Clinical trial NCT03066258: Safety and Tolerability of RGX-314 (Investigational Product) Gene Therapy for Neovascular AMD Trial
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Neovascular Age-related Macular Degeneration
Wet Age-related Macular Degeneration
Keywords: nAMD
wet AMD
gene therapy
Lead sponsor: REGENXBIO Inc.
Sponsor class: INDUSTRY
First posted: 2017-02-28
Enrollment: 42
Sex: ALL
Minimum age (years): 50
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: dose escalation
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events))
timeFrame: 26 weeks (24 weeks following RGX-314 administration)
Secondary outcomes:
measure: Safety (Participants With Ocular and Non-ocular AEs and SAEs)
timeFrame: 106 weeks (104 weeks following RGX-314 administration)
measure: Change From Baseline in BCVA (Best Corrected Visual Acuity)
timeFrame: 106 weeks (104 weeks following RGX-314 administration)
measure: Change From Baseline in CRT (Central Retinal Thickness)
timeFrame: 106 weeks (104 weeks following RGX-314 administration)
measure: Supplemental Injections (Annualized Rate of Supplemental Injections)
timeFrame: 106 weeks (104 weeks following RGX-314 administration)
measure: Mean Change From Baseline in Area of CNV (Choroidal Neovascularization)
timeFrame: 106 weeks (104 weeks following RGX-314 administration)
Other outcomes:
Locations:
city: Santa Barbara
country: United States
facility: Santa Barbara location
state: California
city: Baltimore
country: United States
facility: Baltimore location
state: Maryland
city: Boston
country: United States
facility: Boston location
state: Massachusetts
city: Reno
country: United States
facility: Reno location
state: Nevada
city: Philadelphia
country: United States
facility: Philadelphia location 1
state: Pennsylvania
city: Philadelphia
country: United States
facility: Philadelphia location 2
state: Pennsylvania
city: Germantown
country: United States
facility: Memphis location
state: Tennessee
city: Houston
country: United States
facility: Houston location
state: Texas
Study officials:
affiliation: Ophthalmic Consultants of Boston
name: Jeffrey Heier, MD
role: PRINCIPAL_INVESTIGATOR
References: