If, three years ago, a geographic atrophy (GA) patient walked into your practice, you could do little more beyond recommending a healthy Mediterranean diet, protect their eyes from sunlight, cease any smoking, and begin AREDS2 supplementation—while they’d continue to lose vision. Today, things have changed. In this session, Saagar Pandit, MD, MPH, retina specialist at University Retina & Macula Associates, explores the long-term data that have propelled the acceptance of complement inhibition and explains how they’ve reshaped the clinical calculus for managing GA.
Growing evidence
Skepticism towards complement inhibitors in 2023 wasn’t unfounded. Data up to then showed only modest effects on GA lesion growth—a ~20% reduction over two years—with no improvement in visual acuity.1 Additionally, within months of launching, DERBY, a pivotal pegcetacoplan trial, encountered several occlusive retinal vasculitis cases, some with severe vision loss. Combined with the European Medicines Agency refusing pegcetacoplan and the American Academy of Ophthalmology calling the area controversial, many retina specialists became reluctant to use it. However, since then, two open-label extension (OLE) studies have restored much of the confidence that was once lost.
In the first OLE, GALE, patients who’d received pegcetacoplan in the prior 24 months during the DERBY and OAKS trials continued to receive treatment on their prior regimens—either monthly or every-other-month—while those who had initially received the sham were crossed over to active treatment. At 60 months, patients were then compared to a projected sham. While they all retained retinal tissue compared to the projected sham, patients who’d commenced treatment earlier saved approximately twice the amount of tissue compared to those who started later (3.9mm2 versus 1.9mm2). This study not only highlighted compounding benefits over time,2 but also demonstrated pegcetacoplan’s safety, with endophthalmitis and mild-to-moderate intraocular inflammation rates of <1% and 0.24%, respectively, and no reported retinal vasculitis cases.
The second OLE study was GATHER2. Here, patients with non-center-involved GA were randomized into 2 mg monthly avacincaptad pegol or sham for 12 months,3 after which the treatment group was further rerandomized into monthly or every-other-month treatment for another 12 months.4 At month 24, all patients—including prior sham patients—were shifted to monthly treatment for a further 18 months.5 Over the first 12 months, avacincaptad pegol treatment had already resulted in a 14% lesion growth reduction compared to the sham group, increasing to 40.5% compared to the projected sham at 3.5 years. However, similar to the GALE study, while all patients during the OLE portion of the study experienced retinal tissue preservation, those receiving earlier continuous treatment saw greater benefits compared to delayed treatment (2.9mm2 versus 1.8mm2). Additionally, there was no evidence of either retinal or ocular vasculitis, or increased intraocular inflammation.
“The crossover group still benefited from treatment,” Dr. Pandit highlights. “But, while it works whenever you start it, treatment really never catches up to where you would be if you start it earlier. Really, early is better.”
Missed calls
What does this mean in practice? As Dr. Pandit explains, knowing that these therapeutics are relatively safe and well tolerated—and that their effects compound year-on-year—has shifted the question from, “should we treat using these options?” to “who should we treat first?”. And this really impacts how optometrists should think about diagnosing and referring GA patients.
The first thing he notes is that while GA was long considered a slow-progressing disease, we now know that lesions progress by an average of 1.78 mm2/year, with the median time from any GA diagnosis to central involvement being only 2.5 years (less than the time it took for sentiment regarding complement inhibitors to change). And once central GA appears, patients lose an average of 22 letters by year five.6 ”Visual acuity is a lagging indicator for disease progression,” says Dr. Pandit. “Patients with non-central GA can read the chart well while the disease is actively consuming retina; a stable acuity should never reassure us that GA is actually stable.”
Yet GA is often missed. A Cleveland Clinic review of the OCT imaging of patients carrying intermediate age-related macular degeneration (iAMD) ICD-10 codes, found GA lesions in 7.1% of eyes. None of these had been documented in the chart, and a third already had involvement of the fovea.7 When earlier atrophy stages were considered, the detection rate rose to 11.4%.
Timing is everything
When it comes to frameworks that you can apply to your diagnosis workflow to catch GA as early as possible, Dr. Pandit presents two for you to adopt. The first is a four-step process of:
- Detection – In which you scan every AMD patient with at least OCT (preferably alongside fundus autofluorescence (FAF))
- Documentation – When you observe a GA lesion, note where it is, how large it is, and whether it has changed since the last visit.
- Referral – During this process, include a patient’s images with the referral letter, which the retinal specialist can often use to triage the visit.
- Co-management – After the treatment decision, discuss with the retinal specialist to determine who will follow what, how you will continue to see the patient, and when and how the retinal specialist will take over care.
During the detection and documentation stages, if you are wondering whether to refer a patient, his second framework builds on the Classification of Atrophy Meetings (CAM) classification and gives practitioners actionable recommendations. So, if you see a patient with:
- High-risk iAMD (large drusen, reticular pseudodrusen, hyperreflective foci, and drusenoid pigment epithelial detachments (PED))—consider closer OCT follow-up and AREDS2 counseling
- Incomplete RPE and outer retinal atrophy - iRORA (zone of choroidal hypertransmission and zone of RPE attenuation both <250 µm, and overlying photoreceptor degeneration)—discuss this patient with your retina specialist for a co-managed follow-up
- Complete RPE and outer retinal atrophy - cRORA (zone of choroidal hypertransmission and RPE attenuation or disruption ≥250 µm, with overlying photoreceptor degeneration) —refer to the retinal specialist for treatment options.
“This is just a framework,” he reminds us. “iAMD can be tricky because when it’s high risk, it can be subtle. Nobody will fault you if every 4–6 months, you get an OCT and FAF and send them off to the retinal specialist.
Finally, although it’s important to diagnose GA as early as possible, Dr. Pandit stresses the importance of getting the diagnosis correct. To illustrate this, he points to a large Australian practice’s recent audit of GA diagnoses, which found a possible misdiagnosis rate of 2.9%.8 Some common GA masqueraders he cautions practitioners to be aware of include inherited conditions such as late-onset Stargardt disease, pattern dystrophy, central areolar choroidal dystrophy, and maternally inherited diabetes and deafness (MIDD); alongside medications such as pentosan polysulfate and hydroxychloroquine, and other acquired causes like myopic macular atrophy and central serous chorioretinopathy.
As he says, “When it comes to diagnosing these diseases early and referring these patients to the retinal specialist, you’re the most important person.”
