The New Paradigm: Geographic Atrophy Treatment in Australia

In recent years, two United States Food and Drug Administration (FDA) approved medications have been used in the US in an effort to slow GA disease progression.  Pegcetacoplan (APL-2, Syfovre, Appelis Pharmaceuticals) and avacincaptad pegol (Izervay, Astellas Pharma) have been approved in the US for treatment of geographic atrophy secondary to AMD.

This approval resulted from the OAKS and DERBY (Syfovre)^1,2 and GATHER2 (Izervay)^3,4 studies, which showed favourable slowing of disease progression in the treatment arms compared to sham.

Now, in Australia, the Therapeutic Goods Administration (TGA) has approved Syfovre for every other month treatment of patients with GA due to AMD with an intact fovea. These drugs inhibit the complement pathway in the eye, which has long been associated with the development of AMD.⁵ While the approved indications are narrower than in the US, Australia remains the only other jurisdiction to have approved the medication – a welcome advancement for patients with the condition. The next phase will be to determine if the medication will be subsidised under the Pharmaceutical Benefits Scheme (PBS), which will allow cost effective treatment for the patient.

What this means for eye care professionals is a subtle but important alteration to practice. We must become adept at GA screening, image interpretation, and AMD nomenclature to identify the appropriate patients for treatment, and understand the referral pathway.

GA presents an entirely different paradigm – one in which not everyone should receive therapy

Screening, Classification, and Image Interpretation

The complement inhibition GA trials (OAKS/DERBY and GATHER) used fundus autofluorescence (FAF) as the primary biomarker to both initially diagnose the condition and subsequently determine disease progression. It remains important for optometrists to be able to acquire these images and interpret them accurately if they are to recommend patients for treatment. It is important also to correctly classify disease and use a standardised nomenclature when communicating their findings.

The Beckman Classification of AMD remains the gold standard for AMD grading, and as such, should be used when screening patients. Under this classification, late AMD is either neovascular AMD (nAMD) or GA.⁶

Traditionally, GA was defined by its appearance on colour fundus photography (CFP), however improvement in modern imaging capabilities has led to a greater understanding of the different subtypes of atrophy. Optical coherence tomography (OCT) and FAF have revolutionised how we monitor and treat our AMD patients but have also led to a greater understanding of the disease heterogeneity.

Four different appearances of atrophy have been classified on OCT:

1. Complete retinal pigment epithelium and outer retinal atrophy (cRORA),
2. Incomplete retinal pigment epithelium and outer retinal atrophy (iRORA),
3. Complete outer retinal atrophy, and
4. Incomplete outer retinal atrophy.⁷

GA, as we understand it clinically, usually corresponds to cRORA. In addition, another term – nascent geographic atrophy (nGA) – refers to the subsidence of the outer plexiform layer and inner nuclear layer, or a hyporeflective ‘wedge’ lesion in Henle’s nerve fibre layer. This is an important sign as it is a biomarker that portends the likely progression to GA.⁸

FAF was used in the OAKS, DERBY, and GATHER2 trials for both diagnosis and monitoring progression. GA appears as a dark grey or black lesion on FAF due to reduced or no signal from the retinal pigment epithelium (RPE). However, GA has been long known to have a heterogenous appearance on FAF. Different patterns of FAF predict speed of disease progression.⁹ For example, a hyper-autofluorescent edge to a GA lesion is likely to result in quicker expansion of the atrophic area.¹⁰ Unifocal lesions on FAF are slower growing than multi-focal disease.10 Other abnormal patterns of FAF in GA, such as ‘diffuse trickling’, also confer a risk of faster disease progression.⁹ In addition, FAF also remains a powerful tool to show patients and family members their disease trajectory.

Once optometrists become confident in their use of OCT and FAF to diagnose and monitor patients with GA, screening patients for referral for treatment will be streamlined.

Identifying Patients for Treatment

There are many important considerations when determining who may benefit from anti-complement injections for GA. These include age of the patient, status of the fellow eye, visual requirements, and the goals for treatment.

While very few patients who present with nAMD will not require anti-VEGF treatment, GA presents an entirely different paradigm – one in which not everyone should receive therapy.

It is important to remember that while Syfovre slows the progression of GA, it has not been shown to improve or restore lost vision. In addition, there is an increase of between 7% and 12% in the incidence of nAMD, which may necessitate concurrent anti-VEGF injections.¹¹

Additionally, applying the TGA criteria of non-foveal involving disease may mean patients are relatively asymptomatic when discussions around initiating treatment begin. Patients may still have driving vision and few symptoms. Showing patients serial imaging and calculating speed of lesion expansion will be vital in these cases.

Patients with nAMD tend to present approximately 10 years prior to patients with visually significant GA.¹² Although not universal, this may have important bearing on whether to initiate anti-complement therapy. Ophthalmologists and optometrists must understand each individuals’ visual requirements. Do they drive? Are they the sole carer for a partner? What is the vision in the other eye? The focus in these discussions will be on extending the time with good central vision so they can maintain their independence rather restoration of lost acuity.

We are poised for an exciting new chapter in GA management, and it is beholden on us all to understand who may benefit from treatment

Referral Pathway

Referral for treatment of GA will require a much more nuanced discussion with patients than for nAMD, where most people are a candidate for anti-VEGF therapy.

This is both due to strict TGA definitions regarding eligibility and understanding the appropriateness of asking patients to have every other month intravitreal treatment for life. Certainly, not everyone will be, or should be, a candidate for such treatment.

The first barrier for treatment will be whether Syfovre receives PBS listing – without this it will likely remain in a research setting for most patients.

If the application to the PBS is successful, individual hospitals will make decisions as to whether they will offer Syfovre for public patients, balancing the needs of existing retinal patients with the needs of GA patients. Health care expenditure and public hospital resources will all need to be considered.

In private practice, patients may have the opportunity to receive every other month Syfovre with their ophthalmologist, provided the limitations of the treatment (no visual improvement) and burden of care (every other month injection) are well understood from the outset.

Conclusion

We are poised for an exciting new chapter in GA management, and it is beholden on us all to understand who may benefit from treatment. The use and accurate interpretation of multimodal imaging – especially OCT and FAF – and having frank discussions with our patients will allow us to accurately select the best patients for anti-complement therapy.

Dr Amy Cohn FRANZCO MBBS (Hons) MMed is a Senior Research Fellow for Cerulea’s macular research team and the Head of the Medical Retina Unit at the Royal Victorian Eye and Ear Hospital. She consults privately at Armadale Eye Clinic, Armadale; Victorian Eye Surgeons, Footscray; Specialist Eye Group, Glen Waverley; and Melbourne Retina Associates, East Melbourne.

Dr Cohn’s current areas of research include age-related macular degeneration, diabetic retinopathy, and central cerous retinopathy. She has published widely and delivered several papers at international conferences.

References

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