Adaptive Optics Scanning Light Ophthalmoscopy (AOSLO) and Microperimetry (MP) Sub-study

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with geographic atrophy (GA) representing the advanced, untreatable form of the disease. GA leads to progressive degeneration of retinal cells critical for vision, resulting in irreversible vision loss and a significant impact on patients' quality of life. Despite the prevalence of GA, treatment options remain limited. Current therapeutic strategies focus on slowing the enlargement of atrophic regions, but clinical trials have faced challenges in demonstrating clear patient benefits.

In clinical practice, GA progression is often evaluated by measuring the area of atrophy on retinal imaging, such as fundus autofluorescence (FAF) and, more recently, optical coherence tomography (OCT). These structural biomarkers are used in clinical trials to assess the efficacy of new drugs, with the FDA accepting a reduction in the rate of GA enlargement as a successful outcome. However, these structural metrics often fail to correlate with functional vision loss, leaving patients and physicians disappointed by treatments that may stabilize GA progression without improving their visual outcomes.

The ellipsoid zone (EZ), a hyperreflective layer visualized on OCT, represents the structural integrity of photoreceptors-cells responsible for converting light into visual signals. In patients with one or more GA lesions, OCT imaging shows that the EZ is typically absent within the GA, while the EZ in the perilesional zone may be attenuated or damaged. Perilesional EZ loss is thought to represent the area at highest risk for future vision loss. With the FDA approval of photoreceptor preservation as an endpoint for GA trials, there has been significant interest in measuring EZ loss from OCT scans. Drug approval will now focus on the prevention of EZ loss in the perilesional areas rather than GA area expansion. However, it is important to establish whether the absence of the EZ truly indicates photoreceptor damage and whether there is a functional correlation between EZ loss and visual sensitivity. Adaptive Optics and microperimetry are two modalities that can help address this.

This sub-study is a pilot comparative imaging study. In addition to the imaging procedures collected for the main COCO GA study [NCT05961332], participants will have the following study images obtained:

• Spectralis OCT (if applicable),
• visual acuity,
• ocular biometry, which is a non-invasive eye test using a machine called an IOL master,
• microperimetry, and
• Adaptive Optics Scanning Light Ophthalmoscopy (AOSLO)

Inclusion criteria

(from the main study):

• 50 years or older and may be either male or female and may be of any race
• Established diagnosis of geographic atrophy (GA) due to age-related macular degeneration (AMD)
• GA characteristics: GA area of between 1.25 mm² and 23 mm², with seventy percent of eyes having GA area ranging from 2.5 mm² to 17.5 mm². GA may be unifocal or multifocal. GA may be subfoveal or extrafoveal, with twenty-five percent of eyes having subfoveal GA. The presence of concurrent peripapillary atrophy will not exclude participants from participation
• Willing to participate as evidenced by signing the written informed consent

Additional Sub-study Inclusion Criteria:

• Early-stage GA defined as

• GA area of between 1.25 mm2 and 23 mm2
• GA may be unifocal or multifocal
• GA may be subfoveal or extrafoveal
• Concurrent peripapillary atrophy will not exclude participant from participation
• Phakic and pseudophakic participants are eligible for enrollment, with phakic participants prioritized when feasible.

Exclusion criteria

(from the main study):

• Unable to tolerate ophthalmic imaging
• Presence of neovascular AMD on optical coherence tomography (OCT) as confirmed by an ophthalmologist
• Presence of significant media opacity preventing adequate retinal imaging
• Presence of concurrent retinal disease which may confound assessment

Additional Sub-study Exclusion Criteria:

• Ocular media opacity or other condition(s) that, in the opinion of the investigators, may preclude imaging.
• Individuals who, in the opinion of the investigator, are unable to tolerate study procedures or comply with study requirements.
• Prior or current treatment with intraocular injections for geographic atrophy (e.g., pegcetacoplan [Syfovre] or similar therapies) is not permitted.