Geographic Atrophy: Will Complement Inhibitors and AI Open the Door to Tailored Treatment?

A retinal specialist said she believes the day is coming soon. For now, follow these best practices.

Age-related macular degeneration (AMD) is a chronic condition that can lead to irreversible blindness. The non-neovascular form of AMD, also referred to as dry AMD, can advance to geographic atrophy (GA), which often results in permanent vision loss.

Until recently there were no approved treatments for GA. Several potential treatments have been described, including complement inhibitors, neuroprotective agents, ocular gene therapy, and stem cell therapy. In 2023, two complement inhibitors were approved by the FDA – avacincapatad pegol and pegcetocoplan. With their entry onto the market, ophthalmologists and individuals with GA are provided with options that can slow disease progression. Their availability, along with technological developments, gives rise to the possibility that treatment can be improved via more precise patient selection based on genotypic, phenotypic, or molecular characteristics.

The Current Landscape
Sabah Shah, MD, a retinal specialist based in Garden City, New York, said that while she believes ophthalmologists are eager to use genotypic and phenotypic features to make treatment decisions for GA, it is impractical to do so – at least right now. “In high-volume practices, ophthalmologists are looking for the presence or absence of GA, as well as its presence relative to the fovea,” she explained. “But they are not likely taking measurements in all cases. They need to move quickly in the interest of treating the patient. They’re looking at the fundus photo, making a diagnosis, and, if appropriate, proceeding with treatment.”

Additionally, while research has uncovered genetic subtypes, replication has been inconsistent, and phenotype-genotype associations are thus far absent. A 2020 retrospective analysis  involving 196 individuals with GA identified 3 subtypes of GA, driven primarily by genetic risk score:

• High complement genetic risk score, associated with large soft drusen and foveal atrophy
• Low genetic risk score, associated with foveal atrophy and few drusen (some in this group have a gene linked with an inherited retinal degeneration and, thus, may not have GA)
• Highest genetic risk score for the extracellular matrix and age-related maculopathy susceptibility 2 (ARMS2) gene, high reticular pseudodrusen (RPD) load, and extrafoveal lesions

Researchers noted that “belonging to a determined subgroup can be predicted fairly well as soon as genotype and phenotype are known.” However, they added that the genetic risk score had higher discriminative ability than phenotypic features. Thus, “phenotype guide[s] subgroup members only modestly….Refined phenotyping will require improvements in grading protocols to avoid random measurement error in risk factors.”

AI Shows Promise for Patient Selection
The investigators added that the promise of artificial intelligence (AI) bodes well for advancement. “Machine learning-based algorithms are being developed for automatic RPD detection and quantification using multimodal imaging. Inclusion of microvascular data from OCT angiography and fluorescence lifetime imaging ophthalmoscopy of specific features and peripheral lesions identified on ultra-widefield imaging are promising new tools for improving patient stratification.”

Dr Shah said she expects AI can have a meaningful impact very soon. “AI is catching up extraordinarily fast,” she noted, adding that the strides seen in radiology are coming to ophthalmology. “Imagine an AI program that can almost instantly let you know phenotypic features–such as lesion size and location relative to the fovea–with a high degree of accuracy?” Rather than taking measurements themselves, ophthalmologists can rely on AI and instead focus on vision, patient demographics, and other factors to help stratify patients. To do that, AI will have to be integrated into the electronic medical record, she noted.

The phenotype-genotype association hurdle remains, however. A 2021 study sought to determine if phenotypes in GA could be grouped into subtypes that would respond to customized therapy. The cluster analysis involved 598 individuals with GA. Investigators used phenotypic features to analyze clusters in cross-sectional and longitudinal analyses. The phenotypic clusters were compared using 4 genetic risk scores (complement, extracellular matrix, lipid, and ARMS2). Researchers then performed the analysis in reverse – comparing genotypic clustering by phenotype. Among the results:

• In the phenotypic cross-sectional analysis, clusters showed distinct GA configuration, but little else
• Longitudinal phenotypic analysis showed clusters differing by smoking status, but little else
• Cluster comparison using the 4 genetic risk scores revealed no significant differences between the clusters
• Genotypic clustering revealed clusters differentiated by ARMS2, but researchers saw no genotype-phenotype links

The investigators concluded that “GA phenotypes may vary continuously across a spectrum, rather than consisting of distinct subtypes that arise from separate genetic causes.”

Distinctions by Ethnicity
While tying phenotypes to genetic characteristics remains elusive, researchers have been able to make distinctions by ethnicity. A 2023 multicenter, retrospective series assessed 144 Asian and non-Asian individuals with GA. Investigators looked at GA lesions at baseline and last follow-up, comparing lesion size, foveal involvement, number of foci, drusen status, and choroid status to GA growth rates. Among the results:

• Asian individuals had smaller GA area at baseline, thicker choroids, lower drusen prevalence, fewer GA foci, and slower GA growth rate
• GA lesion growth rate was impacted by (from the highest effect size) ethnicity, junctional zone fundus autofluorescence (FAF) pattern, baseline GA area, and number of GA foci
• Drusen or lesion size and FAF patterns were associated with high GA lesion growth rate in both ethnicities, but growth rate was lower in Asian individuals
• Regardless of ethnicity, lesions that measured ≥5 mm²at baseline had the highest growth rate
• Asian individuals with drusen were found to be prone to faster GA progression (8mm²/year) than Asians overall. The same was found for Asians with large GA lesions at baseline (2.6mm²/year)

The investigators noted “crucial differences…in GA lesion phenotype and slower lesion growth rate in Asian patients than that in non-Asian patients,” as well as “subgroups of Asian patients who are fast progressors and thus may exhibit greater benefit from new GA therapies.”

Distinctions by Disease Stage
Researchers are investigating age-related macular degeneration progression during two disease stages: 1) progression to GA and 2) GA expansion. A  2023 literature review revealed that ARMS2/HtrA Serine Peptidase 1 (HTRA1) variants increase both progression to and expansion of GA. Meanwhile, complement factor H and complement factor H-related (CFH/CFHR) variants alter risk of progression to GA but not GA expansion. Finally, complement factor C (C3) was shown to increase risk of progression to GA but not GA expansion.

Researchers noted that other than ARMS2/HTRA1, genetic risk factor overlap is limited. Differing biologic mechanisms at each stage “has implications for therapeutic approaches and suggests that treatment aimed at the underlying disease processes may need to be tailored by stage.”

Current Best Practices
While Dr Shah is looking forward to incorporating AI into the diagnostic workup of GA, she emphasized that it is an academic discussion for now. As for current best practices, once the diagnosis is made, ophthalmologists have the 2 complement inhibitors at their disposal. Approved in February 2023, pegcetocoplan is a modified pegylated peptide that binds to C3 and C3b, which blocks complement system pathways. Avacincapatad pegol, a pegylated RNA aptamer that binds to complement C5, is the newest addition, approved in August 2023.

Approval of avacincapatad pegol is based on the results of the randomized, double-masked, sham-controlled 24-month phase 3 trial (GATHER 2) performed at 205 eye care centers. Participants were at least 50 years of age with non-centerpoint-involving GA and best corrected visual acuity between 20/25 and 20/320. They were randomized to receive either 2 mg injections of avacincapatad pegol (n = 225) or sham injections (n = 223) monthly for 1 year.

At 1 year, GA area growth was smaller in the treatment group (0.336 mm/year) versus sham treatment (0.392 mm/year) – a 14% difference. Investigators concluded that avacincapatad pegol “slow[s] disease progression and potentially change[s] the trajectory of patients with geographic atrophy.”

Researchers subsequently released 24-month study results showing that avacincapatad pegol continued to slow GA progression. Moreover, efficacy was demonstrated with every other month dosing.

Dr Shah noted that anyone with GA is a candidate for avacincapatad pegol or pegcetocoplan. The goal, she explained, is to slow the progression. “You won’t halt it or reverse it – you want to slow it.” Dr Shah recommends performing a risk-benefit analysis with each patient before prescribing. Certain demographic and social considerations come into play, since both medications are injectables. “Does the patient have a family member or other individual willing to drive them to appointments? Treatment is ongoing with no end, so you need to make sure patients can get to you. This is not about simply toughing it out for 6 months. It’s a long-term commitment.”

Those whose disease is not as advanced may be able to drive themselves. “They might be motivated to receive treatment to slow progression,” and thus are ideal candidates, Dr Shah said. It is also important to review risks, even if they are minimal. Reported risks include conjunctival hemorrhage, increased intraocular pressure, blurred vision/ocular discomfort, vitreous floaters, and neovascular AMD.

Dr Shah typically does not administer treatment right away. “I will send the patient and family members home with a booklet explaining the commitment required and the small risks involved.

This content is independent editorial sponsored by Astellas. Astellas had no input in the development of this content.