RGX-314 Gene Therapy Pharmacodynamic Study for Neovascular Age-related Macular Degeneration (nAMD)

Study Overview
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Brief Summary
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RGX-314 is being developed as a novel one-time gene therapy for the treatment of neovascular (wet) age-related macular degeneration (nAMD) also referred to as Wet AMD. Wet AMD is characterized by loss of vision due to new, leaky blood vessel formation in the retina. The purpose of this phase 2, open label study is to evaluate whether different doses of RGX-314 from two different formulations (clinical versus eventual commercial formulation) perform the same in humans when delivered by subretinal administration

Detailed Description
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Wet AMD is a significant cause of vision loss in the United States, Europe and Japan, with up to 2 million people living with wet AMD in these geographies alone. Current anti-VEGF therapies have significantly changed the landscape for treatment of wet AMD, becoming the standard of care due to their ability to prevent progression of vision loss in the majority of patients. These therapies, however, require life-long repeated intraocular injections to maintain efficacy. Due to the burden of treatment, patients often experience a decline in vision with reduced frequency of treatment over time. RGX-314 is being developed as a potential one-time treatment for wet AMD. RGX-314 uses an AAV8 vector that contains a gene that encodes for a monoclonal antibody fragment which binds to and neutralizes VEGF activity. This phase 2, open label study will explore the pharmacodynamics of two doses in two formulations of RGX-314 gene therapy via subretinal delivery in patients with neovascular Age-related Macular Degeneration. Approximately 60 patients (15 per cohort) who meet the inclusion/exclusion criteria will be enrolled in 4 sequential dose cohorts. A dose cohort will be comprised of 1 of 2 doses of RGX-314 in 1 of 2 formulations in order to explore the pharmacodynamics of RGX-314 based on aqueous humor transgene product (TP) concentrations. If the participants meet the study criteria and choose to participate in the study, their participation in the study will last about 12 months.

Official Title
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A Phase 2, Open-label Study to Explore the Pharmacodynamics of Two Doses in Two Formulations of RGX-314 Gene Therapy Administered Via Subretinal Delivery in Participants With Neovascular Age-related Macular Degeneration

Conditions
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Neovascular Age-related Macular Degeneration, Wet Macular Degeneration, Wet Age-related Macular Degeneration

Intervention / Treatment
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* Genetic: RGX-314


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, aged ≥ 50 years and ≤ 89 years. An Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA-letter score between ≤ 78 and ≥ 40 in the study eye at Screening. Diagnosis of choroidal neovascularization (CNV) secondary to age-related macular degeneration in the study eye previously treated with anti-VEGF. Participants must have demonstrated a meaningful response to anti-VEGF therapy at study entry. Willing and able to provide written, signed informed consent for this study. Must be pseudophakic (at least 12 weeks postcataract surgery) in the study eye. Exclusion Criteria: CNV or macular edema in the study eye secondary to any causes other than AMD. Subfoveal fibrosis or atrophy in study eye. Any condition in the investigator's opinion that could limit visual acuity improvement in the study eye. Active or history of retinal detachment or retinal tear in the study eye. Advanced glaucoma in the study eye. Prior treatment with gene therapy. Myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 89 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: Commercial Formulation Dose 1<br>Dose 1 of RGX-314 | Genetic: RGX-314<br>* RGX-314 is a recombinant adeno-associated virus gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein<br>|
| Experimental: Clinical Formulation Dose 1<br>Dose 1 of RGX-314 | Genetic: RGX-314<br>* RGX-314 is a recombinant adeno-associated virus gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein<br>|
| Experimental: Commercial Formulation Dose 2<br>Dose 2 of RGX-314 | Genetic: RGX-314<br>* RGX-314 is a recombinant adeno-associated virus gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein<br>|
| Experimental: Clinical Formulation Dose 2<br>Dose 2 of RGX-314 | Genetic: RGX-314<br>* RGX-314 is a recombinant adeno-associated virus gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RGX-314 target protein concentration in aqueous humor |  | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of ocular Adverse Events (AEs) and overall AEs | Evaluate the safety and tolerability of RGX-314 | Through Week 48 | 
| Changes in Best Corrected Visual Acuity (BCVA) | BCVA measured by Early Treatment Diabetic Retinopathy Study (ETDRS) | At Week 24 and 48 | 
| Changes in Central Retinal Thickness (CRT) | CRT is measured by spectral domain optical coherence tomography (SD-OCT) | At Week 24 and 48 | 
| Mean Supplemental anti-VEGF injection annualized rate through week 24 and week 48 | To assess the need for supplemental anti-VEGF therapy over 48 weeks | Through Week 24 and week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AMD, wet AMD, wAMD, neovascular AMD, nAMD, gene therapy