At the completion of this article, the reader should be able to:
- Manage patient expectations and adherence to treatment, in light of new and emerging product approvals
- Identify key patient eligibility criteria for potential treatments
- Learn how advanced diagnostics aid in monitoring GA progression
- Recognise the role of optometrists in diagnosing and managing GA patients.
Prof Andrew Chang AM
MBBS (Hons) PhD FRANZCO FRACS
Vitreoretinal surgeon and ophthalmologist
Medical director, Sydney Retina Clinic
Head of ophthalmology, Sydney Eye Hospital
Clinical Associate Professor, Sydney University
Conjoint Professor, Discipline of Surgery, UNSW
Jennifer Chin
BSc (Vision Science), BOptom (Hons)
Research liaison officer, CUREOS Research Network
Dr Long Phan
BPharm, MOrth, PhD
Research officer, CUREOS Research Network
Historically, a geographic atrophy diagnosis left patients with little hope as their condition worsened, but that’s changing as the first therapies emerge. Optometrists will play a pivotal role in identifying these patients, referring them for treatment, and even managing expectations.
During the past two years, the global ophthalmic sector has welcomed some major milestones that will bring significant changes in the way the eyecare providers manage patients with geographic atrophy (GA).
Historically a disease without a treatment, GA is an advanced form of AMD estimated to affect 1-2% of the population over the age of 50.1 It is characterised by progressive death (atrophy) of retinal cells. This results in loss of the photoreceptors, retinal pigment epithelium (RPE) and choriocapillaris (Figure 1).
In early stages, GA does not usually affect the fovea, so patients may only experience scotomas. However, as it progresses and atrophic lesions extend into the fovea, central vision will be lost. This deterioration commonly impairs essential visual functions, including reading, driving and facial recognition, significantly impacting quality-of-life.2
The diagnosis of GA has traditionally signified inevitable, irreversible vision loss with natural progression of the disease. Management has primarily focused on monitoring for the onset of neovascular (or ‘wet’) AMD, patient education on prognosis, improving modifiable risk factors (e.g. smoking cessation and dietary adjustment), and the use of low vision aids to maximise remaining visual function.
But the outlook is becoming more promising after the US became the first country to approve GA therapies in 2023. The first was pegcetacoplan (Trade name: Syfovre, Apellis Pharmaceuticals, Inc.) soon followed by avacincaptad pegol (trade name: Izervay, Astellas Pharma Inc.). In January 2025, the Therapeutic Goods Administration (TGA) approved pegcetacoplan for the treatment of GA secondary to age-related macular degeneration (AMD) for Australian patients. Avacincaptad pegol is currently under review by the TGA.
These developments have prompted RANZCO to update its Referral Pathway for Age-Related Macular Degeneration (AMD) Management in 2024. Regarding GA, they originally recommended optometrists explain the disease to patients, identify and improve risk factors, recommend use of an Amsler grid, optimise spectacles, refer to low vision support services as appropriate, and review them in six to 12 months, depending on individual needs.
Along with stakeholders such as Optometry Australia and the Macular Disease Foundation Australia (MDFA), the guidelines now advise patients to be offered appropriate counselling on new treatments for GA. If interested, they can then be non-urgently referred to an ophthalmologist for baseline imaging, to ensure atrophy is secondary to AMD and to establish a review or treatment plan.
Given these developments, it is now vital for optometrists to understand their role in the new GA landscape and be able to accurately diagnose and counsel patients.
Mechanisms of action
Complement pathways are part of our innate immune system and is responsible for regulating our inflammatory response, usually to injury or infection. Dysregulation of the complement system has been linked to the development and progression of GA, with abnormal activation leading to inflammation and the eventual formation of a protein complex which directly damages the RPE cells of the retina leading to atrophy.3
Current therapies for GA aim to slow down the progression rate of GA by inhibiting different proteins that mediate the process of inflammation along the complement pathway. Pegcetacoplan inhibits complement factors C3 and C3b, whereas avacincaptad pegol inhibits the C5 protein. Both treatments are administered via intravitreal injection.
The efficacy of pegcetacoplan was demonstrated in the DERBY and OAKS Phase 3 clinical trials, where treated patients showed significant reductions in GA lesion growth compared to those receiving sham therapy over 24 months (19% and 22% with monthly injections, 16% and 18% with every other month injections, DERBY and OAKS respectively).4
Meanwhile, the efficacy of avacincaptad pegol was demonstrated in the GATHER1 and GATHER2 Phase 3 trials. In these studies, patients who received avacincaptad pegol 2 mg on a monthly basis showed reductions in GA lesion growth rate over 12 months by 35% in GATHER1 and 17.7% in GATHER2, compared to sham.5,6 Results from the GATHER2 Phase 3 clinical trial further demonstrated avacincaptad pegol continued to reduce the mean rate of GA lesion growth by 14% with monthly dosing and 19% with every-other-month dosing at 24 months, compared vs. sham.7
Which patients will benefit from treatment?
There are three specific requirements so far that clinicians need to consider:
1. GA secondary to AMD
2. An intact fovea
3. GA lesion growth posing a threat to central vision
These were established after reviewing data from pivotal trials to determine which patients would benefit the most from therapy. Only a minimal added benefit of a higher dosing frequency was shown, so the two-monthly regimen was chosen for pegcetacoplan to reduce burdens experienced by patients receiving intravitreal injections. Similarly, long-term data indicate that avacincaptad pegol achieves optimal efficacy with an every-other-month regimen, highlighting the need to balance dosing schedules with treatment effectiveness and patient burden.
It’s important to note, the current therapies approved or in development do not reverse GA growth or restore vision, so patients with non-subfoveal GA will benefit more, since they are more likely to have good central sight to protect and maintain.
AMD or other mimicking conditions
Clinicians need to exclude other diseases in which retinal atrophy occurs because the approved and emerging therapies have only demonstrated efficacy in GA due to AMD. A detailed medical and family history, combined with multimodal imaging patients will aid in the differential diagnosis of GA.
The main group of diseases that commonly masquerade as GA are inherited retinal diseases (IRDs). Common examples include pattern dystrophies, Stargardt’s disease and Best macular dystrophy. These diseases are typically caused by genetic mutations which lead to progressive retinal degeneration, however there are more common presentations to consider, such as atrophy following chronic central serous chorioretinopathy, retinal detachment and secondary to retinal laser.
Intact fovea
Having an ‘intact fovea’ will be another important aspect of treatment eligibility. In clinical trials, GA lesions are classified as either ‘subfoveal’ or ‘non-subfoveal’ (foveal-sparing) based on the anatomic location of the atrophy relative to the fovea centre (Figure 2). However, we know that some patients can maintain good visual function, such as by using eccentric fixation, even though anatomically the central macula may be affected. Since the severity of disease on imaging may not always reflect the patient’s visual function, clinicians should evaluate each individual patient on an anatomic and vision assessment to determine the threat of GA progression on vision by correlating structure and function.
Correlating structure to function
Visual acuity is the main measure of visual function, but for GA it may not provide entire prognostic information as patients may retain very good visual acuity even with significant anatomic macular involvement. Traditional measures of change in visual acuity may not be appropriate for outcomes of treatment as vision loss GA is progressive and irreversible. For these reasons, other measures of visual function need to be explored.
Microperimetry is a visual field test which examines retinal sensitivity in the macular region. Using concurrent optical imaging inside the eye, microperimetry devices track eye movements to precisely examine function at specific spots on the retina. Aside from mapping areas of scotoma which correspond to RPE atrophy, areas of reduced retinal sensitivity which may indicate future areas of GA growth can be identified (Figure 3).
Other functional indicators which have a role in assessing GA patients include low-luminance visual acuity, contrast sensitivity testing, reading speed testing and questionnaires to capture vision-related quality of life (for example, the Vision Function Questionnaire-25 (VFQ-25)). Patients have shown changes in these measures related to GA progression despite having good visual acuity.8
Documenting progression of GA
Clinicians are now required to monitor GA progression over time using multimodal imaging (Figure 4). In practice, recommended modalities include OCT, FAF and fundus photography. While practitioners may not have access to all these equipment in their clinic, repeated scans on at least one imaging modality will allow progression to be documented. With a variety of imaging devices found in various practices, it is important to assess progression on the same device to ensure consistent measurement for the individual patient.
Increase in GA lesion area (mm2) is the main indicator for progression. Some devices automatically provide measurements of RPE atrophy, such as the Advanced RPE Analysis on the Cirrus OCT (Carl Zeiss Meditec. Inc., CA, USA) which is based on infrared (NIR) images, whereas others offer a semi-automated method such as the RegionFinder software on Heidelberg Spectralis machines which rely on FAF images. Aside from GA lesion area, the distance from the closest border of GA to the centre of the foveae can be an alternative indicator for vision threat especially combined with lesion size, and most modern imaging devices have built-in measurement callipers.
Risk factors for GA progression
Aside from actually measuring progression over time, certain lesion characteristics may provide an indication on the risk for future progression. Data obtained by optometrists over time will form a critical part of the ophthalmologist referral and their decision-making process. Characteristics known to be associated with faster rates of progression are multifocal lesions, larger lesion sizes, foveal-sparing lesions, presence of reticular pseudo-drusen, and perilesional hyper-autofluorescence patterns of the diffuse-trickling type.9 The presence of these signs may warrant more frequent monitoring to capture progression in a timely manner.
Discussing treatment with patients
Safety
Endophthalmitis, intraocular inflammation and retinal vasculitis are rare but the most severe vision threatening complications associated with intravitreal injections. Approved and emerging GA therapies have been shown to be well-tolerated, with low rates of adverse effects. However, in 2023 in the US, there have been rare real-world reports of intraocular inflammation following initiating pegcetacoplan.10 These cases are being studied carefully and the exact cause is yet to be elucidated. No cases of retinal vasculitis or retinal artery occlusion have been reported as of yet following real-world use of avacincaptad pegol in the US.
Concurrent GA and neovascular AMD
Macular neovascularisation and atrophy often co-exist in the same eye in advanced AMD. However, clinical trials of GA treatment exclude patients with nAMD at the time of enrolment so the efficacy of treating GA in this population remains unknown. In some trials, patients receiving GA therapy who developed CNV were allowed to initiate intravitreal anti-VEGF therapy and safely continue receiving both treatments concurrently.5,6 Another concern observed in clinical trials was that there was a slighter higher rate of new-onset nAMD.4,5,6 Two year data in GATHER2 showed a 7.3% rate in CNV incidence for those receiving avacincaptad pegol every month and 4.3% on an every-other-month regimen, versus 5.4% in the sham group (total difference was 11.6% for avacincaptad pegol versus 9% in sham).7 However, the underlying mechanisms of this finding is still unknown. Routine monitoring for signs of macular neovascularisation is warranted in patients currently under GA therapy.
Challenges of adherence to therapy
Intravitreal injection of both complement inhibitors once every two months is necessary to maintain efficacy. Since the treatments proportionally reduce GA growth rate, larger reductions in area growth are produced over time.
The GALE study (NCT04770545) is the long-term extension study specifically for pegcetacoplan, showing a 28% reduction in GA growth rate after 48 months of continuous treamtemt.11 Separately, the efficacy of avacincaptad pegol has been demonstrated with monthly dosing over 24 months, and ongoing research continues to evaluate its long-term benefits (NCT05536297).12
Patients should be educated on the ongoing commitment that comes with intravitreal injections in pursuit of preserving vision. The 24-month data for both pegcetacoplan and avacincaptad pegol both show that long term treatment, every other month, will be needed to maintain efficacy. Effectively managing patient expectations as early as possible will improve adherence to the long-term nature of this treatment.
Therapies in clinical trials
There are also other promising therapies on the horizon that patients can look forward to, with several being studied in clinical trials within Australia which may further benefit patients in the future. Most of these investigational therapies still aim to slow progression by targeting different components of the complement pathway (for example, ANX-007, Annexon, Inc, NCT06510816), however there are some which target other pathways associated with GA (e.g. Tinlaberant, Belite Bio, NCT05949593). Some upcoming therapies aim to address the burden associated with treatment, such as using gene therapy (JNJ-1887, Janssen Pharmaceuticals, NCT05811351) to provide long-term effects or oral therapy as a less invasive route of delivery (ALXN2040, Alexion Pharmaceuticals, NCT05019521). Other upcoming therapies aim to target more specific patients, such as patients with gene-defects associated with GA (VOY-101, Perceive BioTherapeutics, Inc, NCT06087458), in order to potentially provide increased efficacy.
Meanwhile, there is also work looking into earlier stages of AMD to explore biomarkers associated with GA development which will allow an increased understanding of the disease and may provide avenues for prevention of atrophy (HONU study, NCT05300724).
Conclusion
GA is a progressive irreversible disease which often presents bilaterally and causes inexorable loss of central sight. Identifying these patients will maximise benefit of the therapies, which includes maintenance of visual function and quality-of-life. Patients will need to be carefully assessed on an individual level using a range of modalities, with considerations for both function and anatomy in mind.
Patient education and support play a vital role in managing expectations and promoting adherence to therapy. In addition to clinical care, services such as Eye Connect, provided by MDFA, offer valuable resources for patients with AMD, helping them navigate their diagnosis, understand their treatment, and access ongoing support as part of a comprehensive management approach.
More reading
Now Australia has an approved therapy for geographic atrophy, what’s next?
FDA approves Iveric Bio’s IZERVAY for geographic atrophy
Evolving GA landscape prompts RANZCO AMD referral pathway update
References:
- Keel S, Xie J, Foreman J, Van Wijngaarden P, Taylor HR, Dirani M. Prevalence of age-related macular degeneration in Australia: the Australian National Eye Health Survey. JAMA ophthalmology. 2017;135(11):1242-9.
- Patel PJ, Ziemssen F, Ng E, Muthutantri A, Silverman D, Tschosik EA, et al. Burden of illness in geographic atrophy: a study of vision-related quality of life and health care resource use. Clinical Ophthalmology. 2020:15-28.
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- Heier JS, Lad EM, Holz FG, Rosenfeld PJ, Guymer RH, Boyer D, 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. The Lancet. 2023;402(10411):1434-48.
- Jaffe GJ, Westby K, Csaky KG, Monés J, Pearlman JA, Patel SS, Joondeph BC, Randolph J, Masonson H, Rezaei KA. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021 Apr 1;128(4):576-86.
- Khanani AM, Patel SS, Staurenghi G, Tadayoni R, Danzig CJ, Eichenbaum DA, 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. The Lancet. 2023;402(10411):1449-58.
- Astellas Pharma Inc News release. IZERVAY™ (avacincaptad pegol intravitreal solution) Monthly or Every Other Month Reduced Geographic Atrophy Lesion Growth Through 2 Years. 2023. Available: https://newsroom.astellas.us/2023-11-04-IZERVAY-TM-avacincaptad-pegol-intravitreal-solution-Monthly-or-Every-Other-Month-Reduced-Geographic-Atrophy-Lesion-Growth-Through-2-Years
- Sadda SR, Chakravarthy U, Birch DG, Staurenghi G, Henry EC, Brittain C. Clinical endpoints for the study of geographic atrophy secondary to age-related macular degeneration. Retina. 2016;36(10):1806-22.
- Schmitz-Valckenberg S, Sahel J-A, Danis R, Fleckenstein M, Jaffe GJ, Wolf S, et al. Natural history of geographic atrophy progression secondary to age-related macular degeneration (Geographic Atrophy Progression Study). Ophthalmology. 2016;123(2):361-8.
- Witkin AJ, Jaffe GJ, Srivastava SK, Davis JL, Kim JE. Retinal vasculitis after intravitreal pegcetacoplan: report from the ASRS Research and Safety in Therapeutics (ReST) Committee. Journal of VitreoRetinal Diseases. 2024;8(1):9-20.
- Singerman LJ. 24-Month Results from the GALE Open-Label Extension Study: 48 Months of Continuous Pegcetacoplan. Macular Society; Charlotte Harbor, Florida, USA.
- Astellas Pharma Inc News release. FDA accepts astellas’ supplemental new drug application for IZERVAY. 2024. Available: https://www.astellas.com/en/news/29016
