GEOGRAPHIC ATROPHY

Will geographic atrophy (GA) be treatable by 2020? Based on current rates of progress and the growing momentum behind clinical trials related to the disease, the answer is a guarded “yes”, according to Monika Fleckenstein MD. Addressing delegates at the 13th EURETINA Congress in Hamburg, Dr Fleckenstein, a research and clinical fellow in the Department of Ophthalmology at the University of Bonn, Germany, said that while she is optimistic that an effective treatment will be available to treat GA by 2020, or perhaps even earlier, she is less confident that all subtypes of the disease will be amenable to treatment.

“There are promising drugs in the pipeline for GA treatment. However, we need to bear in mind that there might exist GA subtypes with differential pathogenesis, and non-critical merging of different GA types may obscure a therapeutic effect in distinct subgroups. For this reason, precise phenotyping in GA is crucial in interventional trials and individualised therapy might be key for treatment of GA in the future,” she said.

Dr Fleckenstein reminded the audience that GA represents an unmet medical need as there is currently no medical or surgical treatment for the disease. “There is a clear need for an effective treatment as GA is a common cause for severe visual loss in the elderly and is characterised by expanding areas of outer retinal atrophy with corresponding absolute scotoma,” she said.

Differant pathways

In advanced AMD, the disease is characterised by progression and regression of drusen deposits, hypopigmentation and ultimately RPE cell death, with focal thickening of Bruch’s membrane and atrophy of the underlying choriocapillaris. Dr Fleckenstein noted that different pathways in the pathogenesis of GA have been described, allowing for subsequent therapeutic targets in dry AMD to be identified. “This includes, for example, the accumulation of toxic by-products of the visual cycle and so-called modulators of the visual cycle appear to be promising as a therapeutic approach. Also complement system dysregulation and inflammation appear to be crucial in the AMD process and different targets have been identified in the pathways,” she said.

Oxidative stress also seems to be a key player in the AMD pathogenesis, added Dr Fleckenstein, with antioxidants and neuroprotective compounds showing some potential in treating the disease. However, the role of the choriocapillaris in the pathogenetic cascade is not fully elucidated at this point, she said. “The role of the choriocapillaris is still under debate and it is not known if changes in the choriocapillaris are a primary factor in the disease process or if these changes are of secondary character. Choroidal perfusion may be beneficial in this particular pathway,” she said.

The encouraging news for patients, however, is that a lot of effort is currently being directed towards finding an effective treatment for GA, said Dr Fleckenstein. “Entering the term ‘geographic atrophy’ into the database at clinicaltrials.gov gave 63 hits and most of these studies involve therapeutic intervention. I think this is promising news for patients with this blinding disease,” she said.

GA subtypes

Dr Fleckenstein specified that the realistic goal for the immediate future is to halt or slow down the progression of the GA. “This target might well be achievable provided there is a potent compound. By contrast, the actual healing of GA with the restoration of functional photoreceptors, retinal pigment epithelium, Bruch’s membrane and choriocapillaris in areas of existent atrophy appears to be a nonachievable ambition at present,” she said. Dr Fleckenstein said that a lot of her own research has been geared to identifying different GA subtypes and understanding whether each subtype has a distinct pathogenesis. “If the answer is ‘yes,’ the question is, will the different subtypes be treatable by the same compound?” she said.

Dr Fleckenstein showed how fundus autofluorescence (FAF) imaging can be used to classify distinct subtypes of GA. One such subgroup, GPS+, is characterised by a fine granular pattern with peripheral punctate spots and is similar to the phenotype in patients with Stargardt’s disease. “The data suggests that the GPS phenotype is accounted for by monoallelic variants in the ATP-binding cassette transporter 4 (ABCA4) gene and we hypothesise, therefore, that there is a differential underlying pathogenesis in GPS compared to other GA subtypes. This means that complement inhibition in GPS patients may be less effective than in other GA subtypes,” she said.

FAF imaging has also helped to identify another variant of GA associated with a lobular appearance of atrophy, rapid progression and an earlier age of onset compared to patients with other GA subtypes. Patients with the trickling phenotype also seem to have a significantly thinner choroid than other GA subtypes, she said. “These characteristics point to a primary involvement of choroidal perfusion in the trickling phenotype and we hypothesise that there is a differential underlying pathogenesis of trickling compared to other GA subtypes. Patients with this phenotype may profit from choroidal perfusion enhancers.”

Dr Fleckenstein said that the recent results of the phase II MAHALO study of the complement inhibitor lampalizumab (Genentech Inc., Novartis) underscore the progress being made in this field of research. “MAHALO is the first study to demonstrate a positive treatment effect with a complement inhibitor in GA. Lampalizumab-treated eyes showed a 20.4 per cent reduction in atrophy progression, and a biomarker-defined subpopulation showed a 44 per cent reduction in GA progression at 18 months. The compound was also found to have an acceptable safety profile with no intraocular infections, inflammation or IOP issues and no serious adverse events suspected to be caused by the study drug,” she said.