RGX-314 Gene Therapy Administered in the Suprachoroidal Space for Participants With 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 potential novel one-time gene therapy treatment 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 twelve 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.

Detailed Description
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This phase 2, randomized, dose-escalation study is designed to evaluate the efficacy, safety and tolerability of RGX-314 gene therapy in subjects with nAMD. Approximately 115 participants who meet the inclusion/exclusion criteria will be enrolled into one of 6 cohorts. Participants will be randomized in Cohorts 1 and 2 to receive RGX-314 or ranibizumab control, and participants enrolled in Cohorts 3 through 5 will receive RGX-314. Participants enrolled in Cohort 6 will receive RGX-314 and will be randomized to one of two different post-procedural steroid regimens. Cohort 1 will evaluate RGX-314 Dose 1, Cohorts 2 and 3 will evaluate RGX-314 Dose 2, and Cohorts 4, 5, and 6 will evaluate RGX-314 Dose 3. Participants will be evaluated for efficacy, safety and tolerability of RGX-314 throughout the study.

Official Title
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A Phase 2, Randomized, Dose-escalation, Ranibizumab-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of RGX-314 Gene Therapy Delivered Via One or Two Suprachoroidal Space (SCS) Injections in Participants With Neovascular Age-Related Macular Degeneration (nAMD) (AAVIATE)

Conditions
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Neovascular Age-Related Macular Degeneration (nAMD)

Intervention / Treatment
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* Genetic: RGX-314 Dose 1
* Genetic: RGX-314 Dose 2
* Biological: Ranibizumab
* Genetic: RGX-314 Dose 3
* Drug: Local steroid
* Drug: Topical steroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >/= 50 and </= 89 Diagnosis of CNV secondary to age-related macular degeneration in the study eye. Participants must have demonstrated a meaningful response to anti-VEGF therapy. Willing and able to provide written, signed informed consent for this study. Exclusion Criteria: CNV or macular edema in the study eye secondary to any causes other than AMD. Subfoveal fibrosis or atrophy in study eye. Participants who have had a prior vitrectomy. Active or history of retinal detachment in the study eye. History of intravitreal therapy in the study eye, such as intravitreal steroid injection or investigational product (IP), other than anti-VEGF therapy, in the 6 months prior to study entry. Received any gene therapy. Any condition preventing visualization of the fundus or VA improvement in the study eye, eg, cataract. History of intraocular surgery in the study eye within 12 weeks of study entry. Receipt of any IP within 30 days of study entry or 5 half-lives of the IP. Myocardial infarction, cerebrovascular accident, or transient ischemic attacks within 6 months of study entry. Cohorts 1 - 5 only: Uncontrolled glaucoma in the study eye. COHORT 6 ONLY: Active or history of glaucoma or ocular hypertension in the study eye. Certain OCT characteristics including: Large Pigment Epithelial Detachments (PED), clinically significant Epiretinal Membrane (ERM) in the study eye at Visit 1. Note: Other inclusion/exclusion criteria apply.

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: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ranibizumab control<br>Control treatment arm | Biological: Ranibizumab<br>* Ranibizumab (anti-VEGF agent)<br>|
| Experimental: RGX-314 Treatment Arm (Dose 1)<br>RGX-314 Dose 1 | Genetic: RGX-314 Dose 1<br>* AAV8 vector containing a transgene for anti-VEGF fab (Dose 1)<br>* Other names: Combination Product;|
| Experimental: RGX-314 Treatment Arm (Dose 2)<br>RGX-314 Dose 2 | Genetic: RGX-314 Dose 2<br>* AAV8 vector containing a transgene for anti-VEGF fab (Dose 2)<br>* Other names: Combination Product;|
| Experimental: RGX-314 Treatment Arm (Dose 3)<br>RGX-314 Dose 3 | Genetic: RGX-314 Dose 3<br>* AAV8 vector containing a transgene for anti-VEGF fab (Dose 3)<br>* Other names: Combination Product;|
| Experimental: RGX-314 Treatment Arm (Dose 3) and Local Steroid<br>RGX-314 Dose 3 and Local Steroid | Genetic: RGX-314 Dose 3<br>* AAV8 vector containing a transgene for anti-VEGF fab (Dose 3)<br>* Other names: Combination Product;Drug: Local steroid<br>* Local Steroid<br>|
| Experimental: RGX-314 Treatment Arm (Dose 3) and Topical Steroid<br>RGX-314 Dose 3 and Topical Steroid | Genetic: RGX-314 Dose 3<br>* AAV8 vector containing a transgene for anti-VEGF fab (Dose 3)<br>* Other names: Combination Product;Drug: Topical steroid<br>* Topical steroid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the mean change in Best Corrected Visual Acuity (BCVA) for RGX-314 compared with ranibizumab monthly. | The scale used is the early treatment diabetic retinopathy study (ETDRS) letter score from 0-100 and higher score being better vision. | 40 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of RGX-314 | Incidence of overall and ocular adverse events (AEs) and serious adverse events (SAEs) | 52 weeks | 
| Evaluate the incidence of ocular inflammation following administration of RGX-314 | Proportion of participants who experience ocular inflammation following SCS RGX-314 administration | 52 weeks | 
| Evaluate the effect of RGX-314 on choroidal neovascularization (CNV) lesion growth and leakage | Mean change from baseline in CNV lesion size and leakage area based on fluorescein angiography (FA) at Week 52. | 52 weeks | 
| Evaluate the effect of RGX-314 on BCVA | Mean change from baseline in BCVA to Week 52 | 52 weeks | 
| Evaluate the effect of RGX-314 on central retinal thickness (CRT) | Mean change from baseline in CRT as measured by spectral domain-optical coherence tomography (SD-OCT) to Week 40 and Week 52 | 52 weeks | 
| Assess the need for supplemental anti-vascular endothelial growth factor (VEGF) therapy in participants who receive RGX-314 treatment | Mean supplemental anti-VEGF injection annualized rate in the RGX-314 treatment arm through Week 40 and Week 52 | 52 weeks | 
| Evaluate the concentration of RGX-314 transgene product (TP) in aqueous humor and serum | Mean change from baseline and Week 54 in serum RGX-314 TP concentration over time | 52 weeks | 

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