Evaluation of RGX-314 Gene Therapy Efficacy and Safety in Neovascular Age-Related Macular Degeneration: A Phase 3 Randomized Controlled Trial

The primary objective of this Phase 3 clinical study is to evaluate the **noninferiority** of ABBV-RGX-314 relative to aflibercept in terms of best-corrected visual acuity (BCVA) from baseline to Week 54 in participants with neovascular age-related macular degeneration (nAMD). This is clinically relevant as it aims to establish ABBV-RGX-314 as a viable alternative to aflibercept, potentially offering a new therapeutic option for managing nAMD, a leading cause of vision loss.

Secondary objectives include: - Assessing the need for supplemental anti-VEGF therapy in the ABBV-RGX-314 treatment arms, which is crucial for understanding the long-term management and potential reduction in treatment burden for patients. - Evaluating the superiority of ABBV-RGX-314 relative to aflibercept on BCVA, which could demonstrate enhanced efficacy and further support its use as a preferred treatment option.

The clinical trial for **neovascular age-related macular degeneration** involves a total of 444 participants. The study population includes both male and female subjects, aged between 50 and 89 years. Participants are required to be in general good health, with specific criteria ensuring they have a diagnosis of choroidal neovascularization secondary to age-related macular degeneration in the study eye. All participants must have previously received and responded to at least one anti-VEGF injection prior to the screening visit. The trial population was selected based on their ability to provide informed consent and their pseudophakic status in the study eye, being at least 12 weeks post-cataract surgery. Lifestyle considerations such as diet and physical activity are not specified, and the trial does not include vulnerable populations. The selection process ensures that participants have demonstrated a meaningful response to anti-VEGF therapy at study entry.

The clinical trial is designed to evaluate the **efficacy** and safety of **RGX-314** gene therapy in participants with neovascular age-related macular degeneration (nAMD). This is a randomized, partially masked, controlled, Phase 3 study. The trial aims to establish the noninferiority of **ABBV-RGX-314** relative to **aflibercept** from baseline to best-corrected visual acuity (BCVA) at Week 54. The study is expected to commence recruitment on February 15, 2024, and conclude by November 30, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, BCVA score, and previous response to anti-VEGF therapy. The trial will include follow-up visits to monitor the participants' response to the treatment and any adverse effects. The end-of-study visit will assess the primary endpoint, which is the mean change from baseline in BCVA to Week 54, and secondary endpoints, including the proportion of participants with reduced supplemental anti-VEGF injections.

The expected length of participant involvement is approximately 54 weeks. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that compromise participant safety. The trial will utilize a subretinal injection of **RGX-314** and intravitreal injections of **aflibercept** and **ranibizumab** as comparators. The study will ensure that all procedures adhere to ethical standards and regulatory requirements.

The clinical trial involves the use of **ABBV-RGX-314**, a **suspension for injection** developed by AbbVie Deutschland GmbH & Co. KG. This experimental medication is administered via **subretinal use**. The active substance, **RGX-314**, is a structurally diverse substance designed to deliver gene therapy targeting the anti-VEGF Fab (anti-vascular endothelial growth factor antigen-binding fragment). The treatment involves a recombinant adeno-associated virus (AAV8.CB7.CI.amd42.RBG) vector, which includes capsid protein from adeno-associated virus serotype 8 and inverted terminal repeats from serotype 2. The administration is facilitated by a DORC Extendible 41G subretinal injection needle and a MedOne 3277 Microdose Injection Kit, ensuring precise delivery with minimal fluid loss. The maximum treatment period for this medication is one day.

**Lucentis** (ranibizumab) is used as a comparator treatment in this study. It is a **solution for injection** provided in a pre-filled syringe by Novartis Europharm Limited. The active substance, **ranibizumab**, is a protein-based therapeutic agent administered via **intravitreal use**. The dosage is 0.5 mg per injection, with a maximum treatment period of one day. This medication is part of the standard-of-care therapy for conditions involving vascular endothelial growth factor (VEGF) inhibition.

**Eylea** (aflibercept) serves as an auxiliary treatment in the trial. Manufactured by Bayer AG, it is also a **solution for injection** in a pre-filled syringe. The active substance, **aflibercept**, is a protein-based agent administered through **intravitreal use**. The dosage is 2 mg per injection, with a maximum total dose of 20 mg over a treatment period of 54 weeks. Eylea is commonly used in the management of neovascular age-related macular degeneration (nAMD) and other retinal conditions.

The efficacy of the clinical trial will be assessed by evaluating the noninferiority of **ABBV-RGX-314** relative to aflibercept from baseline to Best Corrected Visual Acuity (BCVA) at Week 54. The primary endpoint is the mean change from baseline in BCVA to Week 54 based on the Early Treatment Diabetic Retinopathy Study (ETDRS) score, ensuring noninferiority to the active control. Secondary endpoints include the proportion of participants with two or fewer supplemental anti-VEGF injections through Week 54, the proportion of participants with no supplemental anti-VEGF injections through Week 54, the percent reduction in anti-VEGF injection annualized rate through Week 54 compared with the prior year, and the mean change from baseline in BCVA to Week 54 based on the ETDRS score, assessing superiority to the active control.