RGX-314 Gene Therapy Administered in the Suprachoroidal Space for Participants With Diabetic Retinopathy (DR) Without Center Involved-Diabetic Macular Edema (CI-DME)

Study Overview
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Brief Summary
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RGX-314 is being developed as a novel, potential one-time gene therapy treatment for the treatment of diabetic retinopathy, a chronic and progressive complication of diabetes mellitus. Diabetic retinopathy (DR) is a sight-threatening disease characterized in the early stages by neuronal and vascular dysfunction in the retina, and later by neovascularization that leads to further deterioration of functional vision. Despite the availability of current treatments, diabetic retinopathy remains the leading cause of vision loss in working-age adults, those between the ages of 20 and 74. Existing treatment with anti-VEGF agents, although shown to be effective, are limited by short therapeutic half-lives, which then require frequent intravitreal injections over the patient's lifetime, resulting in increased risk of associated adverse events and significant treatment burden. Due to the burden of treatment, patients often do not closely adhere to treatment regimens and experience sub-optimal outcomes and a decline in vision. RGX-314 is being developed as a potential one time treatment for diabetic retinopathy, which may deliver advantages over conventional treatments, such as potentially providing a longer duration of therapeutic effect and intervening at an earlier stage of the disease.

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 DR without center-involved diabetic macular edema (CI-DME). Approximately 100 participants who meet the inclusion/exclusion criteria, will be enrolled into one of 5 cohorts. Participants will be randomized in Cohorts 1, 2, 4 and 5 to receive RGX-314 or to be observed, and participants enrolled in Cohorts 3 will receive RGX-314. Cohort 1 will evaluate RGX-314 Dose 1, Cohorts 2 and 3 will evaluate RGX-314 Dose 2, Cohorts 4 and 5 will evaluate RGX-314 Dose 3. Following SCS RGX-314 administration, participants in Cohorts 4 and 5 will receive a protocol-mandated post-procedure steroid regimen for 7 weeks. Participants who are randomized to be observed in Cohorts 1, 2, 4 and 5 will be offered RGX-314 after completing the study. Efficacy will be the primary focus of the study. Participants will be evaluated for safety and tolerability of RGX-314 throughout the study.

Official Title
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A Phase 2, Randomized, Dose-escalation, Observation-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of RGX-314 Gene Therapy Delivered Via a Single Suprachoroidal Space (SCS) Injections in Participants With Diabetic Retinopathy (DR) Without Center Involved-Diabetic Macular Edema (CI-DME)(ALTITUDE)

Conditions
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Diabetic Retinopathy (DR)

Intervention / Treatment
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* Genetic: RGX-314 Dose 1
* Genetic: RGX-314 Dose 2
* Genetic: RGX-314 Dose 3
* Drug: Topical Steroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 25-89 years of age with a diabetic retinopathy diagnosis of nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) secondary to diabetes mellitus Type 1 or 2 for which PRP or anti-VEGF injections can be safely deferred for at least 6 months Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of ≥69 letters (approximate Snellen equivalent of 20/40 or better) Prior history of CI-DME in the study eye is acceptable. Must be willing and able to provide written, signed informed consent. Exclusion Criteria: Neovascularization in the study eye from a cause other than DR. Presence of any active CI-DME. Active or history of retinal detachment in the study eye. Any evidence or documented history of PRP or retinal laser in the study eye. Patients who had a prior vitrectomy surgery. Women of childbearing potential. Note: Other inclusions/exclusions criteria apply

Ages Eligible for Study
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Minimum Age: 25 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Observation Control Arm<br>Observation Control | |
| 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) 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 effect of RGX-314 on DR by the Early Treatment Diabetic Retinopathy Study (ETDRS)-Diabetic Retinopathy Severity Scale (-DRSS) at week 48 | Proportion of participants achieving a 2-step or greater improvement in DR by Early Treatment Diabetic Retinopathy Study (ETDRS)-Diabetic Retinopathy Severity Scale (-DRSS) at Week 48 scored from Levels 10-85 with higher levels indicating greater DR severity. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of RGX-314 on DR (ETDRS-DRSS) over time | Proportion of participants achieving improvement or worsening in DR per ETDRS-DRSS grading through week 48 | 48 weeks | 
| To assess the safety and tolerability of RGX-314 | Assess the incidence of overall and ocular Adverse Events (AEs) | 48 weeks | 
| To evaluate the need for additional Standard of Care (SOC) intervention due to ocular vision-threatening diabetic complications | Proportion of participants with sight-threatening ocular diabetic complications requiring additional SOC intervention (anti-VEGF, Pan-Retinal Photocoagulation (PRP), laser, steroids, or surgical intervention) | 48 weeks | 
| To evaluate the incidences of ocular inflammation following SCS RGX-314 administration | Proportion of participants who experience ocular inflammation following SCS RGX-314 administration. | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DR