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. Author manuscript; available in PMC: 2017 Jun 15.
Published in final edited form as: Handb Exp Pharmacol. 2017;242:321–336. doi: 10.1007/164_2016_36

Dry Age-Related Macular Degeneration Pharmacology

Charles B Wright 1, Jayakrishna Ambati 1,✉
PMCID: PMC5472449  NIHMSID: NIHMS865110  PMID: 27900609

Abstract

Age-related macular degeneration (AMD), the most common form of irreversible blindness in the industrially developed world, can present years before a patient begins to lose vision. For most of these patients, AMD never progresses past its early stages to the advanced forms that are principally responsible for the vast majority of vision loss. Advanced AMD can manifest as either an advanced avascular form known as geographic atrophy (GA) marked by regional retinal pigment epithelium (RPE) cell death or as an advanced form known as neovascular AMD marked by the intrusion of fragile new blood vessels into the normally avascular retina. Physicians have several therapeutic interventions available to combat neovascular AMD, but GA has no approved effective therapies as of yet. In this chapter, we will discuss the current strategies for limiting dry AMD in patients. We will also discuss previous attempts at pharmacological intervention that were tested in a clinical setting and consider reasons why these putative therapeutics did not perform successfully in large-scale trials. Despite the number of unsuccessful past trials, new pharmacological interventions may succeed. These future therapies may aid millions of AMD patients worldwide.

Keywords: Emixustat, GSK 933776, iPSC-derived RPE, Lampalizumab

1 Introduction

Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly in the USA (Schmier et al. 2012) and affects as many as one in eight individuals over the age of 80 (Zeng et al. 2016). AMD affects many different cell types, including the retinal pigment epithelium (RPE) (Ambati and Fowler 2012), choriocapillaris endothelial cells (ECs) (Zeng et al. 2016), and photoreceptor cells (Carr et al. 2013). Early AMD initially presents with drusen, whitish or yellowish punctate extracellular deposits >63 μm in diameter positioned between the RPE and Bruch’s membrane (Ferris et al. 2013). Changes to RPE pigmentation mark the transition to intermediate AMD (Ratnapriya and Chew 2013). Noticeable declines in visual function do not occur until advanced forms of AMD, which may take years (Buschini et al. 2015). Advanced AMD takes two primary forms defined by whether neovascularization occurs; geographic atrophy (GA) (Buschini et al. 2015) presents with regional RPE cell death without blood vessel intrusion, while exudative (i.e., wet) AMD does (Wong et al. 2008). Over three-quarters of legal blindness results from wet AMD (Buschini et al. 2015), but GA accounts for the vast majority of advanced AMD cases (Tarallo et al. 2012). Unfortunately, no therapeutic options for dry AMD are available (Tarallo et al. 2012).

Because age is the greatest risk factor for AMD (Bora et al. 2014) and the US census data indicates the number of elderly individuals is expected to greatly increase in the next few decades, the number of patients with AMD is expected to almost double by the year 2050 (Rein et al. 2009). Given the large number of patients with untreatable dry AMD and the reduced quality of life experienced by these patients, there is an immediate need for effective medications to treat the disease. To date, no potential therapeutics show efficacy with respect to slowing or reversing dry AMD progression. The purpose of this chapter is to explore the different therapeutic targets and their proposed treatments and to consider reasons for why these approaches have not been effective.

2 Current Strategies for Addressing Dry AMD

Lifestyle modification and dietary supplements are the only options to combat AMD development, progression, and associated visual function decline. Modifiable risk factors for dry AMD include smoking and obesity (Cheung and Eaton 2013). Smoking in particular has been associated with development and progression of AMD (Buschini et al. 2015), and some evidence AMD risk has a dose-dependent relationship with smoking (Velilla et al. 2013). Analysis of pooled datasets from the Beaver Dam Eye Study (Klein et al. 1993), Rotterdam Study (Vingerling et al. 1995), and Blue Mountains Eye Study (Mitchell et al. 1995) suggests smokers have an approximately three-fold greater risk of AMD than patients who never smoked (Smith et al. 2001). Patients who quit smoking greatly reduce their risk for developing AMD, but are still at a greater risk for AMD than patients who never smoked (Velilla et al. 2013; Smith et al. 2001). Much of the RPE toxicity has been attributed to reactive oxygen species (ROS) formation (Woodell and Rohrer 2014). Mice exposed to cigarette smoke exhibit signs of oxidative damage that recapitulate some symptoms of AMD, such as Bruch’s membrane thickening, basal infoldings in the RPE, and RPE cell death (Fujihara et al. 2008). Smoking also promotes the formation of advanced glycation end-products (AGEs) (Kirkham et al. 2003) and deposition of cadmium, which promotes ROS production, in the RPE (Woodell and Rohrer 2014; Kirkham et al. 2003). Like smoking, obesity and high-fat diets have also been associated with early AMD and progression to late AMD (Cheung and Eaton 2013). The Beaver Dam Eye Study, for example, suggested a potential link between obesity and AMD (Howard et al. 2014). High glucose (Ghaem Maralani et al. 2015), high triglycerides (Ghaem Maralani et al. 2015), and daily red meat consumption (Ersoy et al. 2014) all appear to contribute to AMD risk. Collectively, these findings suggest lifestyle modifications may reduce the risk of AMD.

Because observations indicated diets rich in fruits and vegetables may protect against AMD (Ersoy et al. 2014; Seddon et al. 1994), the Age-Related Eye Disease Study (AREDS) (Age-Related Eye Disease Study Research 2001) was conducted to determine whether a dietary supplement containing high-dose vitamins C and E, beta carotene, and zinc could protect against AMD progression by reducing oxidative stress (Cheung and Eaton 2013). A second study, AREDS2, tested lutein, zeaxanthin, and omega-3 fatty acids for AMD protection (Age-Related Eye Disease Study 2 Research G 2013). An initial report suggested the supplement slowed AMD progression (Age-Related Eye Disease Study Research 2001), but closer examination of the data suggested that it was ineffective (Ambati and Ambati 2002). Indeed, a meta-analysis of multiple AREDS trials indicated the supplement was ineffective (Evans 2008), a finding supported by follow-up examination of the original AREDS study participants (Chew et al. 2014). At the moment, lifestyle modification may be the only option to prevent the development and progression of AMD.

3 Previous Pharmacological Interventions

To date, there are no approved therapies effective at treating dry AMD despite decades of intensive research. Unlike neovascular AMD (Cheung and Eaton 2013; Schmidt-Erfurth et al. 2014), dry AMD continues to defy searches for a therapeutic target for intervention (Cheung and Eaton 2013). This section of the chapter will review both previous and current therapeutic interventions being tested for dry AMD treatment and the cell signaling pathways targeted by those interventions.

3.1 Antioxidants, Vitamins, and Herbal Supplements

Oxidative and mitochondrial stress may promote AMD development and progression (Hollyfield et al. 2008; Jarrett and Boulton 2012; Barot et al. 2011; Liang and Godley 2003), but to date, there are no effective therapies targeting oxidative damage or cellular oxidative response pathways. The AREDS dietary supplement formulations do not appear to be effective in preventing AMD progression (Age-Related Eye Disease Study Research G 2001; Evans 2008; Chew et al. 2014). Other herbal supplements and vitamin formulations not related to the AREDS and AREDS2 studies are also being studied for any potential efficacy against AMD progression. Some studies suggest Ginkgo biloba extract may protect against AMD by modulating choroidal blood flow and scavenging free radicals (Wilkinson and Fraunfelder 2011), and small trials conducted in Germany and France suggest the supplement may preserve vision in patients (Evans 2013). No large-scale clinical trials studying G. biloba extract have been conducted, however. Similarly, curcumin may inhibit the formation of oxidized lipids in oxidative stress conditions (Mandal et al. 2009), but no clinical trials have been performed yet. Resveratrol is also of interest because of its antioxidant activity (Pervaiz and Holme 2009), but given its limited testing in a clinical setting (Richer et al. 2014), results are inconclusive pending further investigation.

Other pharmacological interventions targeting the oxidative stress response include 5-hydroxytryptamine1A (5-HT1A) agonists (Collier et al. 2011; Jaffe et al. 2015) and OT-551 (Wong et al. 2010). The 5-HT1A receptor is best known for its role in mediating serotonin-dependent signaling events involved in regulating sleep and anxiety, but receptor activation has also been demonstrated to protect against oxidative stress-induced RPE and photoreceptor cell death (Collier et al. 2011). The 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and tandospirone (AL-8309A) protect against light-induced retinal damage in rodents (Collier et al. 2011; Biswal et al. 2015) by mitigating oxidative damage to mitochondria (Biswal et al. 2015). Unfortunately, tandospirone was not found to prevent lesion growth in GA patients during a phase III trial (Jaffe et al. 2015), casting doubt on the potential utility of 5-HT1A agonists in treating dry AMD. Similarly, OT-551 (Evans and Syed 2013) appeared promising in preliminary studies but failed to significantly halt the GA lesion spread in a phase II clinical trial (Wong et al. 2010).

3.2 Visual Cycle Modulators

Analysis of eyecups obtained from AMD patients found increased amounts of N-retinyl-N-retinylidene ethanolamine (A2E) compared to eyecups obtained from healthy patients (Suter et al. 2000). Two molecules of all-trans-retinal (Redmond et al. 1998) react with ethanolamine in oxidative conditions to produce A2E (Suter et al. 2000), which accumulates in the RPE with age (Eldred 1995). A2E appeared to induce RPE toxicity by suppressing lysosomal function, suggesting visual cycle byproducts may contribute to AMD pathology (Suter et al. 2000). Because A2E is toxic to RPE and was thought to be a principal component of the autofluorescent material lipofuscin that appears in many AMD patients (Eldred 1995), several groups attempted to create therapeutics that could halt its formation and slow AMD progression.

Given the well-defined functional and biochemical role of the visual cycle protein RPE-specific protein 65 kDa (RPE65) (Redmond et al. 1998), inhibitors specific to RPE65 were developed to slow the rate of retinoid metabolism to slow A2E generation (Buschini et al. 2015; Zhang et al. 2015). Emixustat specifically binds RPE65 at its active site to inhibit its activity (Kubota et al. 2014). Later work found emixustat scavenges free retinoids as well, and that this activity heavily contributes to its mechanism-of-action (Zhang et al. 2015). Early phase I clinical trials tested the safety and tolerance of emixustat through oral administration of the drug in doses ranging from 5 to 40 mg over a 14-day period (Kubota et al. 2014). Two-thirds of patients experienced mild adverse reactions to the drug, and because these adverse reactions resolved at the end of the study (Kubota et al. 2014), emixustat proceeded to phase II/III clinical trial (Dugel et al. 2015). This clinical trial is expected to be completed by July 2016.

Fenretinide (N-4-hydroxyphenylretinamide) also targets retinoid metabolism to slow AMD progression. The synthetic retinoid was originally designed as a potential therapeutic to use against various cancers that require retinoids for tumorigenesis, but was found to be ineffective against cancer progression in phase II/III clinical trials (Malone et al. 2003). Similarly to emixustat, fenretinide reduces the total pool of vitamin A-derived retinoids needed to form A2E (Danis et al. 2015). Mechanistically, fenretinide binds to retinol-binding protein 4 (RBP4) in the serum to interfere with vitamin A transport to various tissues (Petrukhin 2013), effectively causing vitamin A to be cleared through the urine (Danis et al. 2015). Unfortunately, phase II clinical trial data indicated fenretinide did not significantly reduce the rate of lesion expansion in GA patients (Mata et al. 2013). There are no known plans to carry out a phase III clinical trial of fenretinide as a GA therapeutic agent (Danis et al. 2015). Other nonretinoid RBP4 antagonists (Cioffi et al. 2015) such as A1120 are also currently being tested for efficacy against AMD-like phenotypes in mouse models with high rates of lipofuscinogenesis (Petrukhin 2013; Dobri et al. 2013), but these studies have not yet been translated to human patients.

3.3 Inflammatory Modulators

With the proliferation of studies suggesting pro-inflammatory pathways may be involved in AMD, anti-inflammatory agents are now of particular interest. A 1992 study reported elevated amounts of complement proteins C1q, C3c, and C3d in subretinal membranes removed from AMD patients (Baudouin et al. 1992). A series of landmark studies also identified the complement factor H Y402H (CFHY402H) polymorphism as the first heritable risk factor for AMD (Haines et al. 2005; Edwards et al. 2005; Klein et al. 2005), further highlighting the potential role of the complement cascade pathway in AMD pathogenesis. Unfortunately, the identification of both complement factor polymorphisms and complement factor proteins in AMD patients have not successfully facilitated the development of AMD therapeutics. The COMPLETE study (Yehoshua et al. 2014), which tested eculizumab, an anti-C5 antibody already approved for use in paroxysomal nocturnal hemoglobinuria (Buschini et al. 2015), found complement cascade inhibition had no effect on GA progression (Yehoshua et al. 2014). Similarly, the anti-C5 antibody LFG316 was ineffective in slowing or halting GA progression. Clinical trial data for another anti-C5 antibody, ARC1905, has not been published (Buschini et al. 2015). A neutralizing antibody targeting complement factor D (CFD) in GA patients, lampalizumab, is now in phase III trials (Danis et al. 2015).

Sirolimus, also known as rapamycin, has known anti-inflammatory properties (Mata and Vogel 2010). Already used as an immunosuppressant for organ transplant patients (Danis et al. 2015), it was hypothesized sirolimus may be effective in treating AMD as well because it was found to prevent RPE cell death in mouse models (Zhao et al. 2011). Two phase II clinical trials found no protective effect of sirolimus against GA, with no reported visual acuity protection or prevention of atrophic lesion spreading (Wong et al. 2013; Petrou et al. 2015).

Other efforts to treat AMD center on the NLRP3 inflammasome. A series of studies published within the last five years indicate DICER1 reduction in GA patients may contribute to RPE cell death because the enzyme is required to degrade cytotoxic Alu RNA transcripts (Kaneko et al. 2011). Increases in Alu RNA transcripts in GA patients cause activation of the NLRP3 inflammasome (Tarallo et al. 2012; Dridi et al. 2012), ultimately resulting in P2X7-dependent Caspase-8-mediated RPE cell death (Kerur et al. 2013; Kim et al. 2014). These observations are supported by other data showing this signaling pathway can be instigated by the presence of excess iron (Gelfand et al. 2015), which has also been previously associated with AMD in humans (Wong et al. 2007). It was recently found that nucleoside reverse transcriptase inhibitors (NRTIs), typically used to treat human immunodeficiency virus (HIV) patients, possessed anti-inflammatory properties because of their ability to block P2X7-dependent NLRP3 inflammasome activation (Wong et al. 2007). Preparations are currently underway to examine NRTIs in an AMD context in a clinical setting.

3.4 Neuroprotective Agents

Given the fact that blindness in GA is the direct result of photoreceptor death over regions with RPE atrophy (Danis et al. 2015), neuroprotective agents preventing photoreceptor cell apoptosis have been proposed as potential therapeutics. Ciliary neurotrophic factor (CNTF), for example, was previously demonstrated to preserve photoreceptor cell function and reduce apoptosis in various models of canine (Tao et al. 2002) and mouse retinal degeneration (LaVail et al. 1998). An encapsulated cell therapy (ECT)-based implant housing mammalian cells engineered to overproduce CNTF (Thanos et al. 2004) was injected into the eyes of GA patients in phase I (Sieving et al. 2006) and II clinical trials (Zhang et al. 2011). The CNTF-producing implant, NT-501 (Thanos et al. 2004), was found to be well-tolerated in patients (Sieving et al. 2006), but could not inhibit lesion spreading in GA patients (Zhang et al. 2011).

More recently, various groups have begun exploring the potential role of amyloid β in AMD. Amyloid β, perhaps best known for its suspected role in Alzheimer’s disease (Kang et al. 1987; Hardy and Higgins 1992; Hardy and Selkoe 2002), was found to be a drusen component in AMD patients (Johnson et al. 2002; Dentchev et al. 2003). Ocular amyloid deposits in a mouse model of Alzheimer’s disease were associated with retinal degeneration (Ning et al. 2008) and RPE stress (Ding et al. 2011), and amyloid β is known to activate the NLRP3 inflammasome (Halle et al. 2008), consistent with other findings that inflammasome activation may mediate GA (Tarallo et al. 2012; Kerur et al. 2013; Kim et al. 2014; Gelfand et al. 2015). Based on the studies suggesting amyloid β accumulation may contribute to ocular pathologies in mouse models of AMD (Ding et al. 2011; Catchpole et al. 2013), a clinical trial testing the efficacy of a monoclonal antibody against amyloid β is currently underway (Danis et al. 2015). The results of the phase II trial are not yet available.

3.5 Cell-Based Therapies

With the advent of human embryonic stem cell (hESC) and induced pluripotent stem cell (iPSC) technologies, recent therapeutic efforts focus on transplanting healthy derived RPE cells into GA patients (Danis et al. 2015). The first hESCs implanted into humans occurred in 2012 when hESCs were differentiated into RPE cells for subretinal implantation in patients with either Stargardt’s disease or dry AMD (Schwartz et al. 2012). Following transplantation, patients were administered immunosuppressive drugs to prevent tissue rejection, and the patients were closely monitored for complications (Schwartz et al. 2012). Preliminary data indicate the therapy may be safe in human patients, but visual acuity improvements appeared marginal (Schwartz et al. 2012). A follow-up phase I/II clinical trial indicated a majority of patients who received RPE transplantation showed small regions of pigmentation several months following treatment, suggesting derived RPE cells injected into the eyes of patients could form a partial monolayer (Schwartz et al. 2015). Although the authors of the study claim visual acuity improvements in eyes receiving treatment compared to control eyes (Schwartz et al. 2015), the small patient sample is not currently sufficient to allow any definitive conclusions on whether hESC-derived RPE cells will effectively restore meaningful vision in AMD patients. The relatively small number of RPE cells surviving transplantation several months following treatments also suggests more refined methods of implantation using improved monolayers may be needed for these treatments to maximize their efficacy (Brandl et al. 2015). iPSC-derived RPE cells may offer advantages over hESC-derived RPE cells with respect to long-term safety. Because iPSC-derived RPE cells allow for autologous transplantation, future patients will hopefully have less risk of transplant rejection and obviate the need for immunosuppressive drugs (Brandl et al. 2015). Clinical trials for iPSC-derived RPE cells are already underway, and a case study of a woman who received iPSC-derived RPE cell transplantation suggests they may be as safe as hESC-derived RPE cells (Forest et al. 2015). The results of these clinical trials will be forthcoming once they are complete.

4 Perspectives on Future Directions

Numerous lines of evidence suggest the field has long suffered from gaps in understanding with respect to basic AMD biology. The inability of the visual cycle therapeutic fenretinide to halt GA lesion growth (Danis et al. 2015; Mata et al. 2013), for example, supports this hypothesis. Fenretinide successfully depletes vitamin A in the serum (Danis et al. 2015) but has no effect on disease progression in humans. A primary reason fenretinide failed in clinical trials could be the fact that the field overestimated the importance of A2E in AMD pathogenesis. It was originally thought A2E correlated with AMD (Suter et al. 2000), but later work found A2E primarily accumulated in the periphery of AMD eyes (Bhosale et al. 2009), not in the macula. Furthermore, later work also demonstrated that lipofuscin only poorly predicted lesion spread in GA (Hwang et al. 2006) and that the presence of A2E and lipofuscin did not even correlate with one another (Ablonczy et al. 2013). Together, these data indicate A2E might be largely irrelevant to AMD and that visual cycle therapeutics like fenretinide would have little chance of having a protective effect in patients. Similarly, numerous clinical trials focused on targeting complement factors to prevent GA spread but were ultimately found ineffective. The biological relevance of CFH polymorphisms in and AMD context (Haines et al. 2005; Edwards et al. 2005; Klein et al. 2005) remains elusive; Cfh mutant mice show only a marginal phenotype (Coffey et al. 2007), and many individuals exhibiting complement deposition in the RPE never present with AMD (Anderson et al. 2010; Mullins et al. 2014). Thus, the field may be missing the biological understanding of AMD needed to create effective therapeutics.

Inadequate experimental design and data interpretation also confound efforts to treat dry AMD. The AREDS study, for example, originally reported the AREDS vitamin supplement could significantly slow the progression of AMD from its earlier to its more advanced stages, but further data analysis and later patient follow-up indicated AREDS was actually ineffective (Ambati and Ambati 2002; Evans 2008; Chew et al. 2014). Similarly, the role of the NLRP3 inflammasome with respect to AMD was at first unclear because of experimental design issues. After the NLRP3 inflammasome was linked to GA (Tarallo et al. 2012), the finding was challenged because of data demonstrating IL-18 antibody neutralization augmented laser-induced choroidal neovascularization in mice (Doyle et al. 2012). It was later found the IL-18 neutralizing antibody solution injected into mice contained glycerol, which is toxic to the retina and RPE; moreover, other laboratories could not replicate findings suggesting the NLRP3 inflammasome was protective (Ijima et al. 2014; Zhang et al. 2016; Wang et al. 2016; Tseng et al. 2013; Kauppinen et al. 2012; Hirano et al. 2014). In order for effective therapeutic options to become available to patients with dry AMD, the field requires a better understanding of the basic biology underpinning disease pathogenesis, which in turn requires rigorous experimental design and analysis.

5 Conclusions

The complexity of AMD pathogenesis continues to stymie the development of effective pharmacological interventions for the disease. Unlike neovascular AMD, which has a number of therapeutic options for patients, dry AMD currently has no effective pharmacological intervention. Previous attempts to slow disease progression have been unsuccessful, but a new generation of novel pharmacological approaches and cell-based therapies may have a greater degree of success in treating the disease (Table 1).

Table 1.

Therapeutics tested in the clinic for dry AMD

Agent Intervention Targeted biology
AREDS supplement Dietary supplement Oxidative stress
G. biloba extract Dietary supplement Oxidative stress
Curcumin Dietary supplement Oxidative stress
Resveratrol Dietary supplement Oxidative stress
8-OH-DPAT Small molecule Oxidative stress
Tandospirone (AL-8309A) Small molecule Oxidative stress
OT-551 Small molecule Oxidative stress
Emixustata Small molecule Visual cycle
Fenretinide Small molecule Visual cycle
A1120 Small molecule Visual cycle
Eculizumab Antibody Complement cascade
LFG316 Antibody Complement cascade
ARC1905 Antibody Complement cascade
Lampalizumaba Antibody Complement cascade
Rapamycin Small molecule Inflammation (mTOR signaling)
CNTF Recombinant protein Neuroprotection
GSK 933776a Antibody Amyloid-β aggregation
iPSC-derived RPEa Cell-based therapy RPE loss
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a

Clinical trials have not yet been completed

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