FUTURE AMD TREATMENT

Anti-VEGF therapy is rightly regarded as a breakthrough in the management of age-related macular degeneration (AMD), and investigation in this area is continuing. Still, there is room for improvement.
Researchers are now focusing on understanding the mechanisms of AMD pathogenesis and retinal cell death and applying that knowledge to develop new therapies that could have a greater benefit for reducing disease-related vision loss.
Delivering the Weisenfeld Award Lecture at the 2015 annual meeting of the Association for Research in Vision and Ophthalmology in Denver, USA, Joan W Miller MD discussed why it is necessary to look beyond VEGF and offered her perspectives about the directions where future treatment should be headed.
“With anti-VEGF therapy, more than 90 per cent of patients avoid moderate vision loss and one-third achieve 20/40 or better vision. However, data from longer-term studies show that one-fourth to one-third of patients end up with 20/200 or worse vision. When we look anatomically with imaging, we see macular atrophy in up to 98 per cent of eyes,” said Dr Miller, Chief of Ophthalmology, Mass Eye and Ear and Mass General Hospital, Henry Willard Williams Professor of Ophthalmology and Chair, Department of Ophthalmology, Harvard Medical School, Boston, USA.

ATROPHIC CHANGES
Postulating that control of neovascularisation with anti-VEGF therapy unveils a degenerative process and hence atrophic changes, Dr Miller proposed intervening with neuroprotection.
“Neuroprotection may provide a broad-based treatment approach to a variety of retinal diseases, including AMD, and it could be conceived of as an adjuvant treatment with anti-VEGF therapy. However, it might also be initiated sooner, to treat early and intermediate AMD,” said Dr Miller.
In the interest of developing neuroprotective treatments for AMD, Dr Miller and colleagues undertook studies to identify the pathways leading to photoreceptor and retinal pigment epithelium (RPE) cell death. Their findings suggest that a strategy targeting inhibition of both caspase to prevent apoptosis and receptor interacting protein kinase to prevent necrosis may be effective. 
Dr Miller reviewed research from various animal models showing that photoreceptor cell death was mediated primarily by apoptosis and RPE cell death primarily by necrosis. However, when the primary pathway was blocked, photoreceptors died by necrosis and apoptosis took over as a compensatory mechanism leading to RPE cell death. Dual inhibition of apoptosis and necrosis supported survival of both cell types. 
Even if introduced early, neuroprotection does not address the underlying cause of AMD. Therefore, early treatment would ideally interfere with a key pathway in AMD pathogenesis to limit disease development and progression.
“It is worth remembering that our success in treating neovascular AMD is based on a treatment targeted to a key pathway. Development of targeted therapies for early AMD will require better understanding of AMD pathogenesis,” Dr Miller said.
Dr Miller cited six pathways for the development of AMD: ageing, lipid and lipoprotein metabolism and transport, inflammation and immunity, extracellular matrix and cell adhesion, angiogenesis, and cellular stress and toxicity leading to cell death. Noting that neuroprotection would address the last pathway, she proposed the development of future biologically-based treatments should focus on lipids and inflammation.
She explained that inflammation is an attractive target because it seems to have an early central role in the development of AMD, but also in progression to the intermediate and advanced stages. 
“Targeting inflammation, the complement pathway, and inflammasomes seems to be a worthy area of therapeutic development. There are many clinical trials under way in this space, and so we will be learning if it is effective,” said Dr Miller. 
A treatment that targets lipids has been explored in the form of studies looking at oral statins, which also affect inflammation. Research investigating the effects of statins on AMD has generated mixed results, which Dr Miller said may be explained by disease heterogeneity, variability in the drugs and doses studied, and the widespread use of statins in the population. 

DRUSEN REGRESSION
However, she mentioned encouraging findings that were achieved in a pilot study investigating high-dose atorvastatin, which was initiated by Dr Miller’s colleague Demetrios Vavvas MD, PhD. The study was undertaken based on earlier positive experience in a single patient. It enrolled 26 patients aged more than 50 years who had soft confluent drusen, no to minimal geographic atrophy, and no neovascular disease. 
Among 23 patients who completed follow-up of at least 12 months, drusen regression was observed in 10, and it was nearly complete in eight patients. Among the 10 responders, visual acuity improved by an average of three letters. Importantly, the changes occurred without any development of atrophy or neovascularisation. 
“When we have seen drusen regression previously, it has been accompanied by atrophy and vision loss. While this is a pilot study, high-dose atorvastatin is tantalising, and I hope it can be pursued.”
Recognising that the heterogeneity of AMD creates challenges to developing effective treatments for early and intermediate disease, Dr Miller also proposed that future progress in therapy will benefit from improvements in phenotyping and classification. 
“We need to use our findings from imaging and dark adaptation and perhaps combine that with metabolomics and genotyping in order to tease out subgroups within this heterogeneous patient population,” she added. 

Joan W Miller: joan_miller@meei.harvard.edu