Long-Term Safety and Efficacy Evaluation of Intravitreal Pegcetacoplan in Geographic Atrophy Secondary to Age-Related Macular Degeneration

The primary objective of this study is to evaluate the long-term **safety** of intravitreal (IVT) injected pegcetacoplan in subjects with **geographic atrophy** secondary to age-related macular degeneration. This is clinically relevant as it aims to ensure the sustained safety profile of pegcetacoplan, a treatment option for a progressive and vision-threatening condition.

Secondary objectives include:

• Assessing changes in the total area of geographic atrophy lesion in the study eye measured by fundus autofluorescence.
• Evaluating changes in visual function as measured by normal-luminance best-corrected visual acuity score, low-luminance best-corrected visual acuity score, and reading speed in the study eye.
• Assessing the macular functional response using mesopic microperimetry in selected participants.
• Evaluating changes in participant-reported outcomes using the National Eye Institute Visual Functioning Questionnaire 25 Item Version and the Functional Reading Independence Index.

The clinical trial involves a total of **994 participants** who are being evaluated for the long-term safety of IVT-injected pegcetacoplan in the context of **Geographic Atrophy Secondary to Age-Related Macular Degeneration**. The study population includes both male and female subjects, with age categories ranging from adults to the elderly. Participants were selected based on their previous involvement in specific antecedent studies, namely APL2-103, APL2-303 (Derby), or APL2-304 (Oaks), and must meet ocular-specific criteria for the study eye. The trial includes individuals who are considered part of a vulnerable population. Participants are required to have clarity of ocular media and adequate pupillary dilation to ensure the collection of high-quality images. Female participants of childbearing potential must have a negative serum pregnancy test at screening and adhere to protocol-defined contraception methods, while male participants with female partners of childbearing potential must also follow specified contraception guidelines. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants must be willing and able to provide informed consent and comply with study procedures and assessments.

The clinical trial is designed to evaluate the long-term safety and efficacy of **pegcetacoplan** in subjects with **geographic atrophy** secondary to age-related macular degeneration. This is a Phase 3, open-label, multicenter extension study. Participants eligible for this trial must have previously participated in specific antecedent studies, namely APL2-103, APL2-303, or APL2-304, and meet ocular-specific inclusion criteria. The trial employs a non-randomized, open-label design, allowing for the collection of comprehensive safety and efficacy data over an extended period.

The trial is expected to last until June 2025, with participant involvement potentially extending up to 36 months. The study involves a series of visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. Participants will undergo regular follow-up visits to monitor the incidence and severity of ocular and systemic adverse events, as well as to assess secondary endpoints such as the total area and growth rate of geographic atrophy lesions, visual acuity scores, and reading speeds. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

Participants are required to comply with study procedures and assessments, including the use of protocol-defined contraception methods for both male and female participants of childbearing potential. Conditions that may lead to early termination from the study include non-compliance with study procedures, withdrawal of consent, or the occurrence of adverse events that, in the investigator's opinion, warrant discontinuation. The study aims to provide valuable insights into the long-term safety profile of pegcetacoplan, contributing to the understanding of its therapeutic potential in managing geographic atrophy associated with age-related macular degeneration.

The clinical trial involves the administration of the experimental medication **APL-2**, which is a **solution for injection**. The active substance in APL-2 is **pegcetacoplan**, a protein-based compound. The pharmaceutical form of APL-2 is specifically designed for **intravitreal use**, meaning it is injected directly into the eye. The maximum daily dose of APL-2 is 15 mg, with a total maximum dose of 540 mg over the course of the treatment period. The treatment period is set to a maximum of 36 months. The administration of APL-2 is conducted under controlled conditions to ensure participant safety and adherence to the dosing schedule.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the long-term safety and efficacy of pegcetacoplan in subjects with **geographic atrophy secondary to age-related macular degeneration**. Participant compliance with the dosing regimen is monitored throughout the trial to ensure accurate assessment of the medication's effects. The trial is conducted in an open-label, multicenter format, allowing for comprehensive data collection and analysis.

The efficacy of **pegcetacoplan** in the clinical trial will be assessed through a series of secondary endpoints. These endpoints include the measurement of the total area of geographic atrophy (GA) lesions in the study eye, evaluated in square millimeters using fundus autofluorescence (FAF). Additionally, the rate of GA lesion growth will be monitored using the same imaging technique. Visual acuity will be assessed through the NL-BCVA and LL-BCVA scores, utilizing the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Reading speed, both monocular and binocular, will be evaluated using the Minnesota Reading (MNRead) charts or Radner charts, with corrections for the number of words read incorrectly.

Further assessments will include the number of absolute scotomatous points and macular sensitivity in the study eye, determined by mesopic microperimetry for selected participants. Changes in additional microperimetry parameters, such as the 95% bivariate contour ellipse area (BCEA) and the number of points with a clinically significant decrease in mean sensitivity, will also be recorded. The mean Functional Reading Independence (FRI) Index score will be calculated, alongside composite scores and subscale scores from the NEI VFQ-25 and NEI VFQ-39 questionnaires, which will be administered at select sites. These assessments will provide a comprehensive evaluation of the efficacy of pegcetacoplan in subjects with geographic atrophy secondary to age-related macular degeneration.