Pivotal 1 Study of RGX-314 Gene Therapy in Participants With 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 (wet AMD). Wet AMD is characterized by loss of vision due to new, leaky blood vessel formation in the retina. 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 intraocular injections, typically repeated every four to 12 weeks in frequency, 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.

Detailed Description
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This randomized, partially masked, controlled, Phase 2b/3 clinical study will evaluate the efficacy and safety of RGX-314 gene therapy in participants with nAMD. The study will evaluate 2 dose levels of RGX-314 relative to an active comparator. The primary endpoint of this study is mean change in best-corrected visual acuity (BCVA) of RGX-314 relative to ranibizumab. Approximately 300 participants who meet the inclusion/exclusion criteria, will be enrolled into one of 3 arms.

Official Title
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A Randomized, Partially Masked, Controlled, Phase 2b/3 Clinical Study to Evaluate the Efficacy and Safety of RGX-314 Gene Therapy in Participants With nAMD (ATMOSPHERE)

Conditions
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AMD, nAMD, Wet Age-related Macular Degeneration, wAMD, Wet AMD, CNV

Intervention / Treatment
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* Genetic: RGX-314
* Genetic: RGX-314
* Biological: Ranibizumab (LUCENTIS®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 50 years and ≤ 89 years An ETDRS BCVA letter score between ≤ 78 and ≥ 40 in the study eye Diagnosis of subfoveal CNV secondary to AMD in the study eye previously treated with anti-VEGF Must be pseudophakic (at least 12 weeks postcataract surgery) in the study eye. Willing and able to provide written, signed informed consent for this study Participants must have demonstrated a meaningful response to anti-VEGF therapy at study entry Exclusion Criteria: CNV or macular edema in the study eye secondary to any causes other than AMD Subfoveal fibrosis or atrophy in the study eye Any condition in the investigator's opinion that could limit VA improvement in the study eye Active or history of retinal detachment in the study eye Uncontrolled glaucoma in the study eye History of intraocular surgery in the study eye within 12 weeks prior to Screening Visit 1 History of intravitreal therapy in the study eye, such as intravitreal steroid injection or investigational product, other than anti-VEGF therapy, in the 6 months prior to Screening Visit 1. Prior treatment with gene therapy. Recent 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2 RGX-314 treatment arms, 1 control arm (ranibizumab)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RGX-314 Dose 1<br>RGX-314 Dose 1 administered via subretinal delivery one time. | Genetic: RGX-314<br>* AAV8 vector containing a transgene for anti-VEGF Fab (Dose 1)<br>|
| Experimental: RGX-314 Dose 2<br>RGX-314 Dose 2 administered via subretinal delivery one time. | Genetic: RGX-314<br>* AAV8 vector containing a transgene for anti-VEGF Fab (Dose 2)<br>|
| Active Comparator: Control Arm<br>Ranibizumab administered via intravitreal injection approximately every 28 days | Biological: Ranibizumab (LUCENTIS®)<br>* 0.5 mg (0.05 mL of 10 mg/mL solution) administered by intravitreal injection approximately every 28 days<br>* Other names: Ranibizumab (anti-VEGF agent);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in Best Corrected Visual Acuity (BCVA) | BCVA measured by Early Treatment Diabetic Retinopathy Study (ETDRS) | At Week 54 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidences of ocular and overall adverse events (AEs) | Evaluate the safety and tolerability of RGX-314 | Through Week 98 | 
| Mean change from baseline in BCVA | BCVA measured by ETDRS | At Week 98 (RGX-314 randomized participants only) | 
| Mean change from baseline in Central Retinal Thickness (CRT) and Center Point Thickness (CPT) as measured by Spectral Domain Optical Coherence Tomography (SD-OCT) |  | At Week 54 and Week 98 | 
| Mean reduction in supplemental anti VEGF injection annualized rate compared with the prior 52 weeks preceding the first ranibizumab injection received as part of the Active Run-in Period (RGX 314 randomized participants) |  | Through Week 54 and Week 98 | 
| Mean supplemental anti-VEGF injection annualized rate in the RGX-314 arms |  | Through Week 54 and Week 98 | 
| Aqueous RGX-314 target protein (TP) concentrations |  | At Week 14, Week 26, Week 38, Week 54, and Week 98 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Age-Related Macular Degeneration, Neovascular Age-Related Macular Degeneration, Macular Degeneration, Wet Macular Degeneration, Choroidal Neovascularization, Retinal Degeneration, Retinal Diseases, Eye Diseases, Ranibizumab, Angiogenesis Inhibitors, Angiogenesis Modulating Agents, Growth Substances, Physiological Effects of Drugs, Growth Inhibitors, Antineoplastic Agents, Gene therapy, Anti-vascular endothelial grown factory therapy, Anti-VEGF therapy