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)

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03066258

Enrollment

Registered

2017-02-28

Start date

2017-03-29

Completion date

2021-06-17

Last updated

2023-05-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neovascular Age-related Macular Degeneration, Wet Age-related Macular Degeneration

Keywords

nAMD, wet AMD, gene therapy

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.

Interventions

GENETICRGX-314

RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

dose escalation

Eligibility

Sex/Gender

ALL

Age

50 Years to 89 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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
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
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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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	6
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	6
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	6
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	12
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	12
Total	42

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Death	1	0	0	0	1

Baseline characteristics

Characteristic	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	6 Participants	6 Participants	6 Participants	12 Participants	12 Participants	42 Participants
Age, Categorical Between 18 and 65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Asian	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Hispanic or Latino	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	5 Participants	6 Participants	6 Participants	11 Participants	12 Participants	40 Participants
Race/Ethnicity, Customized White	6 Participants	6 Participants	6 Participants	12 Participants	11 Participants	41 Participants
Region of Enrollment United States	6 Participants	6 Participants	6 Participants	12 Participants	12 Participants	42 Participants
Sex: Female, Male Female	4 Participants	3 Participants	2 Participants	7 Participants	6 Participants	22 Participants
Sex: Female, Male Male	2 Participants	3 Participants	4 Participants	5 Participants	6 Participants	20 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	1 / 6	0 / 6	0 / 6	0 / 12	1 / 12
other Total, other adverse events	5 / 6	6 / 6	6 / 6	12 / 12	12 / 12
serious Total, serious adverse events	2 / 6	2 / 6	1 / 6	3 / 12	4 / 12

Outcome results

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)

Time frame: 26 weeks (24 weeks following RGX-314 administration)

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort 1	Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events))	6 Participants
Cohort 2	Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events))	6 Participants
Cohort 3	Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events))	6 Participants
Cohort 4	Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events))	12 Participants
Cohort 5	Safety (Participants With Ocular and Non-ocular AEs (Adverse Events) and SAEs (Serious Adverse Events))	12 Participants

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.