On Day 2 of the 17th Congress of the Asia-Pacific Vitreo-retina Society (APVRS 2024), a lunch symposium brought a focused spotlight on geographic atrophy (GA), a leading cause of blindness linked to age-related macular degeneration (AMD).
As GA experts shared the latest insights, the urgency of early detection and innovative treatments became clear, with the disease affecting millions globally. New therapies and technologies show promise in diagnosing and slowing the progression of GA, sparking hope for the many impacted by this debilitating condition.
Understanding the burden of GA
“Geographic atrophy is one of the phenotypes of late AMD, and it affects quite a lot of people,” began Dr. Kelvin Teo (Singapore), setting the stage for a deep dive into a condition that impacts an estimated 5 million individuals worldwide. Beyond its prevalence, he highlighted how the progression of GA reshapes lives, even in its early stages.1
Symptoms such as difficulty with night vision, slower reading speeds and reduced contrast sensitivity may seem minor on the surface, but they significantly disrupt quality of life. “While the Snellen is very objective, it doesn’t really represent what we see in life,” Dr. Teo explained. “We need to… ask direct questions: Are you symptomatic? Is it getting more difficult to see at night? Is it more difficult to read?”
Dr. Teo also dispelled a long-held misconception: that GA progresses more slowly in Asian populations. Citing the latest evidence, he explained that some cases among Asian individuals advance just as rapidly. “There’s a belief that AMD and GA don’t progress quickly in Asian populations, but what we now know with the latest evidence is that there is a proportion of patients with Asian ethnicity that progress quickly as well,” he noted.2
In closing, Dr. Teo underscored the importance of vigilance. “Early diagnosis and referral [are crucial], especially now in this landscape where there are potential treatments to stop the progression of this disease,” he emphasized.
Detecting GA early
According to A/Prof. Fred Chen (Australia), GA lesions often begin in non-foveal regions before advancing toward the fovea—a progression that can lead to severe vision loss. “If a GA progresses, it can either enter the fovea from the site where the lesion grows at the cap, or it can eat it away,” he explained. Once GA involves the fovea, the visual impact is often dramatic.
So how do we detect it? A/Prof. Chen lauded optical coherence tomography (OCT) as the gold standard for detecting GA but also highlighted the complementary roles of near-infrared reflectance (NIR), fundus photography and autofluorescence imaging.
A/Prof. Chen pointed to precursor lesions, such as incomplete retinal pigment epithelium atrophy (iRORA), as warning signs clinicians should act on. “Once you get iRORA, there’s no turning back,” he warned, stressing the urgency of early intervention.
Looking to the future, A/Prof. Chen expressed optimism about the transformative potential of artificial intelligence in improving GA management. Beyond the lesion area, he also highlighted emerging biomarkers like ellipsoid zone attenuation, which could provide deeper insights into disease progression.3
Targeting the complement pathway
So what drives GA? And where does therapy fit in? The complement system plays a pivotal role in the development of GA, as Dr. Michael Singer (United States) outlined in his presentation. This intricate immune pathway, comprising the classical, lectin and alternative arms, converges at C3. Activation here leads to inflammation and membrane attack complex (MAC) formation, a key driver of photoreceptor degeneration. “Multifactorial dysregulation of the complement system plays an important part in the development and progression of geographic atrophy,” he explained.
“Anything we can do to slow that process down may be of great value in terms of slowing the process of geographic atrophy,” Dr. Singer explained, before delving into the promising therapies targeting the complement cascade.
He started with avacincaptad pegol which zeroes in on C5. The GATHER 1 and GATHER 2 clinical trials, which included patients with non-center involving GA, illuminated its potential, showing that monthly dosing reduced lesion growth by 35% and 18%, respectively [at the 12-month time point], compared to sham. While the therapy doesn’t reverse GA, the results mark an important milestone. “We’re not reversing the process, but we’re slowing it down. And that’s an important first step,” Dr. Singer explained.4,5
Adding to the momentum are findings from the OAKS and DERBY trials, which investigated C3-inhibiting pegcetacoplan and included patients with both center-involved and non-center-involved GA. At 24 months, [a monthly treatment of] pegcetacoplan had slowed lesion growth by 22% in the OAKS trial and 19% in the DERBY trial, showcasing its potential to decelerate the disease’s relentless progression.6
Despite these promising strides, a note of caution resonated. “There’s about a 10% chance of developing wet macular degeneration over three years. But we’re really good at treating it,” reassured Dr. Singer, adding that safety data from the trials showed no cases of endophthalmitis and minimal intraocular inflammation.7
Beyond the risk of wet macular degeneration, Dr. Singer also pointed out that “these complement inhibitors increase the rate of CNV [choroidal neovascularization],” urging clinicians to have honest conversations with their patients about the potential downsides. “Nothing is free,” he reminded the audience. “The reality is, you’re going to have something you have to worry about.” It was a reminder that in the world of cutting-edge therapies, even progress comes with its own set of challenges.8
Looking to the future, ANX007 offers a novel approach by targeting C1q in the complement pathway. The ARCHER trial provided a glimpse of its potential, revealing a significant reduction in vision loss—defined as a loss of 15 or more BCVA letters—over 12 months of treatment. Unlike its predecessors, ANX007 demonstrated visual function protection, effective in patients with either foveal or non-foveal involvement.9
As APVRS 2024 continues to unravel new insights, the future of GA management appears increasingly hopeful. With advancements in early detection methods, promising therapies targeting the complement pathway and a focus on personalized patient care, the battle against GA is gaining momentum and the next chapter promises to be one of innovation and hope.
Editor’s Note: Reporting for this story took place during the 17th Congress of the Asia-Pacific Vitreo-retina Society (APVRS 2024) from 22-24 November in Singapore.
References
- Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2014;2:e106–116.
- Teo KYC, Fujimoto S, Sadda SR, et al. Geographic atrophy phenotypes in subjects of different ethnicity: Asia-Pacific Ocular Imaging Society Work Group Report 3. Ophthalmol Retina. 2023;7(7):593-604.
- Amine R, Yordi S, Cetin H, et al. Baseline characterization of advanced ellipsoid zone integrity features in the GATHER1 phase 2/3 clinical trial for AMD with geographic atrophy. IOVS. 2024;64:2265.
- Patel SS, Lally DR, Hsu J, et al. Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial. Eye (Lond). 2023;37(17):3551-3557.
- Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. 2023;402(10411):1449-1458.
- Heier JS, Lad EM, Holz FG, et al. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. 2023;402(10411):1434-1448.
- Wykoff CC, Rosenfeld PJ, Waheed NK, et al. Characterizing new-onset exudation in the randomized phase 2 FILLY trial of complement inhibitor pegcetacoplan for geographic atrophy. Ophthalmology. 2021;128(9):1325-1336.
- Lai E, Lee T, Lee C, et al. New horizons in geographic atrophy treatment: Enthusiasm and caution surrounding complement inhibitors: BMJ Open Ophthalmology 2024;9:e001854.
- Boyer DS. Protection against vision loss by ANX007: Results from the phase 2 ARCHER clinical trial. IOVS. 2024;65:2791.
