At the completion of this article, the reader should be able to improve their management of patients with
geographic atrophy (GA), including:
- Understand the importance of fully characterising GA lesions
- Know the role that identifying key lesion characteristics of GA plays in determining an individual’s risk of vision loss
- Understand what imaging modalities contribute to the detection and documentation of GA size, number and location of lesions
- Understand the importance of distinguishing geographic atrophy secondary to AMD from inherited retinal disease.
Three Australian authorities in the field of retinal disease provide an overview of emerging therapies for the once-untreatable geographic atrophy (GA) and the changing role of optometry in the identification and documentation of the condition.
Carla J Abbott
BOptom PhD PGDOcTher,1,2
Doron G Hickey
MB ChB DPhil, 1
Robyn H Guymer
MBBS PhD 1,2
1. Centre for Eye Research Australia, Royal Victorian Eye and Ear
Hospital, VIC 3002
2. Department of Surgery (Ophthalmology), University of Melbourne, VIC 3002
Novel therapies for geographic atrophy
Age-related macular degeneration (AMD) remains a leading cause of irreversible vision loss in Australia, with 14% of people over the age of 50 years showing signs of AMD, and 1% of people in this age group having late-stage disease.1 Worldwide, the prevalence of late-stage AMD increases significantly after the age of 75; 20% of people of European ancestry have late-stage AMD by 90 years.2 Around half of those with late-stage disease will have geographic atrophy (GA),1 with estimates suggesting that approximately five million people have GA worldwide.3
Until now, there has been no approved treatment to stop – or slow the progression of – GA. However, recently the USA Food and Drug Administration (FDA) approved pegcetacoplan (trade name Syfovre, Apellis Pharmaceuticals) for the treatment of GA secondary to AMD.4
Efficacy of Pegcetacoplan
Pegcetacoplan is an inhibitor of C3, a protein critical to the complement pathway. Pegcetacoplan is administered by intravitreal injections monthly or every-other-month on an ongoing basis. The complement pathway is a key component of the innate immune system and is well-established as being implicated in AMD pathogenesis.5 The FILLY (Phase 2),6 DERBY and OAKS (both Phase 3)7 randomised controlled trials have together shown that pegcetacoplan slows GA lesion growth.
The OAKS trial at 12 months showed a 21% reduction in lesion growth (measured by fundus autofluorescence (FAF) area) in the group treated with monthly pegcetacoplan compared to the sham group, and a 16% reduction in lesion growth in the group treated every-other-month, compared to sham.7 In a sub-analysis, the effect was greater for participants with extrafoveal lesions than those involving the fovea, with a 35% reduction compared to sham for monthly and 21% for
every-other-month treatment at 12 months.
DERBY narrowly missed reaching statistical significance between the treated and sham groups but the treatment effect trend was in the same direction. While treatment reduced the rate of atrophic lesion growth, at 12 months there was no difference in visual acuity between treated and sham groups. Pegcetacoplan is expected to become available for use in the USA in the coming months. In light of that, approvals in other jurisdictions, including Australia, will be considered.
While pegcetacoplan is the first to market, there are several other novel interventions currently in late-stage clinical trials for GA (see section below), signalling that multiple treatments aiming to slow the progression of GA are likely to be just around the corner. These treatments are predicted to not only improve quality-of-life for patients, but will have an enormous impact on the day-to-day practice of eyecare practitioners. Optometrists and ophthalmologists need to be ready for this future.8
How the advent of novel therapies will change optometry
With new treatments on the horizon for patients with GA, the clinical management of these patients is going to change dramatically.8 Currently, people with early and intermediate AMD are principally seen by optometrists, rather than ophthalmologists. Current RANZCO referral guidelines9 and Optometry Australia’s chairside reference for the diagnosis and management of AMD10 indicate that those with GA should be reviewed 6-12 monthly by their optometrist and management focuses on identifying and improving risk factors, counselling regarding home monitoring for symptoms of neovascular AMD (nAMD) and optimising spectacles and visual aids.
Therefore, optometrists are often the first to detect the presence of GA and deliver this news to their patients. As such, the need to accurately diagnose GA is crucial, even more so now, if there is going to be a treatment available for GA secondary to AMD. It is vital to remember that there are other causes of atrophy and, as such, a need to differentiate them from GA, as treatments for GA will not be appropriate (or approved) for other causes of atrophy (see section below).
There is a need to fully characterise GA lesions, as lesion features will play an important role in deciding which, if any, treatment would be recommended. Unlike nAMD, where, in the vast majority of cases, anti-VEGF treatment is required in a timely manner, the decision to treat GA will be much more nuanced and taken on an individualised basis.
Clinical management questions around who to treat, when to treat and which eye/s to treat are not straightforward and will require as much clinical information as possible on the lesion and its behaviour over time.8 Since treatment aims to slow, but not stop, lesion progression, people being treated will need careful counselling with regard to their expectations of outcomes. Also, since there is no clinical measure that can be used to gauge early response to treatment, unlike when treating nAMD, the treatment cannot be as easily individualised and growth characteristics will be collected over the long term, with success measured as a change in rate of growth over an extended period.
GA often starts in the perifoveal region and enlarges to involve the fovea. This means that visual acuity is often normal despite the presence of GA. Hence, identifying key lesion characteristics, such as size, number of lesions and relationship to the fovea, will be important to help understand an individual’s risk of vision loss. In addition, the ability to determine an individual’s GA growth rate over a minimum period of 12 months will be a key factor for an ophthalmologist to consider when advising on the benefits and risks of treatment and deciding if and when to intervene.11
Hence, it is crucial that GA is documented by fundus images as soon as GA is diagnosed so that its characteristics over time can be captured. Both optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging are ideal for documenting GA size, number and location of lesions. They can also help identify high risk characteristics for progression such as particular FAF patterns and presence of reticular pseudodrusen (RPD).
As imaging equipment (OCT and FAF) have become widespread, optometrists are now well positioned to obtain the longitudinal imaging data that will be of critical importance in the clinical decision-making process for GA as treatments become available.
Development of GA secondary to AMD
GA has traditionally been defined on colour fundus photos (CFPs) as a sharply demarcated, pale (hypopigmented) lesion with a choroidal vessel in its base (Figure 1A), often starting in the perifoveal region before expanding towards the fovea over time.12 However, FAF imaging has given us the ability to better delineate GA lesions. In FAF images of a healthy retina, there is a natural auto-fluorescent signal (white) from the RPE. Whereas in GA, the FAF signal is black where the RPE is missing with a sharply demarcated border to areas of relatively healthy RPE, making GA easier to detect on FAF images than CFP (Figure 1B).
Using FAF images is very useful when explaining the disease to patients and relatives as the non-functioning regions are black. FAF images are also well suited to showing how the lesions are changing over time to help understand the potential importance of intervention to slow progression towards the fovea (Figure 2).
Smaller GA lesions tend to grow slower than larger lesions (until they get very large) and extrafoveal and multifocal lesions have higher growth rates than foveal or unifocal lesions.13, 14 Progression towards the periphery is faster than towards the fovea,15 and progression is faster in fellow eyes of those with GA.16 Banded and diffuse (particularly ‘diffuse-trickling’) FAF patterns suggest a faster rate of growth compared to those with no such FAF autofluorescence patterns.17 Furthermore, eyes with RPD have not only faster GA progression but the growth appears to be more towards the RPD.18-20 Regions with ellipsoid zone disruption on OCT may also predict the direction of GA progression.21
Informed referral
Before recommending the commencement of GA treatment, information on GA size, lesion type, growth rate and direction and association with other biomarkers needs to be considered within the context of the patient age, visual acuities and quality-of-life issues.
Optometrists will need to start a discussion on the possibility of treatment options and offer an ophthalmology referral for further treatment discussion. Including longitudinal imaging, especially FAF images, in referrals will be very useful to help determine individual progression rates and the relative merits of intervening.
The importance of distinguishing GA secondary to AMD from inherited retinal disease
It is critical to determine if atrophy seen in the macula is GA secondary to AMD and not atrophy secondary to another condition, such as an inherited retinal disease (IRD). Macular dystrophies are the subset of IRDs that can
mimic GA.
The dystrophy most often mistaken for AMD, with deposits that resemble drusen and atrophy that resemble GA, and in patients whose demographics fit with AMD, is Stargardt disease (caused by ABCA4 mutations in the vast majority), or more commonly its later onset form, fundus flavimaculatus.
Rarely, other diseases with dominantly inherited drusen can be mistaken for AMD such as Sorsby fundus dystrophy (caused by TIMP3 mutations) and familial dominant drusen (EFEMP1).
As Stargardt disease has autosomal recessive inheritance, patients usually do not have a family history of macular disease, so the possibility of an IRD needs to be kept in mind for all patients.
Imaging, especially with FAF, will be often the first clue that the disease is not typical of atrophy secondary to AMD. In Stargardt disease there are very sharply demarcated areas of atrophy, with very hyper autofluorescent linear flecks and no typical drusen. (Figure 3).
Due to their different aetiologies, potential treatments for AMD and IRD will be very different, so it is critical that both sets of patients are correctly differentiated.
Other new GA drug therapies on the horizon
The pathophysiology of AMD is complex, and as such there are many different treatment approaches being considered, including interventions to:
- reduce oxidative stress
- reduce toxic by-products by modulating the visual cycle
- reduce inflammation by complement inhibition
- take a neuroprotective approach
- improve blood flow in the choroid
- replace, repair or regenerate RPE cells and photoreceptors with cell-based therapies.
Several novel interventions are currently in late-stage clinical trials, most of which involve blocking the complement pathway.22 Clinical trials in later-stage development that aim to block the complement cascade and are currently under way in Australia include C5 inhibitor (avacincaptad pegol, trade name Zimura, Iveric Bio), an antisense inhibitor of complement factor B (IONIS-FB-LRx, Ionis) and gene therapy (GT005, Gyroscope Therapeutics). Other complement pathway trials include ANX007 (Annexon), CB2782 (Catalyst), ALXN1720 (Alexion), HMR59 (Janssen) and Danicopan (Achillion), showing the immense interest from the pharmaceutical industry in this pathway.
Of particular note, the GATHER2 trial, testing avacincaptad pegol met its primary 12 month endpoint23 and has filed its new drug application with the USA FDA. In addition, there are a number of later phase trials targeting non-complement pathways underway including ONL1204 (ONL Therapeutics), which targets Fragment Apoptosis Stimulator (Fas) pathways upstream of the death signalling and inflammatory pathways.
Not all these treatments are given via intravitreal injections, with some given orally or by subcutaneous injection, thereby offering the opportunity to treat both eyes, but exposing the patient to potential systemic adverse effects. Gene therapy and cell-based therapies may require retinal surgery or potentially outpatient suprachoroidal or intravitreal delivery. A major benefit of gene or cell-based therapy is the possibility of a one-off treatment.
Summary
It is likely that pegcetacoplan is only the first of what will eventually become multiple treatment options for patients with GA. Optometrists can assist by playing an active role in identifying patients with GA, introducing the topic of potential treatments and ensuring multimodal retinal imaging is undertaken to objectively document lesion progression.
With further treatment options under investigation, there remains a need to identify and refer patients with GA who may be suitable for pegcetacoplan, but also those interested in treatment trials to progress our knowledge of the treatment options.
All eyecare professionals are being called upon to help identify people with GA (and IRDs) and to refer them to clinical trial centres if they are interested in participating in research. With help and advocacy from the eyecare profession, we will continue to make headway towards improving the lives of those with this potentially devastating disease.
For further information regarding trials underway at CERA, visit the website (www.cera.org.au/current-trials/) or contact the research team on: (03) 9929 8113 or amd-studies@cera.org.au (AMD referrals) or IRD@groups.unimelb.edu.au (IRD referrals).
More reading
FDA approves Apellis’ SYFOVRE for first geographic atrophy treatment
New gene therapy offers hope for dry AMD
Prof Robyn Guymer: Is Australia ready for the latest AMD therapies?
