What may and may not be feasible to minimize the worsening of geographic atrophy

Abstract

Age related macular degeneration (AMD) is classified into neovascular AMD and non-neovascular dry AMD (d-AMD). The advanced form of d-AMD is called geographic atrophy. Although intravitreal injection of anti-VEGF drugs currently represents the standard of treatment for neovascular AMD, we are still facing daily challenges in the treatment of the dry form. Several potential options for a new therapy, including nutritional supplements, lipofuscin, inhibitors of complement factors, blood flow of the choroid, neuroprotection and encapsulated cell technology, are the objects of several studies and trials worldwide. Only a few new products will actually enter the market. When this happens, our duty will be to provide the best treatment possible and avoid people with d-AMD progressing toward a more severe form of geographic atrophy and help them maintain their visual acuity and therefore their independence.

Keywords:

• age-related macular degeneration
• blood flow
• dry, encapsulated cell technology
• geographic atrophy
• inflammation
• lipofuscin
• neuroprotection
• nutritional supplements

Age-related macular degeneration (AMD) is classified into neovascular AMD (n-AMD) and non-neovascular dry AMD (d-AMD). With the recent advent of the intravitreal injections of anti-VEGF drugs, there are now powerful drugs for the neovascular form of AMD, but we are still facing daily challenges for the treatment of the dry form.

The advanced form of d-AMD is called geographic atrophy (GA). This form is usually defined as a round or oval area of at least 175 μm in which choroidal vessels are more visible due to the absence of the retinal pigment epithelium [1]. The prevalence of GA increases with age, and in people who are 90 years old, it can reach 22% [2]. The mean overall enlargement rate of atrophic area is 2.6 mm²/year and eyes with larger areas of atrophy at baseline tend to have an increased enlargement rate [3]. Eyes affected by GA might as well develop choroidal neovascularization, a hallmark of n-AMD [4]. GA incidence at the age of 85 years is almost four-times higher that of n-AMD [3] and places a heavy burden on the society due to the potential blindness and the ever-growing life expectancy. If the macula is spared, visual acuity can still be good even in the advanced forms of GA.

At the current time, there are no approved therapies for the treatment of GA. Slowing down the progression is therefore of crucial importance. In this editorial, we will review the potential targets for therapies that have already been evaluated or are being currently assessed.

Nutritional supplements

The AREDS study has shown that certain categories of patients affected by d-AMD who assume the AREDS formula supplementation might have a decreased risk of visual loss. These results were not confirmed for patients affected by GA [5]. This might be due, in part, to the relatively small number of patients affected by GA included in the study. Patients of category 4 (affected by central GA) though were found (similarly to patients with moderate d-AMD) to benefit for a diminished progression toward n-AMD [6].

Several trials are currently ongoing for the evaluation of therapies that aim to reduce the progression of the disease.

Lipofuscin

The visual cycle eventually produces lipofuscin, a substance that is not degradable and is primarily composed of cross-linked protein residues. Lipofuscin is a fluorochrome that may sensitize lysosomes to light and therefore produces oxidative stress, release of lysosomal contents and apoptosis of the retinal cells [7]. Fenretinide (Sirion Therapeutics, Tampa, Fl, USA) blocks the final steps of the visual cycle and therefore the production of lipofuscin [8]. A double-masked clinical trial evaluated two doses of fenretinide, the higher dose only tended (not significantly) to be more effective than placebo in the reduction of GA growth. On the other hand, at the conclusion of the 2-year study, 15 of 82 patients (18.3%) in the placebo arm progressed to choroidal neovascularization, while 15 of 164 patients (9.2%) receiving fenretinide at either dose developed choroidal neovascularization. While the results were statistically significant, this was the result of exploratory and ad hoc analyses.

Emixustat (ACU-4429, Acucela, Seattle, WA) reduces the production of lipofuscin, and the results from the Phase I study showed good tolerability [9]; the results from the Phase IIa evaluated by electroretinogram show biologic activity of the molecule in patients affected by GA [10]. A Phase IIb and III [11] study is currently ongoing to evaluate the efficacy of the drug but results have not been published yet.

Inflammation & complement cascade

Inflammation has now a defined role in the development of GA [12,13]. Anti-inflammatory agents are currently undergoing evaluation. Iluvien (Alimera Sciences, Alpharetta, GA, USA) is an injectable, non-erodible intravitreal implant, which constantly releases fluocinolone acetonide for up to least 30 months. No results are yet available after a Phase II study has been completed [14].

The complement cascade is another target to control inflammation. POT-4 (Potentia Pharmaceuticals, Louisville, KY, USA, and Alcon, Hünenberg, Switzerland) is a complement inhibitor that prevents proteolysis. A Phase I study has been concluded showing that there were only minimal or mild local adverse events related to the injection, with no serious adverse events related to the drug itself. A Phase II study was programmed, but until now no additional data are available [15]. ARC1905 (Ophthotech Corp., Princeton, NJ, USA) is a complement inhibitor that is administered by intravitreal injection and has undergone a Phase I clinical trial. The results have not been published yet. Eculizumab (Soliris; Alexon Pharmaceuticals, Cheshire, CT, USA) is a humanized antibody, which is administered by intravenous injections but failed to provide significant improvement when compared to placebo in patients affected by GA [16]. LFG316 (Novartis Pharmaceuticals, Whippany, NJ, USA), an antibody directed against a subunit of the complement (C5), is administered by intravitreal injections and is currently undergoing a Phase II study [17] that is scheduled to be completed by June 2015. BCX1470 (Alcon, Fort Worth, TX, USA) and lampalizumab (FCFD4514S; Genentech/Roche, San Francisco, CA, USA) block only the alternative complement pathway; the preservation of the functionality of the classical and lecithin pathway might offer a better safety profile when compared to drugs that block the entire complement cascade. The results from the MAHALO study were recently presented (14th ISOPT 2014, Reykyavik, Iceland): patients treated with lampalizumab tended to have a reduction of GA progression. Furthermore, patients who resulted positive to the complement factor I biomarker had a greater reduction of the progression compared to those who tested negative. Studies of Phase III [18,19] are currently recruiting patients and are scheduled to end in October 2018.

Sirolimus (Rapamycin; MacuSight/Santen, Union City, CA, USA) is a macrolide fungicide that inhibits IL-2, a protein involved in the inflammation process. A Phase I and II clinical trial has been concluded, but no significant differences were detected after 24 months [20].

Another promising target is amyloid-β (Aβ); this peptide is thought to be responsible for the activation of factor b, the main activator of the complement alternative pathway. An in vitro study showed that Aβ has an indirect effect on factor b through the upregulation of cytokines and the disruption of the inhibitor of complement alternative pathway [21]. RN6G (Pfizer, New York, NY, USA) is an humanized monoclonal antibody that binds with high affinity to Aβ at the free C-terminal region, thus avoiding damages to retina by preventing the accumulation of Aβ; Phase I and II clinical trials have been concluded in patients with advanced d-AMD. Another monoclonal antibody called GSK933776 (GlaxoSmithKline, Brentford, UK) reduces the accumulation of Aβ and is currently undergoing a Phase II study [22].

Choroid & blood flow

Another target for a new therapy could also be increasing the blood flow of the choroid, which is diminished in thickness in old age patients [23]. MC-1101 has been studied in a small pilot trial [24] and an increase in the volume and the blood flow speed was noticed in eyes treated topically. A Phase II/III trial [25] is currently ongoing to evaluate the safety and efficacy in patients suffering from d-AMD.

Neuroprotection

Another interesting area under development is neuroprotection. Brimonidine is an α-2 agonist that is usually administered in patients affected by glaucoma. In several animal models, this molecule has also showed a protective effect on retinal cells [26,27]. Intravitreal implants have been developed to deliver brimonidine through a sustained release biodegradable implant. A multicenter trial is currently recruiting patients affected by GA due to AMD with a visual acuity better than or equal to 20/80 in the study eye and 20/200 in the fellow eye; 400 μg is administered by the implant every 3 months through month 21. The purpose of the study is to evaluate the change from baseline until the last follow-up in 300 eyes.

Encapsulated cell technology

Ciliary neurotrophic factor has been shown to protect photoreceptors in animal models [28]. Encapsulated cell technology are biotechnical implants that are able to produce continuously recombinant therapeutics. Neurotech has developed an implant called CNTF-ECT (NT-501 implant; Neurotech, Lincoln, RI, USA) which implanted in the vitreous cavity could supply ciliary neurotrophic factor and help to protect the photoreceptors in GA. A Phase II trial resulted in a decrease in the progression of vision loss [29].

There are currently many trials ongoing. Some products will not succeed, and only a few will actually enter the market. It is not an easy task to predict which products will actually be effective since the pathogenesis of AMD is still largely unknown. The mechanisms connected to development of the dry form are far from being understood. All the products that we described focus on one or more targets that seem to play an important role in the development of this disease. Some of these drugs have already shown in preliminary studies that they can be effective, and these are probably the ones that will enter the market first. When this happens, it will definitely be a challenge for the current system to be able to provide all the services that these patients will need and that so far have not been requested. Our duty will be to provide the best treatment possible and avoid people with d-AMD progressing toward a more severe form of GA and help them maintain their visual acuity and therefore their independence.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.