Evaluation of Faricimab Versus Aflibercept in High-Frequency Treated Neovascular Age-Related Macular Degeneration: A Randomized, Double-Masked Study

The primary objective of this study is to assess the **efficacy** of faricimab compared to aflibercept in terms of durability at 32 weeks by extending the treatment interval in patients with previously high-frequent aflibercept-treated neovascular age-related macular degeneration. This is clinically relevant as it may offer a more sustainable treatment regimen, potentially reducing the burden of frequent injections for patients.

Secondary objectives include:

• Evaluating the durability, efficacy on best-corrected visual acuity (BCVA), anatomic outcomes, and safety of faricimab in the same patient population.
• Assessing whether longer durability impacts patients' quality of life and if systemic VEGF and Ang-2 levels are influenced differently under faricimab compared to aflibercept treatment.

The clinical trial involves participants diagnosed with **neovascular age-related macular degeneration**. The study population includes both male and female subjects aged 50 years and older. Participants are required to have a history of receiving at least seven previous intravitreal injections with anti-VEGF, with the last four or more being aflibercept injections administered within the last 35 days. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to have a Best Corrected Visual Acuity (BCVA) between 19 and 75 letters, which corresponds to a Snellen equivalent of approximately 20/400 to 20/32. The selection criteria emphasize the ability and willingness to comply with clinic visits and study-related procedures, as well as the provision of signed written informed consent. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **faricimab** compared to **aflibercept** in patients with neovascular age-related macular degeneration. This study is a monocenter, randomized, double-masked, comparator-controlled trial. The primary objective is to assess the durability of faricimab by extending the treatment interval in patients previously treated with high-frequency aflibercept over a period of 32 weeks. The trial is expected to conclude by February 28, 2025, with recruitment having commenced on July 4, 2023.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed through criteria such as age (≥50 years), previous treatment history, and visual acuity requirements. Following the inclusion visit, participants will be randomized to receive either faricimab or aflibercept via intravitreal injection. The study includes follow-up visits to monitor treatment efficacy and safety, with primary and secondary endpoints evaluated at 32 and 56 weeks. The primary endpoint is the proportion of eyes achieving an extension without retinal fluid from baseline to 32 weeks.

The expected duration of participant involvement is up to 56 weeks, with conditions for early termination including withdrawal of consent or adverse events. Secondary endpoints include the maximum extended treatment interval without retinal fluid, the number of injections received, and changes in visual acuity scores. The study aims to provide insights into the potential benefits of extending treatment intervals in this patient population, contributing to optimized management strategies for neovascular age-related macular degeneration.

The clinical trial involves the administration of **Vabysmo**, a **solution for injection** containing the active substance **faricimab**. This experimental medication is provided in a concentration of 120 mg/mL and is administered via **intravitreal use**. The maximum daily dose is 120 mg, with a total maximum dose of 6720 mg over a treatment period of up to 56 weeks. Faricimab is a bispecific antibody targeting both vascular endothelial growth factor A (VEGF-A) and angiopoietin 2 (Ang-2), and it is classified under the ATC code S01LA09. The pharmaceutical form is a solution for injection, and the product is manufactured by Roche Registration GmbH.

The comparator treatment in this study is **Eylea**, a **solution for injection in a pre-filled syringe** containing the active substance **aflibercept**. This medication is provided at a concentration of 40 mg/mL and is also administered via **intravitreal use**. The maximum daily dose is 40 mg, with a total maximum dose of 1280 mg over a treatment period of up to 32 weeks. Aflibercept acts as a VEGF trap, inhibiting the activity of VEGF-A, and is classified under the ATC code S01LA05. The product is manufactured by Bayer AG.

Both treatments are administered intravitreally, and participant compliance is monitored throughout the study. The trial aims to assess the efficacy of faricimab compared to aflibercept in terms of treatment durability in patients with neovascular age-related macular degeneration previously treated with high-frequency aflibercept. No additional non-experimental treatments, such as placebo or standard-of-care therapy, are utilized in this study.

The efficacy of **faricimab** compared to aflibercept in the treatment of neovascular age-related macular degeneration (nAMD) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of eyes achieving at least one extension without retinal (intra- and subretinal) fluid from baseline to 32 weeks, referred to as the extension success rate. Secondary endpoints include the proportion of eyes with maximum extended intervals without retinal fluid of ≥6, ≥8, and ≥10 weeks at 32 weeks, as well as the maximum extended treatment interval without retinal fluid at 32 weeks. Additional secondary endpoints involve the number of injections received during the 32-week period, and the proportion of eyes maintaining a 4-weekly interval from baseline to the last visit at 56 weeks.

Further secondary endpoints include the mean change in ETDRS letter score from baseline to an averaged score between 24 and 32 weeks, and between 48 and 56 weeks, as well as the mean change in low-luminance BCVA over time. The study will also evaluate the mean change in central subfield thickness (CST) from baseline to an averaged CST between 24 and 32 weeks, and between 48 and 56 weeks. The proportion of eyes with no intraretinal, subretinal, or retinal fluid at baseline and at specified time points will be assessed. Additional analyses will include retinal nerve fiber analysis, incidence and severity of ocular/non-ocular adverse events, and changes in plasma VEGF-A and Ang-2 concentrations over time. The change in NEI VFQ-25 total score will also be monitored throughout the study.