Evaluation of Intravitreal OPT-302 and Aflibercept Versus Aflibercept Monotherapy in Neovascular Age-related Macular Degeneration Patients

The primary objective of this study is to evaluate the **efficacy** of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept in participants with neovascular age-related macular degeneration (nAMD). This is clinically relevant as nAMD is a leading cause of vision loss, and improving treatment efficacy could significantly impact patient outcomes.

The secondary objectives of the study are to determine the effects of intravitreal 2.0 mg OPT-302 in combination with intravitreal 2.0 mg aflibercept from baseline to Week 52, focusing on:

• Changes in ETDRS BCVA (Early Treatment Diabetic Retinopathy Study Best-Corrected Visual Acuity) letter score.

The clinical trial involves a total of **523 participants** diagnosed with **Neovascular Age-related Macular Degeneration (wet AMD)**. The study population includes both male and female subjects who are at least 50 years of age. Participants were selected based on specific criteria, including the presence of an active subfoveal or juxtafoveal choroidal neovascularization (CNV) lesion with foveal involvement secondary to AMD in the study eye, and an Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) score between 60 and 25 letters in the study eye. The trial does not specify particular lifestyle considerations such as diet or physical activity. The selection process ensures a diverse representation of the affected population, including vulnerable groups, to comprehensively assess the efficacy of the treatment under investigation.

The clinical trial is designed to evaluate the **efficacy** and safety of intravitreal OPT-302 in combination with **aflibercept** compared to aflibercept alone in participants with neovascular age-related macular degeneration (nAMD). This is a Phase III, multicenter, double-masked, randomized study. The trial is expected to last until January 20, 2026, with recruitment having started on October 4, 2021. Participants will be randomly assigned to receive either the combination treatment or aflibercept alone, with a sham injection mimicking the OPT-302 injection for the control group.

The study involves several key visits: an initial screening visit to determine eligibility based on criteria such as age (at least 50 years), presence of active subfoveal or juxtafoveal choroidal neovascularization (CNV) lesions, and a specific range of best-corrected visual acuity (BCVA) scores. Following the screening, participants will undergo regular follow-up visits to monitor treatment effects and safety. The primary endpoint is the mean change in BCVA from baseline to Week 52, with secondary endpoints including the proportion of participants gaining significant BCVA improvements and changes in CNV area.

Participant involvement is expected to last up to 96 weeks, with the possibility of early termination if adverse events occur or if the participant withdraws consent. The trial's design ensures that neither the participants nor the investigators know which treatment is being administered, maintaining the double-masked nature of the study. The trial aims to provide robust data on the potential benefits of combining OPT-302 with aflibercept in treating nAMD.

The clinical trial involves the administration of **Eylea** (aflibercept) 40 mg/mL solution for injection in a pre-filled syringe. This pharmaceutical form is a solution for injection, specifically designed for **intravitreal use**. The active substance, aflibercept, is a protein of biotechnological origin. The maximum daily dose is 2 mg, with a total maximum dose of 48 mg over a treatment period of 96 weeks. The administration schedule involves regular intravitreal injections, and participant compliance is monitored throughout the study. Eylea is manufactured by Bayer AG and is authorized for use in several countries, including Liechtenstein, the European Union, Iceland, and Norway.

Another experimental medication used in the trial is **OPT-302**, a solution for injection containing the active substance **vascular endothelial growth factor receptor 3 extracellular domains 1-3 fused to an IgG1 Fc fragment**. This protein-based therapeutic is also administered via intravitreal injection. The dosing regimen mirrors that of Eylea, with a maximum daily dose of 2 mg and a total maximum dose of 48 mg over 96 weeks. OPT-302 is developed by Opthea Ltd and is classified as a biological product of biotechnological origin.

The study also includes a **sham injection** to mimic the administration of OPT-302. This comparator treatment is designed to simulate the intravitreal injection process without delivering an active substance. The sham injection serves as a control to evaluate the efficacy and safety of the experimental treatments. Compliance with the sham procedure is similarly monitored to ensure consistency across the study.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the mean change from baseline to Week 52 in Early Treatment Retinopathy Study (ETDRS) best-corrected visual acuity (**BCVA**) letters. This will be measured using the ETDRS chart, a validated tool for assessing visual acuity in clinical settings.

Secondary endpoints include the proportion of participants gaining 15 or more ETDRS BCVA letters from baseline to Week 52, the proportion of participants gaining 10 or more ETDRS BCVA letters from baseline to Week 52, and the change in choroidal neovascularization (CNV) area by fluorescein angiography (FA) from baseline to Week 52. Additionally, the proportion of participants with the absence of both subretinal fluid (SRF) and intraretinal (IR) cysts by spectral domain optical coherence tomography (SD-OCT) at Week 52 will be evaluated. These measurements will be collected at specified time points and analyzed to determine the efficacy of the treatment regimen involving intravitreal OPT-302 in combination with **aflibercept** compared to aflibercept alone in participants with neovascular age-related macular degeneration (nAMD).