Anes Harid

Abstract

Geographic atrophy caused by age-related macular degeneration is a permanent and worsening cause of central vision loss in older adults. Until recently, care mainly involved monitoring, visual aids, and support. Pegcetacoplan, a complement C3 inhibitor, became an important treatment after the OAKS and DERBY phase 3 trials. The trials showed that it slows the growth of areas of retinal damage, especially over 24 months. However, it did not significantly improve visual function at 24 months, and it increased the risk of new wet age-related macular degeneration. This commentary reviews what these findings mean for patients, including likely benefits, safety risks, treatment burden, and the need for longer-term evidence. Pegcetacoplan is an important advance, but it should be used with realistic expectations and careful patient selection.

Introduction

Geographic atrophy is an advanced form of age-related macular degeneration that causes permanent, worsening vision loss in older adults. It destroys key retinal cells and blood vessels, creating damaged areas that grow over time (1,2). Patients may struggle with reading, recognising faces, seeing in low light, and tasks needing detailed central vision (2–4). Even when standard vision tests remain fairly good, the disease can reduce independence and quality of life (2,4).

For many years, no approved treatment could slow geographic atrophy. Care focused on monitoring, reducing risk factors, low-vision services, visual aids, and counselling (1,2). Interest then grew in treatments targeting the complement system, as abnormal complement activity and long-term inflammation appear to contribute to age-related macular degeneration, although many factors are involved (1).

Pegcetacoplan blocks the complement proteins C3 and C3b (6). Because C3 is central to all three complement pathways, the drug aims to reduce inflammation and slow retinal damage (1,6). The OAKS and DERBY trials provide the main phase 3 evidence for its use in geographic atrophy (5).

Evidence from the OAKS and DERBY trials

OAKS and DERBY were large international phase 3 trials of injections of pegcetacoplan for geographic atrophy (5). OAKS included 637 people at 110 sites, and DERBY included 621 people at 122 sites. Participants were aged 60 or older and received monthly treatment, treatment every other month, or a sham procedure (5).

The trials used randomisation, masking, and sham procedures to reduce bias. The main outcome was the change in the size of the damaged retinal area at 12 months, measured with fundus autofluorescence. Visual and daily-function outcomes were assessed at 24 months (5).

In OAKS, monthly treatment reduced lesion growth by 21% and every-other-month treatment by 16% at 12 months; both results were statistically significant (5). At 24 months, the reductions were 22% and 18% (5).

In DERBY, lesion growth fell by 12% with monthly treatment and 11% with every-other-month treatment at 12 months, but these results were not statistically significant (5). At 24 months, the reductions became significant: 19% and 16%, respectively (5).

Together, the 24-month results show that pegcetacoplan can slow the physical growth of geographic atrophy lesions (5). However, the different 12-month results in OAKS and DERBY show that the size and certainty of benefit may vary. Patients should therefore receive realistic, individual advice.

Anatomical Benefit versus Functional Benefit

The key question is whether slower lesion growth leads to better vision or daily function. At 24 months, OAKS and DERBY found no significant benefit over sham in the main visual-function measures (5). These included best-corrected and low-light visual acuity, reading speed, reading independence, and, in OAKS, microperimetry (5).

Slowing lesion growth matters because no previous treatment could change the course of the disease. However, patients mainly want to keep reading, driving, recognising faces, moving around safely, and living independently. Standard visual-acuity tests may miss important problems. A person can score well while still having blind spots, slow reading, poor contrast, or difficulty in dim light (2,4).

There are several possible reasons why the physical benefit did not yet produce a clear functional benefit. Geographic atrophy progresses slowly, so longer follow-up may be needed. Standard visual-acuity testing may also miss damage outside the centre of vision (2,4). Daily function depends on the lesion’s location, direction of growth, distance from the centre of vision, fixation pattern, and vision in the other eye (2–4). The same reduction in lesion growth may therefore help patients differently.

The lack of a significant functional benefit at 24 months does not mean that slower lesion growth has no value. It does mean that clinicians should not promise a noticeable improvement in daily life during the first two years. Future studies should measure reading, retinal sensitivity, low-light vision, mobility, independence, quality of life, and patient-reported outcomes, as well as lesion size (4,9).

Safety and Treatment Burden

Pegcetacoplan’s safety risks need careful discussion. Serious eye-related events were uncommon in OAKS and DERBY, although some occurred more often with pegcetacoplan than with sham (5). The main concern was a higher risk of new wet or neovascular age-related macular degeneration.

By 24 months, wet age-related macular degeneration developed in about 12% of patients treated monthly, 7% treated every other month, and 3% receiving sham (6). In OAKS, the rates were 11%, 8%, and 2%; in DERBY, they were 13%, 6%, and 4%, respectively (5).

Patients need regular checks for wet age-related macular degeneration. If it develops, separate anti-vascular endothelial growth factor injections may be needed (6). This can add more injections, scans, and clinic visits.

Reports after approval have linked pegcetacoplan to retinal vasculitis, sometimes with blocked retinal blood vessels (6,7). A safety review confirmed vasculitis in 14 eyes of 13 patients. Every reported case occurred after the first injection, and most involved blocked blood flow (7). Because voluntary reports cannot show the true rate, the exact risk is unknown. However, severe vision loss is possible. Patients should urgently report pain, redness, light sensitivity, blurred vision, or any sudden change in vision (6,7).

Other risks include eye inflammation, infection inside the eye, retinal detachment, raised eye pressure, floaters, discomfort, and bleeding on the eye surface (6). These risks should be part of shared decision-making.

Treatment also requires frequent visits. US prescribing information recommends a 15-mg injection in each affected eye every 25 to 60 days (6). The trials used monthly or every-other-month injections (5). Frequent visits may be difficult for older adults with mobility problems, other illnesses, memory problems, or reliance on carers. Treating both eyes or adding injections for wet age-related macular degeneration increases this burden.

Patients should understand that pegcetacoplan slows further damage; it does not rebuild the retina or restore lost vision. Better vision is not the expected result. The aim is to preserve useful retinal function for as long as possible (5,6).

Practical Implications for Clinicians

Pegcetacoplan offers a treatment that can slow geographic atrophy where it is approved. The decision should be individual. Clinicians should consider lesion features, speed of progression, remaining vision, the other eye, treatment burden, patient preferences, and ability to attend regular appointments (2,10).

Treatment may be more suitable for patients whose lesions are progressing towards important retinal areas, who still have useful vision, and who can manage repeated injections. It may offer less practical benefit for people with very advanced damage in both eyes, little remaining visual potential, major health problems, or difficulty attending frequent visits. These are not fixed rules; the decision should be shared with the patient.

Clinicians should clearly explain that the functional benefit is uncertain. OAKS and DERBY showed slower lesion growth but no significant improvement in the planned visual-function measures at 24 months (5). Treatment does not reverse geographic atrophy, restore lost vision, or guarantee that vision will not worsen.

Counselling should explain how much lesion growth may be slowed, that benefit may build over time, and that the effect on everyday vision is uncertain. Absolute changes in lesion size may be easier for patients to understand than percentages alone.

Imaging is important for choosing and monitoring treatment. Fundus autofluorescence can measure lesion growth, while optical coherence tomography can show retinal damage and detect new fluid or other complications (2,3,10). Monitoring should also check symptoms and look for inflammation, retinal vasculitis, and wet age-related macular degeneration (6,7).

Areas for Future Research

The GALE open-label extension has reported results to 36 months. Continued pegcetacoplan treatment was linked to further slowing of lesion growth compared with projected sham results and to fewer new blind points on microperimetry in a planned analysis (8). This suggests that the physical benefit may grow over time and that a functional benefit may appear later.

However, GALE was open label, and patients who had received sham changed to active treatment. After month 24, comparisons partly used projected sham data rather than a current randomised control group (8). The results are encouraging but cannot replace longer controlled trials and real-world studies. Research must show whether benefits last for years and preserve reading, mobility, independence, and quality of life.

Researchers should also study why OAKS and DERBY differed at 12 months. Lesion features, lesion location, speed of progression, participant differences, or measurement variation may have played a part (5). Finding predictors of response could help clinicians select patients most likely to benefit.

Future studies should focus more on outcomes that matter to patients. Visual acuity alone does not show the full effect of geographic atrophy (2,4). Reading speed, contrast, low-light vision, retinal sensitivity, fixation, independence, emotional wellbeing, treatment satisfaction, and caregiver burden may give a fuller picture (4,9).

Research into disease mechanisms and biomarkers may help personalise treatment. Imaging findings, lesion type and location, genes, complement activity, and inflammation markers may identify patients more likely to respond. Because age-related macular degeneration has several causes, combined or step-by-step treatments may eventually be needed (1,2).

Long-term safety monitoring remains essential. It should track injection-related risks, wet age-related macular degeneration, eye inflammation, retinal vasculitis, blocked retinal vessels, and the effects of combining pegcetacoplan with anti-vascular endothelial growth factor treatment (6–8).

Conclusion

Pegcetacoplan is an important advance for geographic atrophy. OAKS and DERBY showed that blocking complement C3 can slow lesion growth in a disease that previously had no approved drug treatment (5).

However, the meaning of this physical benefit is still uncertain. The trials found no significant improvement in key visual-function measures at 24 months, and treatment increased the risk of wet age-related macular degeneration (5,6). Frequent eye injections add burden, while reports of retinal vasculitis and blocked retinal vessels show the need for clear counselling and close safety checks (6,7).

The 36-month GALE results suggest continued slowing of lesion growth and a possible benefit on microperimetry. However, the study was open label and had no concurrent sham group after month 24 (8). Longer controlled and real-world studies are needed to show whether slower lesion growth preserves useful vision, independence, and quality of life.

Pegcetacoplan is a meaningful step forward, but not a complete solution. Its value depends on careful patient selection, honest discussion of benefits and uncertainties, regular imaging, close safety monitoring, and longer-term patient-centred evidence.

References

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