Evaluation of Pozelimab and Cemdisiran, Alone or in Combination, on Geographic Atrophy Progression in Age-Related Macular Degeneration

The primary objective of this study is to evaluate the effect of systemic **Complement Component 5 (C5)** inhibition on the growth of geographic atrophy (GA) lesions over a period of 52 weeks. This is clinically relevant as GA is a progressive condition associated with age-related macular degeneration, leading to significant visual impairment. Understanding the impact of C5 inhibition could provide insights into potential therapeutic strategies to slow or halt the progression of this debilitating disease.

Secondary objectives include:

• Evaluating the effect of systemic C5 inhibition on functional measures of GA disease progression.
• Assessing the effect of systemic C5 inhibition on GA lesion growth over 104 weeks.
• Determining the concentrations of total pozelimab in serum and total C5 and cemdisiran in plasma.
• Assessing the immunogenicity of pozelimab and cemdisiran.
• Evaluating the safety of pozelimab + cemdisiran combination therapy and cemdisiran monotherapy.

The clinical trial involves a total of **511 participants** diagnosed with **Geographic Atrophy Secondary to Age-Related Macular Degeneration**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a diagnosis of geographic atrophy of the macula secondary to age-related macular degeneration, with the condition not involving the foveal center point. The trial does not include a vulnerable population. Participants are required to have a sufficiently clear ocular media and adequate pupillary dilation to permit quality fundus imaging. Additionally, they must be willing and able to comply with clinic visits and study-related procedures, including the completion of necessary vaccinations. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have a **Best Corrected Visual Acuity (BCVA)** of 35 letters or better using ETDRS charts in the study eye, and a total geographic atrophy area measuring between 2.5 mm² and 17.5 mm².

The clinical trial is designed as a **randomized**, double-masked, placebo-controlled Phase 3 study to evaluate the efficacy, safety, and tolerability of subcutaneously administered **pozelimab** in combination with **cemdisiran** or cemdisiran alone in participants with **geographic atrophy** secondary to age-related macular degeneration. The primary objective is to assess the effect of systemic Complement Component 5 (C5) inhibition on geographic atrophy lesion growth over a period of 52 weeks. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, such as a study eye with a diagnosis of geographic atrophy not involving the foveal center and a total geographic atrophy area measuring between 2.5 mm² and 17.5 mm².

Participants will be randomly assigned to receive either the active treatment or a placebo, with the placebo for cemdisiran being 0.9% saline and the placebo for pozelimab provided in an aqueous buffered solution. The trial will include multiple follow-up visits to monitor the growth rate of the total geographic atrophy lesion area, measured by fundus autofluorescence, and to assess secondary endpoints such as changes in best-corrected visual acuity and the incidence of treatment-emergent adverse events. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 280 days, depending on the treatment group.

Participants may be withdrawn from the study early if they experience significant adverse events or if they are unable to comply with the study protocol, including the completion of required vaccinations. The trial is estimated to end by January 5, 2032, with recruitment starting on January 15, 2025. The study is not categorized as low intervention and follows the guidelines for a Phase 3 trial as per EMA guidance. The investigational products, cemdisiran and pozelimab, are administered via subcutaneous injection, and the trial is sponsored by Regeneron Pharmaceuticals, Inc.

The clinical trial involves the administration of **Cemdisiran**, an experimental medication formulated as a **solution for injection**. Cemdisiran is a small interfering RNA (siRNA) targeting Complement Component 5 (C5) and is provided by Regeneron Pharmaceuticals, Inc. The pharmaceutical form is a solution for injection, and it is administered via **subcutaneous injection**. The dosing schedule and frequency are determined by the study protocol, with a maximum treatment period of 260 days. Participant compliance with the dosing regimen is monitored throughout the study duration.

A **placebo** for Cemdisiran is also utilized in the study. This placebo consists of a 0.9% saline solution and is supplied by the sponsor. The placebo is administered in the same manner as Cemdisiran, ensuring blinding in the study design. The placebo is used to assess the efficacy and safety of Cemdisiran by providing a comparator for the experimental treatment.

**Pozelimab** is another experimental medication used in the trial, also provided by Regeneron Pharmaceuticals, Inc. Pozelimab is a monoclonal antibody targeting C5, formulated as a solution for injection. It is administered via **subcutaneous use**. The dosing schedule and frequency are outlined in the study protocol, with a maximum treatment period of 280 days. Compliance with the dosing regimen is closely monitored to ensure adherence to the study protocol.

A **placebo** for Pozelimab is included in the study, provided in an aqueous buffered solution by the sponsor. This placebo is administered in a manner consistent with Pozelimab to maintain the double-masked design of the trial. The use of a placebo allows for a controlled comparison to evaluate the efficacy and safety of Pozelimab in the study population.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the growth rate (slope) of the total **Geographic Atrophy (GA)** lesion area, measured in square millimeters per year, using Fundus autofluorescence (FAF). This measurement will provide a quantitative assessment of the progression of GA over the course of the study.

Secondary endpoints include a variety of visual and biochemical parameters. These encompass the loss of Best Corrected Visual Acuity (BCVA) of 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters at any two consecutive study visits, changes in Low-contrast quantitative visual acuity (LC-qVA), Low-luminance low-contrast quantitative visual acuity (LL-LC-qVA), and Quantitative contrast sensitivity function (qCSF). Additionally, the concentrations of total pozelimab in serum and total cemdisiran in plasma will be monitored, alongside changes in the concentration of total Complement component 5 (C5). The incidence and titer of Antidrug Antibodies (ADA) to both pozelimab and cemdisiran, as well as the incidence of Neutralizing Antibodies (NAb) to pozelimab, will also be evaluated. Furthermore, the occurrence and severity of Treatment-emergent adverse events (TEAEs) will be documented.

These efficacy parameters will be collected and analyzed at specified intervals throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on GA progression and associated visual functions. The use of validated scales and laboratory tests will ensure the reliability and accuracy of the data collected.