Pivotal 2 Study of RGX-314 Gene Therapy in Participants With nAMD

This randomized, partially masked, controlled, Phase 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 RGX-314 gene therapy relative to an active comparator. The primary endpoint of this study is mean change in best-corrected visual acuity (BCVA) of ABBV-RGX-314 relative to aflibercept. Approximately 714 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), while 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.

• ABBV-RGX-314 Dose 1 (Genetic), also known as RGX-314, surabgene lomparvovec: AAV8 vector containing a transgene for anti-VEGF Fab (Dose 1)
• ABBV-RGX-314 Dose 2 (Genetic), also known as RGX-314, surabgene lomparvovec: AAV8 vector containing a transgene for anti-VEGF Fab (Dose 2)
• Aflibercept (EYLEA®) (Biological), also known as Eylea (anti-VEGF agent): 2.0 mg (0.05 mLsolution) administered by intravitreal injection approximately every 8 weeks after 3 monthly injections

Primary outcomes

• Mean change from baseline in Best Corrected Visual Acuity (BCVA) [At Week 54]: To evaluate the noninferiority of ABBV-RGX-314 relative to aflibercept in mean change from Baseline BCVA at Week 54
• Bilateral Treatment Substudy: Incidence of ocular AEs and any SAEs [Week 50]: AEs and SAEs through Week 50

Secondary outcomes

• Incidences of ocular and overall AEs [Through Week 54]: To evaluate the safety and tolerability of ABBV-RGX-314 through Week 54
• Proportion of participants with improved BCVA [Week 54]: To evaluate the effect of ABBV-RGX-314 relative to aflibercept on BCVA
• Proportion of participants with worsened BCVA [Week 54]: To evaluate the effect of ABBV-RGX-314 relative to aflibercept on BCVA
• Proportion of participants (1) gaining or losing greater than 0 letters; (2) maintaining vision compared with baseline as per BCVA [Week 54]: To evaluate the effect of ABBV-RGX-314 relative to aflibercept on BCVA
• Mean change from baseline in BCVA for participants who received 0 or more supplemental anti-VEGF injection (ABBV-RGX- 314 randomized participants) [Week 54]: To evaluate the effect of ABBV-RGX-314 relative to aflibercept on BCVA
• Mean change from Week 54 to Week 108 in BCVA (control arm participants who cross over to ABBV-RGX-314) [Week 54 to Week 108]: To evaluate the effect of ABBV-RGX-314 relative to aflibercept on BCVA
• Mean change in central retinal thickness (CRT) as measured by SD-OCT [Through Week 108]: To evaluate the effect of ABBV-RGX-314 relative to aflibercept on CRT as measured by SD-OCT
• Mean change in central point thickness (CPT) as measured by SD-OCT [Through Week 108]: To evaluate the effect of ABBV-RGX-314 relative to aflibercept on CPT as measured by SD-OCT
• Mean number of supplemental anti-VEGF injections from Baseline through Week 54 (ABBV-RGX-314 randomized participants) and from Week 54 through Week 108 (control arm participants who cross over to ABBV-RGX-314) [Through Week 108]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Proportion of participants with 0, 1, 2, and 3 supplemental injections through Week 54 (ABBV-RGX-314 randomized participants) and from Week 54 through Week 108 (control arm participants who cross over to ABBV-RGX-314) [Through Week 108]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Proportion of participants with ≤ 1, ≤ 2, and ≤ 3 supplemental injections through Week 54 (ABBV-RGX-314 randomized participants) and from Week 54 through Week 108 (control arm participants who cross over to ABBV-RGX-314) [Through Week 108]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Proportion of participants that received 1 or 2 injections through Week 54 (ABBV-RGX-314 randomized participants) and from Week 54 through Week 108 (control arm participants who cross over to ABBV-RGX-314) [Through Week 108]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Proportion of participants with a reduction of ≥ 50% in anti-VEGF injection annualized rate through Week 54 compared with the prior year (ABBV-RGX-314 randomized participants) [Through Week 54]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Proportion of participants with a reduction of ≥ 75% in anti-VEGF injection annualized rate through Week 54 compared with the prior year (ABBV-RGX-314 randomized participants) [Through Week 54]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Percent reduction in anti-VEGF injection annualized rate through Week 54 compared with the prior year (ABBV-RGX-314 randomized participants) [Through Week 54]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Supplemental anti-VEGF injection annualized rate through Week 54 (ABBV-RGX-314 randomized participants) [Through Week 54]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Percent reduction in anti-VEGF injection annualized rate after Week 58 through Week 108 relative to the year prior to study (control arm participants who cross over to ABBV-RGX-314) [Through Week 108]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Supplemental anti-VEGF injection annualized rate after Week 58 through Week 108 (control arm participants who cross over to ABBV-RGX-314) [Through Week 108]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Time to first supplemental anti- VEGF injection after the Week 2 injection (ABBV-RGX-314 randomized participants) [Through Week 54]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Time to first supplemental anti-VEGF injection after the Week 58 injection (control arm participants who cross over to ABBV-RGX-314) [Through Week 108]: To assess the need for supplemental anti-VEGF therapy in participants treated with ABBV-RGX-314
• Mean change from Baseline in NEI VFQ-25 (composite score) at Week 54 and (control arm participants who cross over to ABBV-RGX-314) Week 108 [Week 54 and Week 108]: To evaluate patient-reported visual function and treatment satisfaction using PRO questionnaires
• Mean change from Baseline in MacTSQ (composite score) at Week 54 and (control arm participants who cross over to ABBV-RGX-314) Week 108 [Week 54 and Week 108]: To evaluate patient-reported visual function and treatment satisfaction using PRO questionnaires
• Aqueous humor ABBV-RGX-314 TP concentrations at Week -2, Week 14, Week 38, and Week 54 (ABBV-RGX-314 randomized participants) [Through Week 54]: To assess aqueous humor and serum TP concentrations prior to and after ABBV-RGX-314 administration
• Aqueous humor ABBV-RGX-314 TP concentrations at Week 54, Week 74, Week 90, and Week 108 (control arm participants who cross over to ABBV-RGX-314) [Through Week 108]: To assess aqueous humor and serum TP concentrations prior to and after ABBV-RGX-314 administration
• Serum ABBV-RGX-314 TP concentrations (at select sites) [Through Week 54]: To assess aqueous humor and serum TP concentrations prior to and after ABBV-RGX-314 administration
• Immunogenicity measurements (ABBV-RGX-314 randomized participants) [Week -2, Week 14, Week 38, and Week 54]: Immunogenicity measurements (serum antibodies to AAV8 and serum antibodies to ABBVRGX- 314 TP)
• Immunogenicity measurements (control arm participants who cross over to ABBV-RGX-314) [Week 54, Week 74, Week 90, and Week 108]: Immunogenicity measurements (serum antibodies to AAV8 and serum antibodies to ABBV-RGX- 314 TP)
• Bilateral Treatment Substudy: Incidence of nonocular AEs and any AESIs [Week 50]: To evaluate the safety and tolerability of bilateral treatment of ABBV-RGX-314 gene therapy
• Bilateral Treatment Substudy: Mean change from Baseline in BCVA at assessed time points [Week 50]: BCVA measured by ETDRS
• Bilateral Treatment Substudy: Mean change from Baseline in CRT at assessed time points [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 Treatment Substudy: Mean number of supplemental anti-VEGF injections [Through Week 50]: Mean supplemental anti-VEGF injections
• Bilateral Treatment Substudy: Proportion of participants with 0, ≤ 1, ≤ 2, and ≤ 3 supplemental anti-VEGF injections [Through Week 50]: Proportion of participants with 0, ≤ 1, ≤ 2, and ≤ 3 supplemental anti-VEGF injections
• Bilateral Treatment Substudy: Aqueous humor and serum ABBV-RGX-314 TP concentrations [Week 26, Week 34, Week 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 [Week 50]: Immunogenicity measurements

Sex: All, ages: 50 Years to 89 Years

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 choroidal neovascularization (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
3. Any condition in the investigator's opinion that could limit VA improvement in the study eye
4. Advanced glaucoma or history of secondary glaucoma in the study eye
5. Myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months
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 medicinal product, other than an intravitreal therapy for AMD, in the 6 months prior to Week -6
8. Prior treatment with gene therapy

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. Advanced glaucoma or history of secondary glaucoma in either eye
5. Myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months
6. History of intraocular surgery in either eye within 12 weeks prior to randomization
7. History of intravitreal therapy in the study eye, such as intravitreal steroid injection or investigational medicinal product, other than an intravitreal therapy for AMD, in the 6 months prior to Week -6.
8. Prior treatment with gene therapy (*) For previously treated crossover participants, criteria apply to the eye not treated in the main study only.

Note: Other inclusion/exclusion criteria apply

81 more sites not listed.