjects will be randomized in a 1:1:1 ratio in to either one of two treatment groups (adults and pediatric subjects) or to an untreated (adults and pediatric subjects) control group.

Official Title
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A Phase 1/2 Study to Assess the Safety and Efficacy of OCU410ST for STARGARDT DISEASE

Conditions
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Stargardt Disease

Intervention / Treatment
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* Genetic: OCU410ST


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are aged 18-65. Have clinical evidence of a macular lesion phenotypically consistent with Stargardt Disease The study eye should have at least one well-demarcated area of atrophy with a minimum diameter of 300 microns, and total lesion size <= 18 mmE2 and a BCVA of 50 ETDRS letters or better Have confirmed presence of two pathogenic mutations in the ABCA4 gene Have detectable outer nuclear layer (ONL) in the macular region tomography (SD-OCT). Have BCVA of 50 letters or less (using ETDRS chart) Key Inclusion Criteria for Pediatric Subjects: Are aged 6-17. Have clinical diagnosis of Stargardt Disease The designated primary study eye must have at least one well-demarcated area of atrophy with a minimum diameter of 300 microns and a total lesion area <= 18 mmE2 and a BCVA of 35 ETDRS letters or better. Have two (2) pathogenic mutations confirmed present, in the ABCA4 gene. Key Exclusion Criteria for Adult Subjects: Have previous treatment with a gene therapy or cell therapy product. Have any concurrent retroviral therapy that would inactivate the investigational product. Have any contradictions for subretinal injection and the use of anesthesia. Have genes that mimic Stargardt Disease like ELOVL4, or PROM1. Exclusion Criteria for Pediatric Subjects: Have previous treatment with a gene therapy or cell therapy product. Have any concurrent retroviral therapy that would inactivate the investigational product. Have any intraocular surgery (including lens replacement surgery) within 6 months (prior to Screening), and any ophthalmic condition that may require surgery during the study period. Have genes that mimic Stargardt Disease like ELOVL4, or PROM1.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 65 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: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study will be conducted in two phases. Phase 1 is a multicenter, open-label, dose-ranging/dose escalation study. A 3+3 study design will be used for the sequential dose-escalation cohorts in which subjects will receive a single subretinal injection of OCU410ST. Phase 2 is a dose-expansion phase of the study, where the subjects will be randomized in a 1:1:1 ratio to either one of two treatment groups (adult and pediatric subjects) or to an untreated (adult and pediatric subjects) control group.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Phase1 Dose Escalation- Low Dose (3.75×10E10 vg/mL):<br>Low Dose (3.75×10E10 vg/mL): Subjects will receive a subretinal injection of 200 µL of OCU410ST in the low dose concentration. | Genetic: OCU410ST<br>* Subretinal Administration of OCU410ST<br>|
| Experimental: Experimental: Phase1 Dose Escalation- Medium Dose (7.5×10E10 vg/mL):<br>Medium Dose (7.5×10E10 vg/mL): Subjects will receive a subretinal injection of OCU410ST in the Medium dose concentration. | Genetic: OCU410ST<br>* Subretinal Administration of OCU410ST<br>|
| Experimental: Experimental: Phase1 Dose Escalation- High Dose (2.25×10E11 vg/mL):<br>High Dose (2.25×10E11 vg/mL): Subjects will receive a subretinal injection of OCU410ST in the high dose concentration. | Genetic: OCU410ST<br>* Subretinal Administration of OCU410ST<br>|
| Experimental: Experimental: Phase 2 Dose Expansion: Dose 1 from Phase 1-Randomized Adult Arm<br>Subjects will receive a subretinal injection of OCU410ST with Maximum tolerated dose (MTD) from Phase 1. | Genetic: OCU410ST<br>* Subretinal Administration of OCU410ST<br>|
| Experimental: Experimental: Phase 2 Dose Expansion: Dose 1 from Phase 1-Randomized Pediatric Arm<br>Subjects will receive a subretinal injection of OCU410ST with Maximum tolerated dose (MTD) from Phase 1. | Genetic: OCU410ST<br>* Subretinal Administration of OCU410ST<br>|
| Experimental: Experimental: Phase 2 Dose Expansion: Dose 2 from Phase 1-Randomized Adult Arm<br>Subjects will receive a subretinal injection of OCU410ST with Lower Dose than Maximum tolerated dose (MTD) from Phase 1 | Genetic: OCU410ST<br>* Subretinal Administration of OCU410ST<br>|
| Experimental: Experimental: Phase 2 Dose Expansion: Dose 2 from Phase 1-Randomized Pediatric Arm<br>Subjects will receive a subretinal injection of OCU410ST with Lower Dose than Maximum tolerated dose (MTD) from Phase 1 | Genetic: OCU410ST<br>* Subretinal Administration of OCU410ST<br>|
| No Intervention: No Intervention- Randomized Control Adult Arm<br>No Intervention Control Arm: Subject will not receive any active study intervention | |
| No Intervention: No Intervention- Randomized Control Pediatric Arm<br>No Intervention Control Arm: Subject will not receive any active study intervention | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events)) | The primary endpoint is safety, determined by the number of ocular and non-ocular Study Drug-related adverse events (SDAE), treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). | 12 months (Screening to 12 months post OCU410ST administration) | 
| Ophthalmic Safety: Change From Baseline in BCVA (Best Corrected Visual Acuity) | Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. A higher score represents better vision. | 12 months (Screening to 12 months post OCU410ST administration) | 
| Ophthalmic Safety: Ophthalmoscope Measurements | We will use Slit-lamp Biomicroscopy to visualize the anatomy of ocular structures before and after sub-retinal injections and follow-up visits. | 12 months (Screening to 12 months post OCU410ST administration) | 
| Ophthalmic Safety: Change in the Intraocular Pressure (mmHg) | Measured by applanation or rebound tonometry with confirmation with Goldmann tonometer if IOP is outside normal range (8-21mmHg). | 12 months (Screening to 12 months post OCU410ST administration) | 
| Change Using Qualitative and quantitative assessments of autofluorescence pattern (FAF) | Changes in the intensity of FAF will be evaluated from the baseline measurements, to assess the loss of retinal layers. | 12 months (Screening to 12 months post OCU410ST administration) | 
| Ophthalmic Safety: Changes in Full Field ERG | The International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines will be followed for conducting ff-ERG (Full-field Electroretinography) | 12 months (Screening to 12 months post OCU410ST administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Humoral and cellular immune response | Blood samples will be collected for the assessment. The secondary safety endpoints include change from baseline in Humoral and cellular immune response in response to OCU410ST administration | 12 months (Screening to 12 months post OCU410ST administration) | 
| Shedding of Viral Vector | Blood samples will be collected for the assessment to determine AAV vector shedding in systemic circulation after OCU410ST administration | 12 months (Screening to 12 months post OCU410ST administration) | 
| Change in laboratory parameters for Hematology | Blood samples will be collected to determine any significant change in hematology parameters including hematocrit, hemoglobin, red and white blood cell count, and any other parameters deemed necessary by study investigator from baseline after OCU410ST administration. | 12 months (Screening to 12 months post OCU410ST administration) | 
| Change in laboratory parameters for Serum Chemistry | Blood samples will be collected to determine any significant change in serum chemistry parameters including electrolytes, renal functions, liver functions, comprehensive metabolic panel and any other parameters deemed necessary by study investigator from baseline after OCU410ST administration. | 12 months (Screening to 12 months post OCU410ST administration) |