On Day 3 of the 17th Congress of the Asia-Pacific Vitreo-Retina Society (APVRS 2024), a captivating debate unfolded, centered on the evolving landscape of dry age-related macular degeneration (AMD) and, in particular, geographic atrophy (GA).
With the spotlight on emerging therapies and groundbreaking discoveries, global experts delved into novel treatment approaches and their potential to reshape the future of GA management. From the promise of complement inhibitors to cutting-edge retinal pigment epithelium cell replacement therapy, the session explored new frontiers in retinal care, sparking lively discussions and leaving the audience eager for more.
The complement inhibition debate continues
Geographic atrophy, a late-stage manifestation of dry AMD, brings irreversible retinal cell death and progressive vision loss. Complement inhibitors like pegcetacoplan and avacincaptad pegol target the immune system’s complement cascade, a suspected contributor to GA’s degenerative process. By modulating this pathway, these therapies aim to slow lesion expansion—a promising approach that remains steeped in uncertainties.
This divide was vividly illustrated in a debate between Dr. Phil Ferrone (United States), Apellis Pharmaceuticals’ chief medical retina advisor, and Dr. Richard F. Spaide (United States), a private practitioner and noted skeptic, offering sharply contrasting views on the viability of complement inhibition.
Dr. Ferrone presented compelling data in favor of pegcetacoplan, citing the OAKS, DERBY and GALE trials, which demonstrated a significant reduction in GA lesion growth. He emphasized functional gains often overlooked by critics, particularly the therapy’s ability to reduce progression to absolute scotomas within central loci.
Addressing concerns about the lack of visual function benefits, he argued that best-corrected visual acuity (BCVA) is an inadequate representation of GA’s impact—or the therapeutics that treat it. “Microperimetry shows the strongest correlation with GA area—this is where we see functional benefits of treatment,” he explained.
Dr. Ferrone also tackled criticism about the therapy’s retinal pigment epithelium (RPE) cellular impact. He highlighted long-term findings: “At 36 months, pegcetacoplan saves about 15,000 RPE cells in the monthly group and about 12,000 RPE cells in the every other month group.” For him, pegcetacoplan represents a paradigm shift, though he acknowledged hurdles, particularly in Europe, where regulators demand clear visual function improvements.
In stark contrast, Dr. Spaide questioned the foundational science of complement inhibition. “Complement is used in your eye for normal homeostasis… If you knock out complement, those [lab] animals develop retinal degeneration,” he stated, expressing safety concerns.
He dismissed the therapy’s benefits as marginal, citing high dropout rates in pivotal trials like OAKS and DERBY. “GALE [the Phase III extension study] really had a subgroup of a subgroup.” he remarked. Dr. Spaide further criticized increased complications, including neovascularization, uveitis and endophthalmitis, in treated groups.
Pegcetacoplan was not the only drug in Dr. Spaide’s crosshairs. The GATHER avacincaptad pegol studies also drew his scrutiny, showing reductions he called “microscopic” and clinically insignificant. “The treated patients did not do better than sham… In every case, trends for all five functional endpoints were worse in treated patients,” he said, pointing to minimal quality-adjusted life years (QALY) benefits. “What would the QALYs be for a treatment that causes no benefit but requires frequent injections? Maybe close to zero, or even negative.”
Dr. Spaide concluded with a sobering reflection: “Hope is an important part of medicine and people look to us for hope. And it’s the belief that the future is going to be a better place, or a better future is possible for them. But you can see that this is a complement of vision that does not lead really to a better future. In a sense, we’re peddling false hope.”
A new frontier for GA treatment
As if taking a cue from Dr. Spaide, Prof. Yuichiro Ogura (Japan) invited the audience to explore a groundbreaking alternative: OpRegen®. This novel allogeneic RPE cell therapy from Lineage Cell Therapeutics (Carlsbad, CA, USA) [currently in a Phase I/IIa, clinical trial for dry AMD] offers a bold approach to tackling GA, aiming to restore function by addressing RPE dysfunction and cell loss—a contrast to complement therapies that slow lesion growth.
Prof. Ogura presented compelling Phase I/IIa trial data, shedding light on the therapy’s potential to deliver both functional and anatomical benefits. “Eyes with extensive bleb coverage showed an average BCVA improvement of 12.8 letters at month 12, compared to a 4-letter improvement in eyes with limited coverage,” he shared, underscoring gains that outpace those achieved by complement inhibitors.
Beyond visual acuity, structural recovery added weight to the case for OpRegen. Quantitative OCT analyses highlighted reduced loss in critical layers like the RPE and the external limiting membrane (ELM), signaling significant anatomical repair.
While promising, Prof. Ogura acknowledged the challenges ahead, particularly in refining delivery techniques to optimize outcomes. With a sense of cautious optimism, he expressed hope that OpRegen could “redefine outcomes for patients with GA,” offering a new horizon in the fight against this progressive disease.
Pachychoroid GA and ethnicity
The evolving understanding of geographic atrophy is revealing a diverse spectrum of phenotypes, challenging traditional classifications and inspiring new clinical approaches. At a recent session, two thought-provoking lectures shed light on pachychoroid GA and its distinct prevalence across ethnic groups, emphasizing how these differences reshape our understanding of the disease.
Pachychoroid GA, a unique phenotype separate from conventional GA linked to AMD, emerged as a focal point. “Pachychoroid atrophy shows male dominance, affects younger individuals and presents as solitary, round lesions with slow progression,” explained Prof. Seung-Young Yu (South Korea). More commonly observed in Asian populations, pachychoroid GA exhibits growth patterns and characteristics that differ markedly from drusen-associated GA.
Prof. Yu shared findings from a Korean cohort, where pachychoroid lesions demonstrated a slower growth rate compared to conventional GA cases. However, variability within Asian populations adds complexity, with discrepancies in lesion size, growth rates and male-to-female ratios reported in studies from Japan and Korea. “Should we classify pachychoroid atrophy as a subtype of geographic atrophy secondary to AMD? Or should it be considered a different disease entity?… We don’t have a clear-cut answer yet,” she noted.
Extending the discussion, Dr. Kelvin Teo (Singapore) examined the role of ethnicity in GA prevalence and progression. “There is a much higher proportion of Asian patients with neovascular AMD versus GA. In Caucasian populations, it’s almost a 1:1 ratio,” he explained. He also highlighted how Asian patients tend to have smaller lesions, fewer focal sites, and slower growth rates, though lesion size often supersedes ethnicity in determining progression. “Large lesions, regardless of ethnicity, grow at similar rates,” he added.
Challenging existing terminology, Dr. Teo proposed a shift in perspective: “I want to try and move away from the idea of pachychoroid-driven geographic atrophy… We need to start to think about how we differentiate this from AMD-driven atrophy.” His insights underscore the need for tailored management strategies for Asian populations and a broader approach to AMD research.
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.
