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

• ClinicalTrials.gov Identifier: NCT03066258
• Recruitment Status: Completed
• First Posted: February 28, 2017
• Results First Posted: May 16, 2023
• Last Update Posted: May 16, 2023
• Sponsor: REGENXBIO Inc.
• Information provided by (Responsible Party): REGENXBIO Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Neovascular Age-related Macular Degeneration; Wet Age-related Macular Degeneration	Genetic: RGX-314	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 42 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: dose escalation
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: March 29, 2017
• Actual Primary Completion Date: November 24, 2019
• Actual Study Completion Date: June 17, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events)) [ Time Frame: 26 weeks (24 weeks following RGX-314 administration) ]
   Participants with ocular and non-ocular AEs and SAEs through 26 weeks (24 weeks following RGX-314 administration)

Secondary Outcome Measures :

1. Safety (Participants With Ocular and Non-ocular AEs and SAEs) [ Time Frame: 106 weeks (104 weeks following RGX-314 administration) ]
   Participants with ocular and non-ocular AEs and SAEs
2. Change From Baseline in BCVA (Best Corrected Visual Acuity) [ Time Frame: 106 weeks (104 weeks following RGX-314 administration) ]
   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.
3. Change From Baseline in CRT (Central Retinal Thickness) [ Time Frame: 106 weeks (104 weeks following RGX-314 administration) ]
   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
4. Supplemental Injections (Annualized Rate of Supplemental Injections) [ Time Frame: 106 weeks (104 weeks following RGX-314 administration) ]
   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.
5. Mean Change From Baseline in Area of CNV (Choroidal Neovascularization) [ Time Frame: 106 weeks (104 weeks following RGX-314 administration) ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 89 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Santa Barbara location

Santa Barbara, California, United States, 93103

United States, Maryland

Baltimore location

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Boston location

Boston, Massachusetts, United States, 02114

United States, Nevada

Reno location

Reno, Nevada, United States, 89502

United States, Pennsylvania

Philadelphia location 1

Philadelphia, Pennsylvania, United States, 19104

Philadelphia location 2

Philadelphia, Pennsylvania, United States, 19107

United States, Tennessee

Memphis location

Germantown, Tennessee, United States, 38138

United States, Texas

Houston location

Houston, Texas, United States, 77030

Sponsors and Collaborators

REGENXBIO Inc.

Investigators

• Principal Investigator: Jeffrey Heier, MD; Ophthalmic Consultants of Boston

  Study Documents (Full-Text)

Documents provided by REGENXBIO Inc.:

Study Protocol  [PDF] February 10, 2020

Statistical Analysis Plan  [PDF] December 2, 2019

More Information

• Responsible Party: REGENXBIO Inc.
• ClinicalTrials.gov Identifier: NCT03066258
• Other Study ID Numbers: RGX-314-001
• First Posted: February 28, 2017
• Results First Posted: May 16, 2023
• Last Update Posted: May 16, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by REGENXBIO Inc.:

nAMD; wet AMD; gene therapy

Additional relevant MeSH terms:

Macular Degeneration; Retinal Degeneration; Retinal Diseases; Eye Diseases