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

Phase 1

Completed

• Conditions: Neovascular Age-related Macular Degeneration; Wet Age-related Macular Degeneration
• Interventions: Genetic: RGX-314

• Registration Number: NCT03066258
• Lead Sponsor: REGENXBIO Inc.

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.

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 Timeline

• Study First Submitted: 2017-02-17
• Study First Submitted QC: 2017-02-22
• Study First Posted: 2017-02-28
• Study Start: 2017-03-29
• Primary Completion: 2019-11-24
• Study Completion: 2021-06-17
• Results First Submitted: 2023-02-13
• Status Verified: 2023-05
• Results First Submitted QC: 2023-05-12
• Last Update Submitted: 2023-05-12
• Results First Posted: 2023-05-16
• Last Update Posted: 2023-05-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 42

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 5	RGX-314	2.5E11 GC/eye of RGX-314
Cohort 1	RGX-314	3E9 GC (genome copies)/eye of RGX-314 (E means the exponential constant)
Cohort 2	RGX-314	1E10 GC/eye of RGX-314
Cohort 3	RGX-314	6E10 GC/eye of RGX-314
Cohort 4	RGX-314	1.6E11 GC/eye of RGX-314

Primary Outcome Measures

Name	Time	Method
Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events))	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

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

Trial Locations

Locations (8)

Reno location; 🇺🇸 Reno, Nevada, United States

Baltimore location; 🇺🇸 Baltimore, Maryland, United States

Santa Barbara location; 🇺🇸 Santa Barbara, California, United States

Boston location; 🇺🇸 Boston, Massachusetts, United States

Memphis location; 🇺🇸 Germantown, Tennessee, United States

Philadelphia location 1; 🇺🇸 Philadelphia, Pennsylvania, United States

Philadelphia location 2; 🇺🇸 Philadelphia, Pennsylvania, United States

Houston location; 🇺🇸 Houston, Texas, United States