Efficacy and Safety Evaluation of Xelafaslatide (ONL1204) in Geographic Atrophy Secondary to Age-related Macular Degeneration: A Phase 2 Randomized Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of ONL1204 compared to a sham injection in patients with **geographic atrophy** (GA) associated with **age-related macular degeneration** (AMD). This is clinically relevant as GA is a progressive and irreversible condition that leads to vision loss, and there are currently limited treatment options available. The study aims to determine whether ONL1204 can slow the progression of this debilitating disease, potentially offering a new therapeutic avenue for affected patients.

The clinical trial involves a total of **142 participants** diagnosed with **Atrophic Age-related Macular Degeneration (AMD)**, specifically focusing on those with geographic atrophy (GA). The study population includes both male and female subjects aged **55 years or older**, ensuring a broad representation of the demographic typically affected by AMD. Participants were selected based on specific criteria, including the absence of exudative macular neovascularization (eMNV) in the study eye and a best-corrected visual acuity (BCVA) of 24 letters or more in the study eye, as well as 19 letters or more in the fellow eye, measured using ETDRS charts. The trial also considers lifestyle factors, such as the use of Age-related Eye Disease Study 2 (AREDS2) nutraceutical therapy, requiring participants to maintain their current regimen or abstain from it throughout the study. The trial includes a vulnerable population, indicating additional ethical considerations in the study design and execution.

The clinical trial is designed as a **randomized**, double-masked, sham-controlled, reference-arm study to evaluate the efficacy and safety of ONL1204 Ophthalmic Solution in patients with **geographic atrophy** associated with **age-related macular degeneration** (AMD). The trial is set to commence recruitment on June 2, 2025, and is expected to conclude by January 24, 2028. Participants will be randomly assigned to receive either the ONL1204 Ophthalmic Solution or a sham injection, with the primary objective being the assessment of the geographic atrophy lesion area.

The study will involve several key visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age (55 years or older) and visual acuity requirements. Participants must either continue or refrain from using Age-related Eye Disease Study 2 (AREDS2) nutraceutical therapy throughout the study, depending on their current usage at screening. Following the screening, participants will undergo regular follow-up visits to monitor treatment effects and safety. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.

The expected duration of participant involvement is up to 60 weeks, with the maximum treatment period being 60 days. Participants may be subject to early termination from the study if they do not adhere to the study protocol, experience adverse effects that necessitate withdrawal, or if the investigator deems it in the participant's best interest. The trial aims to provide valuable insights into the potential of ONL1204 to slow the progression of atrophic AMD, contributing to the development of effective treatments for this condition.

The clinical trial involves the evaluation of **ONL1204 Ophthalmic Solution**, an experimental medication formulated as a **solution for intravitreal injection**. The active substance in this solution is **Xelafaslatide**, a protein-based compound. The solution is administered via intravitreal injection, with a maximum daily dose of 200 micrograms and a total maximum dose of 1200 micrograms over a treatment period of 60 days. The administration schedule is designed to ensure optimal efficacy while monitoring for safety and tolerability in patients with geographic atrophy associated with age-related macular degeneration.

In addition to the experimental treatment, the study includes a **sham injection** as a comparator. The sham injection serves as a placebo control to evaluate the efficacy of ONL1204. The sham injection does not contain any active pharmaceutical ingredients and is administered in a manner that mimics the procedure of the experimental treatment without delivering an active substance. This approach allows for a double-masked study design, ensuring that neither the participants nor the investigators are aware of the treatment allocation, thereby reducing bias and enhancing the reliability of the study outcomes.

The efficacy of ONL1204 in patients with **Geographic Atrophy (GA)** associated with Age-related Macular Degeneration (AMD) will be assessed in a Phase 2 multicenter, randomized, double-masked, sham-controlled, reference-arm study. The primary endpoint for evaluating efficacy is the assessment of the GA lesion area. This will involve measuring changes in the size of the GA lesions over the course of the study. The study will compare the effects of ONL1204 Ophthalmic Solution, administered as a solution for intravitreal injection, against a sham injection.