Age-related macular degeneration: current treatments.

Abstract

Although important progress has been made in understanding age-related macular degeneration (AMD), management of the disease continues to be a challenge. AMD research has led to a widening of available treatment options and improved prognostic perspectives. This essay reviews these treatment options.
Interpretative essay.
Literature review and interpretation.
Current treatments to preserve vision in patients with non-exudative AMD include antioxidant vitamins and mineral supplementations. Exudative AMD is currently most often treated monthly with anti-VEGF intravitreal injections. However, investigators are beginning to experiment with combination therapy and surgical approaches in an attempt to limit the number of treatment and reduce the financial burden on the health care system.
By better understanding the basis and pathogenesis of AMD, newer therapies will continue to be developed that target specific pathways in patients with AMD, with the hoped for outcome of better management of the disease and improved visual acuity.

Full text

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© 2009 Hubschman et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access
article which permits unrestricted noncommercial use, provided the original work is properly cited.
Clinical Ophthalmology 2009:3 155–166
155
R E V I E W
Age-related macular degeneration: current
treatments
Jean Pierre Hubschman
Shantan Reddy
Steven D Schwartz
Jules Stein Eye Institute,
Department of Ophthalmology,
University of California, David Geffen
School of Medicine, Los Angeles,
California, USA
Correspondence: Jean-Pierre Hubschman
Jules Stein Eye Institute – UCLA,
200 Stein Plaza, 90095 Los Angeles,
California, USA
Tel 310 206 5004
Fax 310 794 7905
Email hubschman@jsei.ucla.edu
Purpose: Although important progress has been made in understanding age-related macular
degeneration (AMD), management of the disease continues to be a challenge. AMD research
has led to a widening of available treatment options and improved prognostic perspectives. This
essay reviews these treatment options.
Design: Interpretative essay.
Methods: Literature review and interpretation.
Results: Current treatments to preserve vision in patients with non-exudative AMD include
antioxidant vitamins and mineral supplementations. Exudative AMD is currently most often
treated monthly with anti-VEGF intra-vitreal injections. However, investigators are beginning to
experiment with combination therapy and surgical approaches in an attempt to limit the number
of treatment and reduce the fi nancial burden on the health care system.
Conclusion: By better understanding the basis and pathogenesis of AMD, newer therapies will
continue to be developed that target specifi c pathways in patients with AMD, with the hoped
for outcome of better management of the disease and improved visual acuity.
Keywords: age-related macular degeneration, VEGF, photodynamic therapy, laser, surgery
Introduction
In industrialized nations, age-related macular degeneration (AMD) is the leading
cause of vision loss and blindness in people over age 65.1–4 As the disease affects the
central regions of the retina and choroid, central visual loss can ensue. Approximately
30% of adults aged 75 or older have some signs of maculopathy, and 6% to 8% of
these individuals are affl icted with the advanced stages of AMD. Due to increased life
expectancy and current demographics, the prevalence of AMD is expected to double
by the year 2020.5–7
There are two major clinical presentations of AMD: non-exudative or atrophic
AMD, which is characterized by the degeneration of choriocapillaries, retinal pig-
ment epithelium (RPE) and neurosensory retina; and neovascular or exudative AMD,
which is characterized by the development of serous RPE (retinal pigment epithelium)
detachments and/or new choroidal vessels that can lead to bleeding, exudation, and
eventual scar formation. Although the exudative form of AMD only accounts for 10%
to 20% of the overall incidence of AMD, it is responsible for over 90% of cases with
severe visual loss.8,9
The management of either type of AMD continues to be a challenge for patients,
ophthalmologists, and the healthcare system. The primary purpose of AMD disease
management is to minimize visual loss and the related physical and emotional
impairment, and to optimize vision-related quality of life. Recently, the important
progress made in the comprehension and knowledge about basic pathologic mechanisms
in both types of AMD has led to novel developments in therapeutic strategies resulting
in a widening of available treatment options and improved prognostic perspectives.10

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Treatment options span a broad range of therapeutic
approaches, including thermal laser photocoagulation,
surgical approaches (excision, displacement, or transplan-
tation), and new treatments targeting the CNV component
and its pathogenic cascade, such as verteporfi n with photo-
dynamic therapy (vPDT) and more recently anti-vascular
endothelial growth factor (VEGF) therapies. Because of
relatively revolutionary effi cacy results using anti-VEGF
therapy, we can now, for the fi rst time, anticipate that over a
quarter of our patients with exudative AMD will show visual
improvement. Emerging strategies such as RNA interference,
gene therapy, and new treatment targets such as integrin
inhibitors and complement modifying agents great promise
and are under study. This review will focus on summarizing
the actual therapeutic options in the clinical management of
the different forms of AMD and provide an overview about
therapeutic perspectives.
Current treatment in clinical use
Prevention in intermediate
and advanced AMD
It is well recognized that oxidative stress likely contrib-
utes to the pathogenesis of AMD. The retina’s defenses
to such processes include glutathione (GSH) peroxides,
catalases, and antioxidant nutrients such as vitamins E
and C and carotenoids. With this understanding, it has been
hypothesized that people with low levels of these antioxi-
dants may be more prone to oxidative damage in the retina,
which may ultimately lead to AMD. It is reasonable to
speculate that consuming higher levels of these antioxidants
may protect an individual from developing AMD. This was
hypothesized and proven by the Age-Related Eye Disease
Study Group who showed that antioxidants and zinc supple-
ments could reduce the risk of progression in some forms
of AMD. More specifi cally, early AMD (AREDS category
2), characterized by small and intermediate drusen with no
or minimal pigment epithelial abnormalities in the macula,
progressed to advanced AMD in only 1.3% of cases at 5
years.11 Alternatively, intermediate AMD (AREDS cat-
egory 3), charaterized by extensive medium-sized drusen
(?125 μm in diameter) in one or both eyes, progressed to
advanced AMD in 18% of cases. No evidence was found
to support the use of antioxidant vitamins and mineral
supplementation in early AMD. Conversely, patients with
either intermediate or advanced AMD (in one eye) benefi ted
from a combination of antioxidant vitamin and mineral
supplementation (AREDS formulation: vitamin C 500 mg,
vitamin E 400 IU, beta-carotene 15 mg, zinc oxide 80 mg,
and cupric oxide 2 mg). The relative risk of developing
advanced AMD (in the other eye in the advanced AMD
group) was reduced by 25%, and the relative risk of vision
loss of 3 or more lines was reduced by 19%.11 Since studies
also found that beta-carotene increased the risk of lung can-
cer in smokers, it was recommended that smokers consider
omitting beta-carotene from the formulation.12,13 Lutein
and zeaxanthin, major components in macular pigment,
may reduce the likelihood of having advanced AMD.14
Direct evidence of neuro-protection is still lacking but it
is hypothesized that macular xanthophylls play a role as:
an important structural molecule within cell membrane, a
modulator of intra- and extra-cellular reduction-oxidation
balance; and a short-wavelength light (which is damaging to
retinal tissues) fi lter.15 In the same way, omega-3 LCPUAs
present some structural and functional properties which
indicate a probable role in visual-sensory process and as a
protective factor against retinal diseases.16 Indeed, inverse
relationship of dietary omega-3 LCPUFA intake with
advanced AMD has been reported in different studies.17,18
Studies investigating the impact of lutein and omega-3
fatty acids on the incidence and progression of AMD pro-
vided confl icted results, though they have been shown to
be non-toxic to the retina. In response, AREDS 2, which
started in late 2006, is a multi-center randomized phase III
study designed to assess the effects of oral supplementation
of high doses of macular xanthophylls (lutein and zea-
xanthin) and omega-3 LCPUFAs [docosahexaenoic acid
(DHA) and eicosapentaenoic acid (EPA)] for the treatment
of AMD and cataract. This study will enroll 4000 subjects
for a 6-year period.
In addition to the intake of vitamin and minerals
supplements described by the AREDS study, stopping
smoking and a healthy diet are strongly recommended.
Treatment of advanced AMD
Exudative AMD
Laser photocoagulation
Thermal laser photocoagulation was fi rst introduced in an
attempt to halt the progression of neovascular AMD. The
Macular Photocoagulation Study (MPS) Group trials assessed
laser treatment for CNV in three locations: extra-foveal
(?200 μm from the geographic center of the foveal avascular
zone), juxta-foveal (1–199 μm), and sub-foveal (extending
directly beneath the geographic center of the foveal avascular
zone).19–23 In each trial, the control group of untreated
eyes provided natural history data. Photocoagulation of
well-demarcated extra-foveal CNV resulted in a signifi cant

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AMD current treatments
reduction in the risk of severe vision loss over the fi rst
2 years. A recurrence rate of 54% reduced this benefi t over
the subsequent 3 years of follow-up. Laser photocoagulation,
however, did not result in better vision over a longer period
of time. The relative risk of severe visual loss of 6 or more
lines among untreated eyes compared to treated eyes was
1.5 from 6 months through 5 years.19 Photocoagulation of
well-demarcated juxta-foveal CNV membranes resulted in a
small overall treatment benefi t.20–23 The benefi t was limited
because of the high rate of persistence and recurrence (80%)
over a 5-year observation period.24–26 Laser photocoagulation
of sub-foveal CNV was primarily recommended for lesions
smaller than two optic discs and with visual acuity below
20/200. Unfortunately, 82% of treated subjects developed
visual loss below 20/200 and the laser photocoagulation of
sub-foveal CNV is no longer recommended as a primary
treatment option for such lesions.
In summary, while the MPS group trials demonstrated
an effective therapy for extra-foveal CNV, visual results for
sub-foveal disease and the high rate of foveal recurrence
within the fi rst year were disappointing to patients and to
their physicians.
Photodynamic therapy using verteporfi n (Visudyne®)
Photodynamic therapy (PDT) with verteporfi n (Visudyne®)
(vPDT) emerged as a welcome alternative to thermal laser for
the treatment of CNV. This technique employs intravenous
administration of a pharmacological photo-sensitizer (eg,
verteporfi n) followed by physical activation of the substance
using a 689 nm laser light. Excitation of the photo-sensitizer
initiates a photochemical reaction involving singlet oxygen
and reactive oxygen intermediates, which damage endothelial
cells lining the CNV and can lead to selective occlusion of
the CNV with less severe effects on the retina and underlying
choroid. Because a non-thermal light intensity is used to
induce the photochemical oxidation within the vascular
endothelium, thermal tissue damage does not theoretically
occur but vaso-occlusion with concomitant thrombosis
of the normal choriocapillaris has been documented.27
Moreover, the thrombotic effect induce an hypoxia which
locally increase the expression of VEGF.28 The Treatment
of Age Related Macular Degeneration with Photodynamic
Therapy (TAP) study found a benefi t to treatment after 1 and
2 years.29–31 Subjects with sub-foveal lesions (containing any
proportion of a classic component) of up to 5400 μm in the
greatest linear diameter were enrolled in these trials, and
pre-randomization visual acuity ranged from an approximate
Snellen equivalent of 20/40 to 20/200. A benefi t was found
for the entire population, with 53% of the vPDT-treated
subjects and 38% of the sham-treated subjects losing fewer
than 15 letters in visual acuity at 2 years (p ? 0.001).
Sub-group analysis by angiographic classifi cation revealed
that the benefi t was largest in predominantly classic lesions
(in which the area of classic CNV is greater than 50% of the
entire lesion). In this type of lesion, 59% of vPDT-treated
eyes compared with 31% of sham-treated eyes lost fewer than
15 letters. An improvement in vision by 15 letters or more was
seen in only 9% of treated subjects (including predominantly
and minimally classic lesions) at the 24 month visit.
The Verteporfi n in Photodynamic therapy (VIP) trial
enrolled subjects with sub-foveal CNV lesions composed
of angiographically occult lesion sub-type only, and with a
presumed recent disease progression (vision loss by at least
one line, new hemorrhage, or an enlargement of the CNV
by at least 10% seen by angiography). At 2 years, 45% of
vPDT-treated eyes compared to 32% of sham-treated eyes lost
fewer than 15 letters and an improvement in vision by at least
15 letters was seen in 5% of treated subjects. Loss of 30 letters
or more was observed in 29% of eyes in the vPDT group versus
47% of eyes in the placebo group. Sub-group analysis revealed
that CNV with relatively small size (less than 4 MPS disc
areas) or relatively low visual acuity (?65 letters) had better
outcomes.32 In this sub-group, 51% of the vPDT-treated eyes
lost less than 15 letters versus 25% of placebo-treated eyes.
The benefi t or stabilization achieved during the fi rst 2 years
was often maintained for at least the following 3 years.
The ocular and systemic safety of verteporfi n therapy was
confi rmed in the TAP and VIP trials.33 Acute severe visual
loss (loss of more than 20 letters or 4 lines of vision within
7 days of verteporfi n therapy) was noted however (0.7% in
the TAP investigation and 4.9% in the VIP trial) and was
more often seen in the treatment of large occult lesions with
better initial visual acuity.34
Participants in the TAP study received on average
5 treatments over the 2 years and the risk ratio of
losing 3 or more lines and 6 or more lines of visual acuity
was 0.77 (95% confi dence interval 0.69–0.87) and 0.62 (95%
confi dence interval 0.50–0.76), respectively.33 The frequency
of re-treatments decreased from an average of 3.4 in the fi rst
year, to 2.2 in the second year, to 0.4 by the fourth year (TAP
Study Group 2005). An analysis of treatment outcomes by
lesion size following vPDT from the TAP and VIP studies
suggested that therapy might reduce the risk of visual loss
in small, minimally classic lesions.35
In summary, the TAP and VIP studies provided evidence
of the efficacy and safety of the verteporfin therapy.

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Hubschman et al
This therapy reduces the risk of further loss in vision by 50%;
however, an improvement in vision was still a rare event.
Predominantly classic or purely occult lesions smaller than
four disc diameters that showed recent progression were
shown to have better outcomes. Considering the durability
and need for fewer repeated treatments, in the pre- anti-VEGF
era, vPDT was an appropriate therapy for sub-foveal CNV,
new or recurrent, where the classic component is greater than
50% of the entire lesion (?5400 μm; or in an occult CNV
when the visual acuity is worse than 20/50 or greater than
20/50 with a lesion size less than a disc diameter).
Anti-VEGF therapies
The VEGF family consists of 6 growth factors (VEGF-A,
-B, -C, -D, -E, and placental growth factor or PIGF) that
bind three distinct tyrosine kinase receptors (VEGF-R1,
VEGF-R2, and VEGF-R3). VEGF-R2 seems to be the
functional receptor that mediates endothelial cell migration.36
Different factors appeared to be regulators for VEGF-induced
angiogenesis, but hypoxia seems to be the most important
one.37 When activated angiogenesis and vascular permeability
induced by VEGF are mediated by different pathways.38,39
Multiple studies have suggested that vascular endothelial
growth factor (VEGF) increases vascular permeability and
is involved in the pathogenesis of neovascularization in
human eye disease.40 Current approaches to inhibit VEGF
involve binding it to a molecule that prevents receptor
0-ligand interaction, thus incapacitating the effect of VEGF
on the local environment. Options currently include either a
full-length recombinant monoclonal antibody (bevacizumab)
or a highly affi nitized fragment of the antibody (ranibizumab),
or a pegylated aptamer (pegabtanib sodium).
Intravitreal injection of pegaptanib (Macugen®): Vascular
endothelial growth factor 165 has been found to play a major
role in blood-retinal barrier breakdown and pathological
intraocular neovascularization.41 Pegaptanib sodium is an
aptamer composed of ribonucleic acids, which competitively
blocks VEGF 165 and selectively inhibits angiogenesis and
leakage.42 Pegaptanib has to be injected into the vitreous
cavity and re-injections have to be performed every 6 weeks
as the molecule is rapidly degraded enzymatically by
intraocular nucleases. Pegaptanib was the fi rst biological
molecule to selectively counteract one of the main pathogenic
stimuli of CNV, while preserving all the physiologic
structures of the macula.
The efficacy of pegaptanib has been evaluated in a
randomized, double-masked, multicenter, dose ranging,
controlled clinical trial (VEGF Inhibition Study in Ocular
Neovascularization (VISION)).43 A total of 1,186 subjects
with either classic, minimally classic, or occult membranes
were included. An intravitreous injection of pegaptanib at
a dose of 0.3 mg, 1 mg, or 3 mg or a sham injection was
administered every 6 weeks over a period of 48 weeks.
Subjects enrolled in the trial were allowed one vPDT
before the start of the study and any number of vPDT
treatments throughout the study period at the discretion
of the investigator. The effi cacy was demonstrated, for all
three doses of pegaptanib. In the group given pegaptanib at
0.3 mg (which was identifi ed as the lowest safe and effec-
tive dosage), 70% of subjects lost fewer than 15 letters
of visual acuity, as compared with 55% of subjects in the
control group (p ? 0.001). The risk of severe visual loss
(loss of 30 letters or more) was reduced from 22% in the
sham-injection group to 10% in the group receiving 0.3 mg of
pegaptanib (p ? 0.001). More subjects receiving pegaptanib
(0.3 mg), as compared to the sham injection, maintained or
gained visual acuity (33% vs 23%; p = 0.003). The benefi cial
effect was seen for all types of neovascularization. Subgroup
analysis did, however, reveal a slightly larger benefi t in
minimally classic lesions, with stabilization in 76% of eyes
as compared to 54% in the sham group. A 2-year evaluation
showed that mean visual acuity was maintained in subjects
continuing with 0.3 mg pegaptanib.44 In order to maintain
the initial stabilization rates, the injections of pegaptanib
had to be given throughout the entire 2 years. Twenty-six
percent of subjects discontinuing treatment after the fi rst
year experienced an additional loss of ?15 letters versus
16% in the continued group. Despite treatment, the total size
of the lesion increased from 3.7 disk diameters at baseline
to 5.5 at the 2-year follow-up. Six percent of treated eyes
improved by 3 lines compared to 2% in the sham group. No
statistical difference was found between the various CNV
subgroups, however predominantly classic lesions tended to
do better. Early detection may result in superior visual out-
comes (improvement or stabilization in 76% versus 50% in
the usual care group).45
The safety profi le of pegaptanib is favorable at 2 years.
The most common ocular adverse events were transient,
mild to moderate in intensity, and related to injection
preparation and procedure. The injection procedure itself
can lead to serious ocular adverse events at a rate of 2.1 to
2.3%/year (endophthalmitis 1.3%/patient, retinal detachment
0.6%/patient, traumatic cataract 0.6%/patient). In events
associated with systemic VEGF inhibition, or in severe ocular
complications when compared to sham treated subjects, there
was no evidence of an increase in deaths.

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AMD current treatments
Pegaptanib was approved as the fi rst anti-VEGF agent
by the FDA in December 2004 and by the European
Medicines Agency in January 2006 for all lesion types
in neovascular AMD. Similar to vPDT monotherapy, the
benefi t of a pegaptanib is limited to visual stabilization
with an overall inability to improve vision. This warrants
clinicians to examine the risks of intravitreal injections
versus vPDt.
It is accepted now that intravitreal injections are well
tolerated and safe when performed according to protocol.
Though there is an increase in risk of endophthalmitis or
retinal detachment with intravitreal injections, RPE atrophy
and photoreceptor loss than can ensue after vPDt is far
less common with anti-VEGF therapy. In our opinion,
the benefi ts of pegaptanib therapy for AMD outweigh the
risks even though pegaptanib treatment entails intravitreal
injections every 6 weeks instead of PDT every 12 weeks.
vPDT is not equally effi cacious across the lesion subtypes
and sizes, whereas pegaptanib has effect with all lesion
subtypes and pharmacotherapy opens up the possibility of
combination therapy in attacking neovascularization through
multiple ways.
Intra-vitreal injection of ranibizumab (Lucentis®):
Ranibizumab is a humanized IgG1 kappa recombinant
monoclonal antibody fragment that recognizes and binds
extra-cellular VEGF with high affi nity. Ranibizumab has the
ability to bind and inactivate all isoforms of VEGF-A includ-
ing the soluble VEGF fragments (110, 121, and 165) and the
tissue-bound isoforms 189 and 206.46 Theoretically, ranibi-
zumab, due to its small molecular size, is able to penetrate
the retina and reach the sub-retinal space and inhibit VEGF.
Its half life is 2 to 4 days which results in a rapid systemic
clearance and improved safety.41
A large randomized, multicenter, sham controlled phase
III study (MARINA study) enrolled 716 subjects with
minimally classic and occult lesions with evidence of recent
disease progression. Subjects were randomized to 2 treatment
groups and 1 sham group. The treatment groups received a
mean of 22 injections (monthly interval) of ranibizumab
(0.3 or 0.5 mg) through 24 months. Another prospective
randomized phase III trial, (ANCHOR), enrolled 423 subjects
with predominantly classic sub-foveal lesions. This study
included a monthly injection of either 0.3 or 0.5 mg of
ranibizumab versus the vPDT treated group. The PIER study
included 184 subjects with all types of macular exudative
lesions and evaluated the effi cacy and safety of ranibizumab,
which was administered monthly for 3 doses, followed by a
fi xed regimen of re-treatments in 3-month intervals.47
The results of the MARINA and ANCHOR studies
showed that 95% to 96% of the subjects treated with
ranibizumab (0.5 mg) maintained stable vision within
3 lines (compared to 62%–64% of sham or PDT group
treated eyes) at 1 year.48-50 Thirty-four percent to 40% of the
treated eyes improved by ?3 lines of vision (compared to
6% in the vPDT group and 4% in the sham group). In the
PIER study, only 13% of the treated subjects experienced an
improvement in vision, which highlights the importance of an
individualized re-treatment regimen on a monthly basis. On
average, subjects treated with Lucentis in the MARINA study
experienced an improvement from baseline of 6.6 letters at
2 years compared to a loss of 14.9 letters in the sham group.
In the ANCHOR study, subjects treated with ranibizumab, on
average, experienced a 11.3 letter gain from baseline at one
year compared to a loss of 9.5 letters in the vPDT group. Up
to 40% of subjects treated with ranibizumab achieved vision
of 20/40 or better. Patient age, initial visual acuity, lesion
composition or size did correlate with the functional results
(visual acuity stabilization or improvement).
The Optical Coherence Tomography Imaging Patients
with Neovacular AMD Treated with Intra-Ocular Lucentis
(PrONTO) study evaluated an OCT-guided, variable-dosing
regimen with intra-vitreal ranibizumab for the treatment of
subjects with neovascular age-related macular degeneration.51
This was a prospective open-label study which evaluated
whether OCT criteria at monthly intervals could be used to
guide re-treatment with ranibizumab. Patients were enrolled
within the study regardless of lesion type or previous
treatment. Patients received intravitreal 0.5-mg ranibizumab
injections at 0, 1, and 2 months. For the remainder of the
study, strict criteria were established to determine whether
the patient received additional intra-vitreal ranibizumab.
The criteria used were: 1) decrease in acuity of 5 letters and
any fl uid by OCT, 2) increase in central macular thickness
of 100 μm even if visual acuity did not, 3) new hemorrhage,
4) new classic CNV by fluorescein angiography, and
5) persistent fl uid from CNV after last treatment. Forty
patients were enrolled in the study and received a total
of 222 injections over the 12 months of follow-up. On
average, patients gained 9.3 letters at 12 months with 95% of
patients stable or improved. Only 37.5% of patients needed
3 or 3 + 1 dose of intra-vitreal ranibizumab to quiesce the
choroidal neovascular membrane. The mean time to fi rst
retreatment was 4.3 months.
Preliminary results from the PrONTO study suggest
that fewer injections will most likely result in visual acuity
improvements similar to the results from the phase III trials