Management of GA Perspectives of Three Retina Specialists

mivision sat down with three leading Australian ophthalmologists – Associate Professors Samantha Fraser-Bell and Hemal Mehta, and Dr James Wong – who discussed their perspectives and current approaches to managing GA, patient communication, and the potential for upcoming treatments to make a difference.

Geographic atrophy is an advanced form of dry age-related macular degeneration (AMD) and a leading cause of blindness, impacting more than five million people worldwide.¹

Globally, more than 196 million patients have AMD,² including about 1.3 million people in Australia or 14% of 9.3 million people over age 50. All have a potential risk of progressing to GA. Estimates suggest 1–2% of the Australian population over 50 has late-stage AMD or 100,000 to 200,000 people, with half having currently untreatable GA.³

These figures from the 2016–2017 National Eye Health Survey may be an underestimate as the Macular Disease Foundation Australia estimates there are now about 1.5 million Australians with some evidence of AMD.⁴ Incidence is expected to increase as the population ages.

GA can severely impair visual function, independence, and quality of life as it takes, on average, only 2.5 years for GA lesions to encroach the fovea, which is responsible for central vision.⁵

GA is the progressive destruction of retinal cells through irreversible lesion growth that is associated with excessive complement activation.⁶

Lesions begin to appear outside the centre of the fovea, but loss of vision may not be noticeable. Loss of peripheral low light vision may become more noticeable as lesion size increases. Patches of missing vision start to develop as lesions approach the fovea. As central lesions become more severe, a person with GA will experience near complete loss of central vision.⁷

Cumulative damage to the retina through ageing, environmental stress, and other factors, triggers inflammation via multiple pathways, including the complement cascade. When regulation of the complement cascade is compromised, this can lead to overactivation, inflammation and retinal cell death. Complement inhibition was identified as a key candidate for therapeutic intervention.⁸

TREATMENT PIPELINE

In February 2023, the United States Food and Drug Administration (FDA) approved Syfovre (pegcetacoplan) from Apellis Pharmaceuticals. It is the first FDA approved treatment for GA, secondary to AMD.⁹

Izervay (avacincaptad pegol) from Astellas received FDA approval for GA treatment in August 2023.¹⁰

Both target the immune system’s complement pathway through intravitreal injection. Syfovre targets C3 and C3b, while Izervay is a C5 inhibitor, to regulate complement overactivation in GA.

The US National Eye Institute, which has funded research to advance AMD therapeutics, has explained that the complement pathway protects against pathogens by triggering a cascade of proteins that enhance the body’s immune response.¹⁰

In Australia, the Therapeutic Goods Administration (TGA) is evaluating Syfovre for the treatment of adults with GA.¹¹

Other treatments in late phase clinical trials, including in Australia, include oral tablets tinlarebant¹² and danicopan,¹³ and the gene therapy JNJ-81201887.¹⁴ The first AI-based GA-algorithm to measure progression is also being used in Australia for research purposes.

PATIENTS AND GEOGRAPHIC ATROPHY

Q. How would you categorise the GA patients you see in your clinic?

Assoc Prof Mehta: I categorise according to subfoveal or non-subfoveal lesions, presence of concurrent neovascular AMD; and visual acuity changes. Multimodal imaging can provide further insights.

Using optical coherence tomography (OCT), I categorise as iRORA (incomplete retinal pigment epithelial and outer retinal atrophy) or cRORA (complete retinal pigment epithelial and outer retinal atrophy).

Using autofluorescence, I categorise according to the hyperautofluorescent features at the lesion margin, with diffuse trickling pattern being at risk of the highest rate of progression. Autofluoresence is also helpful to exclude inherited retinal disease.

Near infrared reflectance imaging can be useful for detecting the presence of reticular pseudodrusen if not already established on looking at OCT imaging.

Additionally, I record the area of GA and the closest margin of GA lesion to the foveal centre, as well as whether lesions are unifocal or multifocal (which are included as fields in the updated Fight Retinal Blindness! AMD registry).

Q. What proportion of your GA patients would have subfoveal lesions vs non-subfoveal lesions?

Assoc Prof Fraser-Bell: More patients have non-subfoveal lesions in my practice than subfoveal lesions.Many of these patients have wet AMD in their fellow eye, which is why they have come to be in my care. They often describe how difficult it is to read as words are missing in the areas that align with the geographic atrophy.

Q. How many of your wet AMD patients have GA?

Assoc Prof Fraser-Bell: A significant number of patients I treat have coexisting macular atrophy. We looked at this issue with our findings published in the journal Ophthalmology.¹⁵

We found that one quarter of eyes had coexisting atrophy when diagnosed with wet AMD and this increased to 50% at four years after treatment started with anti-VEGF (vascular endothelial growth factor) injections.

Q. Who are the patients most at risk and what are the indicators for those who may progress faster?

Assoc Prof Fraser-Bell: The prevalence and size of geographic atrophy increases significantly with age. Smoking and family history are also major risk factors.

Dr Wong: Some of the risk factors for higher rates of progression relate to the affected eye and also the fellow eye. Higher rates of GA progression are associated with larger lesion size, multifocal lesions, and a non-subfoveal location.¹⁶ Large drusen (>125microns) or pigmentary changes of the retinal pigment epithelium (RPE) are additional risk factors.¹⁷

Patients with reticular pseudodrusen in the affected eye and those who have had a higher rate of progression of GA in the fellow eye are also at higher risk.¹⁸ Particular patterns of autofluorescence place patients at higher risk, including the perilesional hyper-autofluorescence of the diffuse, banded or diffuse-trickling type.¹⁹

Assoc Prof Mehta: It is also important to consider the baseline GA area and previous rate of disease progression to identify patients most at risk; all of this points to the importance of historical imaging.²⁰

Q. How do you manage your GA patients, and what are the management goals in GA?

Assoc Prof Mehta: I educate them about the natural history of GA, about the use of AREDS2 multivitamins, and the need to include plenty of green leafy vegetables in their diet. With smokers, I discuss smoking cessation and I encourage all patients to use an Amsler grid to monitor for neovascular AMD.

I provide patients the option to enrol in clinical trials for treatments that have potential to slow disease progression.

There are two FDA approved treatments for GA, and it is likely that treatments will become available to Australians in the near future.

The aim of these treatments is to slow disease progression to maintain function such as driving level vision or the ability to live independently at home, to reduce the risks of falls and depression, and maintain quality of life. As treatments become less invasive and safer, we would aim to initiate treatment earlier in the disease process.

IMPACT OF GEOGRAPHIC ATROPHY

Q. Tell me about the conversations you have with your GA patients? What do you tell them and what is their level of understanding or reaction to their diagnosis.

Assoc Prof Fraser-Bell: I show them their colour fundus photos and fundus autofluorescence (FAF) images, and I explain how the areas of atrophy correspond to their symptoms.

I have to tell them that there is no treatment that is proven to reverse the areas of atrophy. I explain that while there is currently no approved treatment in Australia to slow the rate of progression, there are treatments available overseas, such as in the US.

I also tell them that there are other ongoing trials as it is an area of great interest. I advise that they are still at risk of developing the wet type of AMD and ask them to use an Amsler grid to screen for new distortion or vision loss. They know to present urgently if they notice a change.

Most patients are worried about going completely blind. I explain that in most cases, they maintain their peripheral vision.

Assoc Prof Mehta: The conversations I have vary considerably, based on the patient’s current understanding of GA.

For example, a patient who has subfoveal GA in one eye and extrafoveal GA in the other is highly aware of the sight-threatening nature of the disease and often highly motivated to seek treatment to slow disease progression in their better seeing eye.

They can naturally be anxious about what the future holds for them. Similarly, patients who have had friends or relatives who have suffered from GA will have a greater understanding of the functional impairment GA can cause.

On the other end of the spectrum, patients may not be aware of the natural history of GA. I try to explain GA and how the disease progresses and the potential impact on the patient’s sight.

Showing the retinal imaging to the patient can be educational. Having serial imaging allows me to discuss their rate of disease progression more accurately.

There are also additional helpful patient educational materials available from organisations such as Macular Disease Foundation Australia.

Q. What impact does GA have on a patients’ daily life/activities?

Assoc Prof Mehta: GA has a range of presentations. Early in the disease’s natural history, the initial impact on visual function can be less pronounced, with most patients presenting with non-subfoveal lesions.

Areas of non-central vision may be obscured at this stage, making tasks like tracking words in books more difficult. It can also take time to adjust from bright to dim light settings. However, within a period of years, visual function further deteriorates, which can significantly impact the patient’s reading and driving level vision, for example.

Patients who present late in the disease’s natural history may already have quite limited vision in both eyes. They may also have lost the level of vision required to drive. These patients will likely already have disease progression that involves the foveal centre (subfoveal), which is the most sensitive part of the macula responsible for fine vision.

Once that is lost, they may already have quite significantly reduced visual acuity when measured on a visual acuity chart. The disease can still progress from this stage, leading to even larger areas of lost central vision and continued loss of visual function. As the macular disease progresses, there is a significantly higher risk of falls, as Assoc Prof Fraser-Bell mentioned.

Multiple studies demonstrate that as macular degeneration progresses, it can have quite a severe negative impact on a patient’s mental health and increase rates of depression. Delaying these negative impacts is a major goal.

Q. What are the impacts on their carers/family?

Assoc Prof Fraser-Bell: With significant vision loss comes the loss of independence and greater reliance on carers/family.

Assoc Prof Mehta: Yes, patients that lose independence and the ability to drive will have an increased reliance on their carers/family for day-to-day activities. They may also need additional social support.

Because of the higher risk of falls with advanced macular degeneration, family and carers are often heavily involved in adapting the living environment to make it as safe as possible.

Additional medical appointments are often required, necessitating a family member or carer to take time off work to attend, which can have financial implications.

There can also be mental health impacts on carers, and it is important to let carers as well as patients know about support groups.

MONITORING GEOGRAPHIC ATROPHY

Q. How often do you monitor/track and measure GA; what imaging modalities do you routinely use, and what biomarkers are most important in this process?

Dr Wong: I routinely monitor patients with GA every six to 12 months. Patients with GA often have no symptoms initially, however those who are symptomatic are more likely to have subfoveal lesions or lesions close to the fovea, which have progressed from non-subfoveal lesions. I think it is helpful to follow this subgroup of patients more closely as some will develop macular neovascularisation and some will have a more rapid rate of progression of GA.

I use a combination of OCT and FAF to monitor progression of GA. FAF (using short wave or blue autofluorescence) has been a gold standard in clinical trials to measure the area of GA and is a useful imaging modality in clinical practice to track lesion growth. FAF scans can be compared qualitatively and quantitatively by measuring with inbuilt software that is usually provided with most camera manufacturers.

I find that it can be a useful feedback tool for patients to see if their GA is progressing and it can sometimes be reassuring to show them that the fovea is still preserved or that their progression has been slow.

OCT scans are still the standard of care in assessing macular anatomy, including GA and the presence of neovascular macular degeneration. I think we are becoming more familiar with identifying the features distinguishing cRORA from iRORA, and cORA (complete outer retinal atrophy) and iORA (incomplete outer retinal atrophy) on OCT scans.

Colour fundus photography is also helpful in the diagnosis and monitoring progression of GA, and was widely available even before OCT. GA can be diagnosed by sharp demarcations of RPE loss with more visible choroidal vessels within the area of GA. Other imaging modalities that may also be helpful include near-infrared autofluorescence and near-infrared reflectance. For all imaging modalities, I think it is important to obtain high quality images that can be used to compare from visit to visit.

There are certain biomarkers that I think are important to monitor in GA as they can be prognostic factors and determine rates of progression. The size, location, presence of multifocal lesions, pattern of perilesional hyper-autofluorescence, and certain drusen phenotypes, such as reticular pseudodrusen can all influence rates of progression.

Q. Do you currently use functional tests on patients with GA, and why? What are your thoughts on best corrected visual acuity as a test to assess function for GA patients?

Dr Wong: As an investigator in several GA trials, I know that it can take hours for patients to complete the full range of functional vision tests. Low luminance visual acuity, reading speed and microperimetry are all useful functional investigations. Of these, I would use microperimetry the most, as an adjunct test, as it is quantifiable and reproduceable. However, it can still be difficult to perform in an elderly population.

Best corrected visual acuity (BCVA) is not the best test to assess function in GA patients as it often underrepresents functional deficits and there is not much evidence that BCVA correlates to GA lesion enlargement. Patients may have significant paracentral scotomas from non-subfoveal lesions, which affect their visual field, and yet they can still have good BCVA if the fovea is spared. Unlike other macular diseases, such as neovascular macular degeneration where BCVA is an effective functional test, this may be problematic when seeking approval for new treatments for GA from regulatory authorities.

LOOKING TO THE HORIZON

Q. Most therapeutics options in clinical development work to slow lesion progression. What are your thoughts on this approach?

Assoc Prof Fraser-Bell: In an ideal world, we would be able to reverse the process and ‘grow back’ the retina.

There has been research using stem cells with this aim, but unfortunately this has not translated into a clinically beneficial treatment.

The difficulty is being able to measure the effectiveness of a treatment at slowing progression, since GA can progress at different rates in different people.

Dr Wong: Slowing GA lesion progression can delay vision loss until later, which may allow patients to have longer time with preserved functional vision. I think that if a treatment can maintain a patient’s vision compared with inevitable deterioration, then it would still represent a valid therapeutic approach.

Patients need to be counselled in depth about the risks and benefits of this treatment. We need to ensure they understand that vision will not be improved but hopefully maintained. Ideally, the optimal therapeutic option would be a treatment that could restore or improve vision, and there are ongoing early phase trials of agents that could potentially offer this.

CONCLUSION

Q. With potential treatment options on the horizon, what are you doing now to prepare?

Assoc Prof Mehta: No treatment to slow GA progression currently has TGA approval.

However, given that two intravitreal therapies targeting the complement pathway already have FDA approval in the USA and many other treatments are in late phase clinical trials, we should anticipate treatments becoming available in Australia in the near future.

The patients most likely to benefit from treatment will have a confirmed diagnosis of GA and have evidence of disease progression.

I am offering FAF and high-density macular OCT imaging for all patients with intermediate AMD or later stages of the disease. Currently, I am monitoring disease progression at six to 12-month intervals.

It is useful to create a database of patients with their imaging characteristics to make it easier to identify patients who will be able to access treatments in the future.

For patients who meet eligibility criteria, I am offering involvement in ongoing clinical trials.

At Strathfield Retina Clinic, we recently enrolled the first patient in the Southern Hemisphere into a gene therapy trial aimed at slowing geographic atrophy.

Q. As all current treatments in development for GA act to slow lesion growth, how would your patients with GA react if you were able to offer a treatment like this?

Assoc Prof Mehta: Eye care professionals are already used to the concept of slowing disease progression to maintain visual function in conditions like glaucoma.

Some patients are highly motivated to seek treatments that will slow GA progression, particularly if they have had experience of this disease affecting them or a family member or friend. They will be hugely encouraged to know treatments are on the way.

Other patients may not be aware of the natural history of AMD and the current unmet need for treatments.

It will be important for eye care professionals to contribute to efforts to raise public awareness as treatments become available.

Associate Professor Samantha Fraser-Bell has been chief investigator for more than 50 medical retinal trials at the Macular Research Unit, Save Sight Institute, including clinical trials aimed at slowing the progression of geographic atrophy. She is an Associate Professor in the discipline of Ophthalmology, University of Sydney, and a Consultant Medical Retinal subspecialist at the Royal North Shore and Sydney Eye Hospitals. Other significant positions held include: Deputy Director of Clinical Trials, Save Sight Institute, Medical Retinal section editor for the journal Clinical and Experimental Ophthalmology, AVR (ORIA) research advisory committee and board member.

Associate Professor Hemal Mehta is an ophthalmic surgeon specialising in medical retina conditions and cataract surgery. He offers retinal clinical trials at Strathfield Retina Clinic and Sydney Retina Clinic and is Co-

Director of Research at Strathfield Retina Clinic. He is involved in tracking treatment outcomes in routine clinical practice, for example of intravitreal therapy for wet age-related macular degeneration, via the University of Sydney’s Fight Retinal Blindness! (FRB!) registry. He was recently awarded the Australian Vision Research Primer Grant to link imaging with clinical data from the FRB! registry to improve patient outcomes. He is on the Editorial Board of the journal Eye and Therapeutics Committee of RANZCO.

Dr James Wong is a Medical Retina specialist and is Medical Director and Co-Director of Research at Strathfield Retina Clinic. He is a consultant ophthalmologist in the Medical Retina unit at Sydney Eye Hospital and Sydney Retina Clinic. Dr Wong is a Clinical Lecturer at the University of Sydney and has been Principal Investigator on International Clinical Therapeutic Research Trials of macular diseases for over a decade.

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