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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 | Experimental | 3E9 GC (genome copies)/eye of RGX-314 (E means the exponential constant) |
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| Cohort 2 | Experimental | 1E10 GC/eye of RGX-314 |
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| Cohort 3 | Experimental | 6E10 GC/eye of RGX-314 |
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| Cohort 4 | Experimental | 1.6E11 GC/eye of RGX-314 |
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| Cohort 5 | Experimental | 2.5E11 GC/eye of RGX-314 |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| RGX-314 | Genetic | RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
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| 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) |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey Heier, MD | Ophthalmic Consultants of Boston | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Santa Barbara location | Santa Barbara | California | 93103 | United States | ||
| Baltimore location |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38554726 | Derived | Campochiaro PA, Avery R, Brown DM, Heier JS, Ho AC, Huddleston SM, Jaffe GJ, Khanani AM, Pakola S, Pieramici DJ, Wykoff CC, Van Everen S. Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study. Lancet. 2024 Apr 20;403(10436):1563-1573. doi: 10.1016/S0140-6736(24)00310-6. Epub 2024 Mar 27. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1 | 3E9 GC (genome copies)/eye of RGX-314 (E means exponential constant) RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF (Vascular endothelial growth factor) protein |
| FG001 | Cohort 2 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 10, 2020 | Oct 10, 2022 |
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dose escalation
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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) |
| Baltimore |
| Maryland |
| 21287 |
| United States |
| Boston location | Boston | Massachusetts | 02114 | United States |
| Reno location | Reno | Nevada | 89502 | United States |
| Philadelphia location 1 | Philadelphia | Pennsylvania | 19104 | United States |
| Philadelphia location 2 | Philadelphia | Pennsylvania | 19107 | United States |
| Memphis location | Germantown | Tennessee | 38138 | United States |
| Houston location | Houston | Texas | 77030 | United States |
1E10 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| FG002 | Cohort 3 | 6E10 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| FG003 | Cohort 4 | 1.6E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| FG004 | Cohort 5 | 2.5E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1 | 3E9 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| BG001 | Cohort 2 | 1E10 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| BG002 | Cohort 3 | 6E10 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| BG003 | Cohort 4 | 1.6E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| BG004 | Cohort 5 | 2.5E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| BG005 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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) | Posted | Count of Participants | Participants | 26 weeks (24 weeks following RGX-314 administration) |
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| Secondary | Safety (Participants With Ocular and Non-ocular AEs and SAEs) | Participants with ocular and non-ocular AEs and SAEs | Posted | Count of Participants | Participants | 106 weeks (104 weeks following RGX-314 administration) |
| |||||||||||||||||||||||||||||||||||||||||
| Secondary | 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. | Posted | Mean | Full Range | ETDRS letters | 106 weeks (104 weeks following RGX-314 administration) |
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| Secondary | 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 | Posted | Mean | Full Range | μm | 106 weeks (104 weeks following RGX-314 administration) |
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| Secondary | 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. | Posted | Mean | Standard Error | supplemental injections per year | 106 weeks (104 weeks following RGX-314 administration) |
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| Secondary | 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. | Posted | Mean | Standard Deviation | mm^2 | 106 weeks (104 weeks following RGX-314 administration) |
|
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 (Week 106). At the end of the study, subjects were invited to participate in a long-term follow-up study (NCT03999801).
Other AEs reported include: RGX-314-emergent Non-serious Ocular Adverse Events Occurring in >5% of Subjects by Preferred Term, Sorted by Frequency in Total Group As-treated Population
SAE reported include: RGX-314-emergent Serious Adverse Events by System Organ Class and Preferred Term As-treated Population
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort 1 | 3E9 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein | 1 | 6 | 2 | 6 | 5 | 6 |
| EG001 | Cohort 2 | 1E10 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein | 0 | 6 | 2 | 6 | 6 | 6 |
| EG002 | Cohort 3 | 6E10 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein | 0 | 6 | 1 | 6 | 6 | 6 |
| EG003 | Cohort 4 | 1.6E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein | 0 | 12 | 3 | 12 | 12 | 12 |
| EG004 | Cohort 5 | 2.5E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein | 1 | 12 | 4 | 12 | 12 | 12 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Retinal Detachment | Eye disorders | Systematic Assessment |
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| Endophthalmitis | Infections and infestations | Systematic Assessment |
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| Visual Impairment | Eye disorders | Systematic Assessment |
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| Atrial Fibrillation | Cardiac disorders | Systematic Assessment |
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| Colitis Ischaemic | Gastrointestinal disorders | Systematic Assessment |
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| Asthenia | General disorders | Systematic Assessment |
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| Cholelithiasis | Hepatobiliary disorders | Systematic Assessment |
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| Diverticulitis | Infections and infestations | Systematic Assessment |
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| Pneumonia | Infections and infestations | Systematic Assessment |
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| Urinary Tract Infection | Infections and infestations | Systematic Assessment |
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| Deep Vein Thrombosis Postoperative | Injury, poisoning and procedural complications | Systematic Assessment |
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| Femoral Neck Fracture | Injury, poisoning and procedural complications | Systematic Assessment |
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| Hypervolaemia | Metabolism and nutrition disorders | Systematic Assessment |
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| Arthritis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Encephalopathy | Nervous system disorders | Systematic Assessment |
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| Delirium | Psychiatric disorders | Systematic Assessment |
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| Respiratory Failure | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Hypertension | Vascular disorders | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Conjunctival Haemorrhage | Eye disorders | Systematic Assessment |
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| Intraocular Pressure Increased | Eye disorders | Systematic Assessment |
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| Visual Acuity Reduced/Impairment | Eye disorders | Systematic Assessment | Visual Acuity Reduced & Impairment will be presented as a group term including the AE preferred terms (PTs) of "Visual Acuity Reduced" and "Visual Impairment" |
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| Eye Irritation | Eye disorders | Systematic Assessment |
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| Eye Pain | Eye disorders | Systematic Assessment |
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| Retinal Degeneration | Eye disorders | Systematic Assessment |
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| Photopsia | Eye disorders | Systematic Assessment |
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| Conjunctival Hyperaemia | Eye disorders | Systematic Assessment |
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| Vision Blurred | Eye disorders | Systematic Assessment |
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| Retinal pigmentary changes (depigmentation, pigment epitheliopathy & pigmentation) | Eye disorders | Systematic Assessment | Retinal pigmentary changes is a group term including AE preferred terms of 'Retinal Depigmentation', 'Retinal Pigment Epitheliopathy', and 'Retinal Pigmentation'. |
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| Retinal Haemorrhage | Eye disorders | Systematic Assessment |
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| Intraocular Inflammation | Eye disorders | Systematic Assessment | Intraocular Inflammation is a group term including AE preferred terms of 'Anterior Chamber Cell', 'Anterior Chamber Flare', and 'Anterior Chamber Inflammation'. |
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| Metamorphopsia | Eye disorders | Systematic Assessment |
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| Retinal Thickening | Eye disorders | Systematic Assessment |
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| Dry Age-Related Macular Degeneration | Eye disorders | Systematic Assessment |
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| Erythema Of Eyelid | Eye disorders | Systematic Assessment |
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| Photophobia | Eye disorders | Systematic Assessment |
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| Posterior Capsule Opacification | Eye disorders | Systematic Assessment |
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| Vitreous Floaters | Eye disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Sherri Van Everen, PharmD/ Vice President of Clinical Development | Regenxbio Inc. | 240.552.8181 | svaneveren@regenxbio.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Dec 2, 2019 | Oct 10, 2022 | SAP_001.pdf |
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| Between 18 and 65 years |
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| >=65 years |
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| Male |
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| Asian |
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| Hispanic or Latino |
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| Not Hispanic or Latino |
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| OG004 | Cohort 5 | 2.5E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
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| OG004 | Cohort 5 | 2.5E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
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| OG004 | Cohort 5 | 2.5E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
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| Cohort 4 |
1.6E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
| OG004 | Cohort 5 | 2.5E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
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| OG004 | Cohort 5 | 2.5E11 GC/eye of RGX-314 RGX-314: RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein |
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