Pivotal 1 Study of ABBV-RGX-314 (Also Known as RGX-314) Gene Therapy Administered Via Subretinal Delivery One Time in Participants With nAMD

Phase 2

Recruiting

• Conditions: AMD; nAMD; Wet Age-related Macular Degeneration; Neovascular AMD; wAMD; Wet AMD; CNV; Neovascular Age-related Macular Degeneration; Choroidal Neovascularization
• Interventions: Genetic: ABBV-RGX-314; Biological: Ranibizumab (LUCENTIS®)

• Registration Number: NCT04704921
• Lead Sponsor: AbbVie

Brief Summary

ABBV-RGX-314 (also known as RGX-314) is being developed as a novel one-time gene therapy for the treatment of neovascular (wet) age-related macular degeneration (wet AMD or nAMD). Wet AMD is characterized by loss of vision due to new, leaky blood vessel formation in the retina. Wet AMD is a significant cause of vision loss in the United States, Europe and Japan, with up to 2 million people living with wet AMD in these geographies alone. Current anti-vascular endothelial growth factor (anti-VEGF) therapies have significantly changed the landscape for treatment of wet AMD, becoming the standard of care due to their ability to maintain or prevent progression of vision loss in the majority of patients. These therapies, however, require life-long intraocular injections, typically repeated every 4 to 16 weeks in frequency, to maintain efficacy. Due to the burden of these treatments, patients often experience a decline in vision with reduced frequency of treatment over time.

Detailed Description

This randomized, partially masked, active-controlled, Phase 2b/3 clinical study will evaluate the efficacy and safety of ABBV-RGX-314 gene therapy in participants with nAMD. The study will evaluate 2 dose levels of ABBV-RGX-314 relative to an active comparator. The primary endpoint of this study is the mean change from baseline in best-corrected visual acuity (BCVA) of ABBV-RGX-314 relative to ranibizumab at Week 54. Approximately 630 participants who meet the inclusion/exclusion criteria, will be enrolled into one of 3 arms.

A bilateral treatment substudy conducted at US sites is an open-label, partially randomized, parallel arm study to evaluate the safety and efficacy of subretinal ABBV-RGX-314 administered bilaterally in participants who have bilateral nAMD. Previously treated crossover participants from the control arm of the main study who crossed over and received ABBV-RGX-314 in the study eye will receive the same ABBV-RGX-314 dose in the contralateral eye (ie, same dose as in the study eye), and newcomers (participants who have not been randomized in an ABBV-RGX-314 study) and untreated crossover participants (ongoing control participants in the main study who have completed Week 54 but have not crossed over to receive ABBV-RGX-314 in the main study) will be randomized in a 2:1 ratio to receive ABBV-RGX-314 Dose 1 or ABBV-RGX-314 Dose 2 in both eyes. Up to 15 participants who qualify for the substudy will be enrolled and followed for a minimum of 50 weeks.

Study Timeline

• Study Start: 2020-12-29
• Study First Submitted: 2021-01-08
• Study First Submitted QC: 2021-01-08
• Study First Posted: 2021-01-12
• Status Verified: 2025-08
• Last Update Submitted: 2025-08-15
• Last Update Posted: 2025-08-20
• Primary Completion: 2026-12
• Study Completion: 2027-11-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 630

Inclusion Criteria

1. Age ≥ 50 years and ≤ 89 years
2. An ETDRS BCVA letter score between ≤ 78 and ≥ 40 in the study eye
3. Diagnosis of subfoveal CNV secondary to AMD in the study eye previously treated with anti-VEGF
4. Must be pseudophakic (at least 12 weeks postcataract surgery) in the study eye.
5. Willing and able to provide written, signed informed consent for this study
6. Participants must have demonstrated a meaningful response to anti-VEGF therapy at study entry

Inclusion Criteria (Bilateral Treatment Substudy)*:

1. An ETDRS BCVA letter score between ≤ 83 and ≥ 40 in both eyes
2. Diagnosis of subfoveal choroidal neovascularization (CNV) secondary to AMD in both eyes
3. Must be pseudophakic (at least 12 weeks postcataract surgery) in both eyes
4. Willing and able to provide written, signed informed consent for this study
5. Newcomers must have active disease in the study eye; crossover participants must have active disease in the eye not treated in the main study

Exclusion Criteria

1. CNV or macular edema in the study eye secondary to any causes other than AMD
2. Subfoveal fibrosis or atrophy in the study eye, as determined by CRC
3. Any condition in the investigator's opinion that could limit VA improvement in the study eye
4. Active or history of retinal detachment, or current retinal tear that cannot be treated, in the study eye
5. Advanced glaucoma or history of secondary glaucoma in the study eye
6. History of intraocular surgery in the study eye within 12 weeks prior to randomization
7. 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 Visit 1
8. Prior treatment with gene therapy
9. Recent myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months

Exclusion Criteria (Bilateral Treatment Substudy)*:

1. CNV or macular edema in either eye secondary to any causes other than AMD
2. Subfoveal fibrosis or atrophy in either eye
3. Any condition in the investigator's opinion that could limit VA improvement in either eye
4. Active or history of retinal detachment, or current retinal tear that cannot be treated in either eye
5. Advanced glaucoma or history of secondary glaucoma in either eye
6. Myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months
7. History of intraocular surgery in either eye within 12 weeks prior to randomization
8. History of intravitreal therapy in either eye, such as intravitreal steroid injection or investigational product, other than anti-VEGF therapy, in the 6 months prior to screening
9. Prior treatment with gene therapy (*) For previously treated crossover participants, criteria apply to the eye not treated in the main study only.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ABBV-RGX-314 Dose 1	ABBV-RGX-314	ABBV-RGX-314 Dose 1 administered via subretinal delivery one time.
Control Arm	Ranibizumab (LUCENTIS®)	Ranibizumab administered via intravitreal injection approximately every 28 days
ABBV-RGX-314 Dose 2	ABBV-RGX-314	ABBV-RGX-314 Dose 2 administered via subretinal delivery one time.
ABBV-RGX-314 Dose 1	ABBV-RGX-314	ABBV-RGX-314 Dose 1 administered via subretinal delivery one time.
ABBV-RGX-314 Dose 2	ABBV-RGX-314	ABBV-RGX-314 Dose 2 administered via subretinal delivery one time.
Control Arm	Ranibizumab (LUCENTIS®)	Ranibizumab administered via intravitreal injection approximately every 28 days
ABBV-RGX-314 Dose 1	ABBV-RGX-314	ABBV-RGX-314 Dose 1 administered via subretinal delivery one time.
ABBV-RGX-314 Dose 2	ABBV-RGX-314	ABBV-RGX-314 Dose 2 administered via subretinal delivery one time.
Control Arm	Ranibizumab (LUCENTIS®)	Ranibizumab administered via intravitreal injection approximately every 28 days

Primary Outcome Measures

Name	Time	Method
Mean change from baseline in Best Corrected Visual Acuity (BCVA)	At Week 54	BCVA measured by Early Treatment Diabetic Retinopathy Study (ETDRS)
Bilateral Treatment Substudy: Incidence of ocular AEs and any SAEs	Week 50	Incidence of ocular AEs and any SAEs

Secondary Outcome Measures

Name	Time	Method
Proportion of participants with ≤ 2 supplemental anti-VEGF injections through Week 54 (ABBV-RGX-314 randomized participants)	Through Week 54	Proportion of supplemental anti-VEGF injections.
Proportion of participants with no supplemental anti-VEGF injections through Week 54 (ABBV-RGX-314 randomized participants)	Through Week 54	Proportion of supplemental anti-VEGF injections.
Incidences of ocular and overall AEs over 54 weeks	Through Week 54	AEs over 54 weeks
Incidences of ocular and overall AEs over 98 weeks	Through Week 98	AEs over 98 weeks
Mean change from baseline in BCVA to Week 98 (ABBV-RGX-314 randomized participants) based on the ETDRS score	Week 98	BCVA measured by ETDRS
Proportion of participants with worsened BCVA	Week 54; Week 98	Proportion with worsened BCVA
Proportion of participants with improved BCVA	Week 54; Week 98	Proportion with improved BCVA
Proportion of participants (1) gaining > 0 letters; (2) losing > 0 letters; maintaining vision (not losing ≥ 15 letters) compared with baseline as per BCVA	Week 54; Week 98	Proportion gaining or losing \> 0 letters based on ETDRS score; proportion maintaining vision
Mean change from baseline in BCVA for participants who received 0 or more supplemental anti-VEGF injections (ABBV-RGX-314 randomized participants)	Week 54	Mean change in BCVA based on ETDRS score for participants who received 0 or more supplemental anti-VEGF injection
Mean change from Week 54 to Week 98 in BCVA (control arm participants who cross over to ABBV-RGX-314)	Week 54 to Week 98	Mean change in BCVA based on ETDRS score
Mean change from baseline in CRT as measured by SD-OCT	Week 54; (ABBV-RGX-314 randomized participants) Week 98	Mean change in CRT as measured by SD-OCT
Mean change from Week 54 to Week 98 in CRT as measured by SD-OCT (control arm participants who cross over to ABBV-RGX-314)	from Week 54 to Week 98	Mean change in CRT as measured by SD-OCT
Mean change from baseline in CPT as measured by SD-OCT	Week 54; (ABBV-RGX-314 randomized participants) Week 98	Mean change in CPT as measured by SD-OCT
Mean change from Week 54 to Week 98 in CPT as measured by SD-OCT (control arm participants who cross over to ABBV-RGX-314)	from Week 54 to Week 98	Mean change in CPT as measured by SD-OCT
Proportion of participants with a reduction in anti-VEGF injection annualized rate through Week 54 and Week 98 compared with the prior year (ABBV-RGX-314 randomized participants)	Through Week 54 and Week 98	Proportion of participants with a reduction of in anti-VEGF injection annualized rate compared with the prior year
Percent reduction in anti-VEGF injection annualized rate compared with the prior year (ABBV-RGX-314 randomized participants)	Through Week 54 and Week 98	Supplemental anti-VEGF injection annualized rate
Supplemental anti-VEGF injection annualized rate in the ABBV-RGX-314 arms through Week 54 and Week 98	Through Week 54 and Week 98	Supplemental anti-VEGF injection annualized rate
Percent reduction in anti-VEGF injection annualized rate after Week 58 through Week 98 relative to the year prior to the study (control arm participants who cross over to ABBV-RGX-314)	After Week 58 through Week 98	Percent reduction in anti-VEGF injection annualized rate
Supplemental anti-VEGF injection annualized rate after Week 58 through Week 98 (control arm participants who cross over to ABBV-RGX-314)	After Week 58 to Week 98	Supplemental anti-VEGF injection annualized rate
22. Time to first supplemental anti-VEGF injection after the Week 2 injection in the ABBV-RGX-314 arms	Week 98	Time to first supplemental anti-VEGF injection
Time to first supplemental anti-VEGF injection after the Week 58 injection in the control arm participants who cross over to ABBV-RGX-314	After Week 58 to Week 98	Time to first supplemental anti-VEGF injection
Mean change from baseline in NEI-VFQ-25 (composite score) at Week 54 and (for ABBV-RGX-314 randomized participants and control arm participants who cross over to ABBV-RGX-314) Week 98	Week 54; Week 98	Mean change in NEI VGQ-25 (composite score) at week 54 (control arm participants who cross over to ABBV-RGX-314)
Mean change from baseline in MacTSQ (composite score) at Week 54 and (for ABBV-RGX-314 randomized participants and control arm participants who cross over to ABBV-RGX-314) Week 98	Week 54; Week 98	Mean change from baseline in MacTSQ (composite score) at week 54 and (control arm participants who cross over to ABBV-RGX-314) at Week 98
Aqueous ABBV-RGX-314 TP concentrations (ABBV-RGX-314 randomized participants)	Wk -2, Wk 14, Wk 26, Wk 38, Wk 54, and Wk 98	Aqueous ABBV-RGX-314 TP concentration
Aqueous ABBV-RGX-314 TP concentrations (control arm participants who cross over to ABBV-RGX-314)	Wk 54, Wk 66, Wk 78, Wk 90, and Wk 98	Aqueous ABBV-RGX-314 TP concentration
Immunogenicity measurements (ABBV-RGX-314 randomized participants)	Wk -2, Wk 14, Wk 26, Wk 38, Wk 54, and Wk 98	Immunogenicity measurements (serum antibodies to AAV8 and serum antibodies to ABBV-RGX-314 TP)
Immunogenicity measurements (control arm participants who cross over to ABBV-RGX-314)	Wk 54, Wk 66, Wk 78, Wk 90, and Wk 98	Immunogenicity measurements (serum antibodies to AAV8 and serum antibodies to ABBV-RGX-314 TP)
Bilateral Treatment Substudy: Incidence of nonocular AEs and any AEs of special interest	Week 50	Nonocular AEs and AEs of Special interest
Bilateral Treatment Substudy: Mean change from Baseline in BCVA at assessed timepoints	Through Week 50	BCVA measured by ETDRS
Bilateral Treatment Substudy: Mean change from Baseline in CRT at assessed timepoints	Through Week 50	Mean change in CRT as measured by SD-OCT
Bilateral Treatment Substudy: Supplemental anti-VEGF injection annualized rate	Through Week 50	Supplemental anti-VEGF injection annualized rate
Bilateral Treatement Substudy: Mean number of supplemental anti-VEGF injections	Through Week 50	Mean supplemental anti-VEGF injections
Bilateral Treatment Substudy: Proportion of participants with no supplemental anti-VEGF injections	Through Week 50	Proportion of participants with no supplemental anti-VEGF injections
Bilateral Treatment Substudy: Proportion of particpants with ≤2 supplemental anti-VEGF injections	Through Week 50	Proportion of participants with ≤2 supplemental anti-VEGF injections
Bilateral Treatment Substudy: Aqueous humor and serum ABBV-RGX-314 TP concentrations	Wk 26, Wk 34, Wk 50	Aqueous humor and serum ABBV-RGX-314 TP Concentrations
Bilateral Treatment Substudy: Immunogenicity measurements (serum anti-ABBV-RGX-314 TP antibodies, serum anti-AAV8 antibodies) and enzyme-linked immunospot at assessed time points	Wk 18, Wk 34, Wk 50	Immunogenicity measurements

Trial Locations

Locations (89)

Retinal Research Institute /ID# 256019; 🇺🇸 Phoenix, Arizona, United States

Barnet Dulaney Perkins Eye Center - Sun City /ID# 256055; 🇺🇸 Sun City, Arizona, United States

University of Arkansas for Medical Sciences /ID# 271290; 🇺🇸 Little Rock, Arkansas, United States

Retina Vitreous Assoc Med Grp /ID# 256299; 🇺🇸 Beverly Hills, California, United States

Retinal Diagnostic Center /ID# 256137; 🇺🇸 Campbell, California, United States

The Retina Partners - Encino /ID# 256054; 🇺🇸 Encino, California, United States

Retina Consultants of Orange County /ID# 256152; 🇺🇸 Fullerton, California, United States

Salehi Retina Institute /ID# 263485; 🇺🇸 Huntington Beach, California, United States

UC Irvine/Gavin Herbert Eye Institute /ID# 256145; 🇺🇸 Irvine, California, United States

Northern California Retina Vitreous Associates Medical Group, Inc /ID# 256298; 🇺🇸 Mountain View, California, United States

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