Safety and Tolerability of RGX-314 (Investigational Product) Gene Therapy for Neovascular AMD Trial

A Phase I/IIa (Phase 1/Phase 2a), Open-label, Multiple-cohort, Dose-escalation Study to Evaluate the Safety and Tolerability of Gene Therapy With RGX-314 in Subjects With Neovascular AMD (nAMD)

Excessive vascular endothelial growth factor (VEGF) plays a key part in promoting neovascularization and edema in neovascular (wet) age-related macular degeneration (nAMD). VEGF inhibitors (anti-VEGF), including ranibizumab (LUCENTIS®, Genentech) and aflibercept (EYLEA®, Regeneron), have been shown to be safe and effective for treating nAMD and have demonstrated improvement in vision. However, anti-VEGF therapy is administered frequently via intravitreal injection and can be a significant burden to the patients. RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein. The long-term, stable delivery of this therapeutic protein following a 1 time gene therapy treatment for nAMD could potentially reduce the treatment burden of currently available therapies while maintaining vision with a favorable benefit:risk profile.

Study Overview

• Status: Completed
• Conditions: Neovascular Age-related Macular Degeneration; Wet Age-related Macular Degeneration
• Intervention / Treatment: Genetic: RGX-314

Detailed Description

This Phase I/IIa, open-label, multiple-cohort, dose-escalation study was designed to evaluate the safety and tolerability of RGX-314 gene therapy in subjects with previously treated nAMD. Five doses were studied in approximately 42 subjects. Subjects who met the inclusion/exclusion criteria and had an anatomic response to an initial anti-VEGF injection received a single dose of RGX-314 administered by subretinal delivery. RGX-314 uses an AAV8 vector that contains a gene that encodes for a monoclonal antibody fragment which binds to and neutralizes VEGF activity. Safety was the primary focus for the initial 24 weeks after RGX-314 administration (primary study period). Following completion of the primary study period, subjects continued to be assessed until 104 weeks following treatment with RGX-314.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Santa Barbara, California, United States, 93103
      • Santa Barbara Location
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Baltimore Location
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Boston Location
  • Nevada
    • Reno, Nevada, United States, 89502
      • Reno Location
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Philadelphia location 1
    • Philadelphia, Pennsylvania, United States, 19107
      • Philadelphia location 2
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Memphis location
  • Texas
    • Houston, Texas, United States, 77030
      • Houston location

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years to 87 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients ≥ 50 and ≤ 89 years with a diagnosis of subfoveal CNV (Choroidal neovascularization) secondary to AMD in the study eye receiving prior intravitreal anti-VEGF therapy.
2. BCVA (Best Corrected Visual Acuity) between ≤20/63 and ≥20/400 (≤63 and ≥19 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) for the first patient in each cohort followed by BCVA between ≤20/40 and ≥20/400 (≤73 and ≥19 ETDRS letters) for the rest of the cohort.
3. History of need for and response to anti-VEGF therapy.
4. Response to anti-VEGF at trial entry (assessed by SD-OCT (Spectral Domain Optical Coherence Tomography) at week 1)
5. Must be pseudophakic (status post cataract surgery) in the study eye.
6. AST (Aspartate aminotransferase)/ALT (Alanine aminotransferase) < 2.5 × ULN (Upper limit of normal); TB (Total bilirubin) < 1.5 × ULN; PT (Prothrombin time) < 1.5 × ULN; Hb > 10 g/dL (males) and > 9 g/dL (females); Platelets > 100 × 10^3/µL; eGFR (Estimated glomerular filtration rate) > 30 mL/min/1.73 m^2
7. Must be willing and able to provide written, signed informed consent.

Exclusion Criteria:

1. CNV or macular edema in the study eye secondary to any causes other than AMD.
2. Any condition preventing visual acuity improvement in the study eye, eg, fibrosis, atrophy, or retinal epithelial tear in the center of the fovea.
3. Active or history of retinal detachment in the study eye.
4. Advanced glaucoma in the study eye.
5. 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.
6. Presence of an implant in the study eye at screening (excluding intraocular lens).
7. Myocardial infarction, cerebrovascular accident, or transient ischemic attacks within the past 6 months.
8. Uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg, diastolic BP >100 mmHg) despite maximal medical treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; 3E9 GC (genome copies)/eye of RGX-314 (E means the exponential constant)	Genetic: RGX-314; RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein
Experimental: Cohort 2; 1E10 GC/eye of RGX-314	Genetic: RGX-314; RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein
Experimental: Cohort 3; 6E10 GC/eye of RGX-314	Genetic: RGX-314; RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein
Experimental: Cohort 4; 1.6E11 GC/eye of RGX-314	Genetic: RGX-314; RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein
Experimental: Cohort 5; 2.5E11 GC/eye of RGX-314	Genetic: RGX-314; RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events))	Participants with ocular and non-ocular AEs and SAEs through 26 weeks (24 weeks following RGX-314 administration)	26 weeks (24 weeks following RGX-314 administration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (Participants With Ocular and Non-ocular AEs and SAEs)	Participants with ocular and non-ocular AEs and SAEs	106 weeks (104 weeks following RGX-314 administration)
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.	106 weeks (104 weeks following RGX-314 administration)
Change From Baseline in CRT (Central Retinal Thickness)	Retinal fluid status of the study eye was evaluated using spectral domain OCT (Optical Coherence Tomography). A decrease in value indicates a decrease in fluid	106 weeks (104 weeks following RGX-314 administration)
Supplemental Injections (Annualized Rate of Supplemental Injections)	The number of supplemental anti-VEGF injections given after RGX-314 was administered. Injections per year which were determined by the number of supplemental injections divided total follow-up in study days which is annualized to a per year rate. Injections were given for signs of worsening disease at a study visit, per the discretion of the investigator.	106 weeks (104 weeks following RGX-314 administration)
Mean Change From Baseline in Area of CNV (Choroidal Neovascularization)	Area of Choroidal Neovascularization of the study eye was assessed with color fundus photography. Analysis was performed by the central reading center. An increase in value represents an increase in CNV.	106 weeks (104 weeks following RGX-314 administration)

Collaborators and Investigators

• Sponsor: REGENXBIO Inc.
• Investigators: Principal Investigator: Jeffrey Heier, MD, Ophthalmic Consultants of Boston

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2017
• Primary Completion (Actual): November 24, 2019
• Study Completion (Actual): June 17, 2021

Study Registration Dates

• First Submitted: February 17, 2017
• First Submitted That Met QC Criteria: February 22, 2017
• First Posted (Actual): February 28, 2017

Study Record Updates

• Last Update Posted (Actual): May 16, 2023
• Last Update Submitted That Met QC Criteria: May 12, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: gene therapy; wet AMD; nAMD
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration
• Other Study ID Numbers: RGX-314-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No