1. 1
Therapeutic
intervention
for
age
related
macular
degeneration
Nicholas
G.
P.
Harper
MDEMO
29/03/2010
–
02/06/2010
Word
count:
1995
Candidate
No.
21019
Tutor:
Mr
Kesavan
Ramanujam
“This
project
is
all
my
own
work
unless
otherwise
stated.
All
text,
figures,
tables,
data
or
results
which
are
not
my
own
work
are
indicated
and
the
sources
acknowledged.”

2. 2
Therapeutic
intervention
for
age
related
macular
degeneration
Introduction
Age
related
macular
degeneration
was
first
described
in
1874
as
a
“symmetrical
central
choroido-­‐retinal
disease
occurring
in
senile
persons”13
.
Today,
it
is
widely
recognised
as
one
of
the
leading
causes
of
blindness
in
the
developed
world19
.
AMD
mainly
affects
the
elderly,
with
a
prevalence
of
15%
for
those
80
years
or
older8
.
This
figure
is
projected
to
increase
by
50%
over
the
next
10
years,
in
line
with
the
aging
population21
.
The macula is the area of the retina that contains the highest density of
photoreceptors. It is this area that is responsible for high-resolution vision, enabling
us to see fine detail crucial for reading and recognising face
Clinical
features
Progressive
loss
of
central
vision
• Decrease
in
visual
acuity
• Blurring
• Central
scotomas
• Decreased
contrast
sensitivity
• Decreased
colour
discrimination
Sparing
of
peripheral
vision
-­‐
The
area
of
the
retina
surrounding
the
macula
is
responsible
for
peripheral
vision
important
for
navigation.
As
this
is
largely
spared
in
AMD,
patients
are
usually
able
to
maintain
independent
lifestyles.
Fig 1. A representation of the
vision experienced by patients
with AMD. (From 31)

3. 3
Pathogenesis
Age
related
changes
to
the
macula
can
be
viewed
as
a
progression.
Until
there
is
visual
impairment,
they
are
classified
as
an
age
related
maculopathy.
Past
this
point,
they
are
referred
to
as
age
related
macular
degeneration.
It
is
important
to
note
that
this
is
a
distinction
based
purely
on
function
rather
than
pathogenesis.
Drusen
The
principal
feature
of
AMD
is
the
deposition
of
drusen
between
the
retinal
pigment
epithelium
and
Bruch’s
membrane.
The
word
Druse
is
derived
from
the
German,
meaning
Geode
(a
crystal
lined
rock).
They
are
visible
on
opthalmoscopy
when
≥25um
and
appear
as
yellow/white
dots
within
the
macula.
Geographic
atrophy
(GA)
• Atrophy
of
the
retinal
pigment
epithelium
• Causes
visual
loss
in
affected
areas
Choroidal
neovascularisation
(CNV)
• New
vessel
growth
within
the
choroid.
This
can
lead
to
many
complications
including:
subretinal
fluid,
hemorrhage,
retinal
detachment
and
fibrotic
scars.
• Present
in
10%
of
patients
with
AMD
• Referred
to
as
“wet”
AMD
Fig 4. A.) Fundus photograph. B.)
fluorescein
angiogram
showing
vascular
leakage.
(From
30)
Fig 2. From 34
Fig 3. From 33
A
B

4. 4
Treatment
Aetiology
The
main
risk
factor
for
AMD
is
age35
.
Studies
have
however
consistently
found
associations
between
AMD
and
smoking.
Zanke
et
al
(2010)
reports
that
current
smokers
are
3.14
times
more
likely
to
develop
geographic
atrophy
or
choroidal
neovascularisation
compared
to
non-­‐smokers35
.
On
the
grounds
of
this
research,
all
patients
with
AMD
should
be
advised
to
stop
smoking.
Research
has
also
pointed
to
obesity,
hypertension,
high
fat
intake
and
low
dietary
antioxidant
intake
as
further
modifiable
risk
factors
for
AMD14
.
Treating
-­‐
CNV
Although
only
present
in
about
10%
of
people
with
AMD,
choroidal
neovascularisation
accounts
for
80%
of
all
severe
visual
loss
caused
by
AMD7
.
Due
to
this
huge
impact
on
vision
and
the
fact
that
pathological
angiogenesis
occurs
in
many
disease
processes,
this
is
the
area
of
AMD
research
that
has
seen
the
most
progress.
The
following
are
some
of
the
methods
developed
for
halting
this
process.
Vitreoretinal
surgery
Surgical
methods
for
removing
CNV
have
been
described
since
the
1980s11
.
To
investigate
their
effectiveness,
the
Submacular
Surgery
Trials
(SST)
carried
out
3
RCTs
between
1997
and
2003.
Unfortunately,
results
showed
that
after
24
months,
there
was
no
difference
in
visual
acuity
between
surgical
treatment
and
observation11
.
For
subfoveal
neovascular
AMD,
a
method
has
since
been
developed
where
instead
of
removing
the
vessels
themselves,
the
fovea
is
moved
to
an
area
free
from
CNV.
This
macular
translocation
has
shown
positive
results
in
a
small
study
in
which
50%
of
treated
patients
experienced
a
1
line
improvement
in
visual
acuity
at
12
months
26
.
Due
to
the
invasive
nature
and
only
mild
improvements
gained
from
this
procedure,
it
is
not
considered
routine
treatment.

5. 5
Laser
Photocoagulation
This
was
the
first
laser-­‐based
treatment
used
for
neovascular
AMD.
The
aim
was
to
use
a
laser
to
coagulate
the
newly
formed
choroidal
vessels.
The
Macular
Photocoagulation
Study
Group
carried
out
a
number
of
clinical
trials
between
1979
and
199417
.
They
showed
that
compared
to
patients
treated
with
laser
photocoagulation,
untreated
patients
had
a
1.2-­‐1.5
relative
risk
of
significant
visual
deterioration.
(Results
summarised
in
fig
6).
There
are
however
serious
limitations
to
this
treatment:
1. The
laser
creates
a
burn
that
destroys
vision
in
that
area
of
the
retina.
As
such,
this
treatment
is
only
appropriate
when
the
neovascularisation
is
outside
the
central
area
of
the
macula.
Only
10-­‐15%
of
patients
with
CNV
were
suitable
for
this
treatment17
.
2. Inadvertent
coagulation
of
the
fovea
(rare)
3. Subretinal
Haemorrhage
4. At
2
years,
>50%
of
the
patients
had
a
recurrence
of
neovascularisation17
.
Fig 6. Relative risk of visual loss in
photocoagulation treated vs observed
patients for A.) All patients with
extrafoveal lesion, B.) New subfoveal
lesions C.) Recurrent subfoveal
lesions. (From 28)
Fig 5. Retinal scars produced by
photocoagulation. (From 32)
A C
B

6. 6
Laser
Photodynamic
therapy
Laser
photocoagulation
causes
irreversible,
non-­‐specific
thermal
damage.
In
the
aim
of
minimising
this
retinal
damage,
the
method
of
laser
photodynamic
therapy
(PDT)
was
developed
in
the
late
1990s:
A
light
sensitive
dye,
which
concentrates
in
newly
formed
vessels,
is
injected
into
the
patient.
when
excited
by
laser
light
of
a
specific
wavelength,
the
dye
undergoes
a
reaction,
causing
selective
chemical
destruction
of
those
vessels.
The
groundbreaking
“treatment
of
age
related
macular
degeneration
with
photodynamic
therapy”
(TAP)
study
used
a
verteporfin
(Visudyne)
as
their
light
sensitive
dye24
.
Results
showed
that
photodynamic
treatment
lead
to
a
significant
improvement
in
visual
acuity,
contrast
sensitivity
and
retinal
appearance
under
fluorescein
angiography
compared
to
placebo
treated
patients
at
1
and
2
years
follow
up24
.
Side
effects
included
transient
visual
disturbances
(18%),
an
adverse
reaction
at
the
injection
site
(13%)
and
transient
photosensitivity
(3%)24
.
This
TAP
study
lead
to
the
FDA’s
approval
of
verteporfin
photodynamic
therapy
in
2000.
The
main
drawback
of
photodynamic
therapy
is
that
for
macular
lesions
in
which
CNV
accounted
for
<50%
of
the
total,
PDT
showed
no
significant
benefit
in
any
of
the
measured
outcome
variables24
.
Fig
7.
A
typical
patient
from
the
TAP
study
-­‐
Fundus
photographs
and
late-­‐phase
fluorescein
angiograms
taken
at
baseline
(A,B),
3
months
(C&D)
and
12
months
(E,F),
during
the
12
month
course
of
verteporfin
PDT
therapy.
Therapy
was
applied
every
3
months.
Images
clearly
show
an
improvement
in
fundus
appearance,
with
no
deterioration
in
vascular
leakage.
(From
24)

7. 7
Anti
VEGF
Vascular
Endothelial
Growth
Factor
A
(VEGF-­‐A)
is
a
key
regulatory
cytokine
in
the
process
of
angiogenesis.
As
well
as
being
researched
extensively
in
the
fields
of
oncology
and
cardiology,
it
has
been
shown
to
have
a
central
role
in
neovascular
ocular
diseases20
.
Pegaptanib
The
first
anti-­‐VEGF
agent
shown
to
be
effective
in
AMD
was
pegaptanib
(Macugen),
a
ribonucleic
acid
aptamer
that
prevents
VEGF
from
binding
to
its
receptor.
The
“VEGF
Inhibition
Study
in
Ocular
Neovascularization
Clinical
Trial
Group”
found
pegaptanib
to
be
effective
in
70%
of
patients,
with
the
risk
of
severe
loss
in
visual
acuity
12%
lower
in
pegaptanib
treated
patients
compared
to
controls10
.
They
also
observed
a
43%
increase
in
the
number
of
patients
who
had
maintained
or
gained
visual
acuity
after
the
1
year
duration
of
the
study10
.
Unlike
photodynamic
therapy,
this
treatment
was
found
to
be
effective
in
neovascular
AMD
independently
of
precise
lesion
composition.
On
the
basis
of
these
results
pegaptanib
became
the
first
FDA
licensed
anti-­‐angiogenic
therapy
for
AMD
in
2004.
Bevacizumab
VEGF
can
also
be
silenced
effectively
using
monoclonal
antibodies.
Genentech
had
indeed
already
developed
bevacizumab
(Avastin),
an
anti
VEGF
antibody
for
the
treatment
of
colon
cancer.
Although
still
only
indicated
for
colon
cancer,
several
small-­‐uncontrolled
pilot
studies
have
reported
improved
visual
outcome
and
decreased
macular
oedema
when
used
for
AMD2,
22,
25
.
On
the
grounds
of
these
results
and
its
low
cost,
bevacizumab
is
being
increasingly
used
off
label
for
the
treatment
of
neovascular
AMD.
Due
to
a
lack
of
large
trials,
it
is
still
however
unclear
as
to
its
safety
and
the
most
effective
method
and
timing
of
administration.
Ranibizumab
In
trying
to
develop
the
most
effective
monoclonal
antibody
treatment
for
AMD,
Genentech
developed
ranibizumab
(Lucentis).
Essentially
the
antigen-­‐binding
fragment
of
bevacizumab,
engineered
to
have
an
even
higher
affinity
for
VEGF.
The
first
RCT
to
assess
the
effectiveness
of
this
treatment
was
the
“Minimally
Classic/Occult
Trial
of
the
Anti-­‐VEGF
Antibody
ranibizumab
in
the
Treatment
of
Neovascular
Age-­‐
Related
Macular
Degeneration
(MARINA)”.
Results
showed
that
after
24
months,
on
average,
ranibizumab
treated
patients
gained
6.5
letters
of
visual
acuity,
whereas
sham
injected
patients
lost
10.4
letters23
.
Endopthalmitis
was
observed
in
1%
of
treated
patients
and
uveitis
in
1.3%.

8. 8
The
“Anti
–VEGF
Antibody
for
the
Treatment
of
Predominantly
Classic
Choroidal
Neovascularization
in
Age
–
related
Macular
Degeneration
(ANCHOR)
study
went
on
to
compare
the
effectiveness
of
ranibizumab
against
verteporfin
PDT4
.
Results
showed
that
fewer
Ranibizumab
patients
experienced
15
letters
visual
loss
(RR
0.13,
NNT
3.33)
and
more
patients
experienced
visual
gain
(RR
6.79)4
.
The
2008
Cochrane
review
comparing
pegaptanib,
ranibizumab
and
verteporfin
PDT
concluded
that
whilst
all
three
significantly
decrease
visual
loss,
ranibizumab
is
most
likely
to
actually
cause
an
improvement
in
visual
acuity27
.
Cost
effectiveness
As
can
be
seen
from
Table
1,
there
is
a
large
discrepancy
in
price
for
these
treatments.
NICE
analysis
of
the
incremental
cost
effectiveness
ratio
(ICER)
per
quality
adjusted
life
year
(QALY)
found
Ranibizumab
to
be
more
cost
effective
than
pergaptanib18
.
As
a
result,
NICE
have
decided
not
to
recommend
the
use
of
Pegaptanib
for
neovascular
AMD18
.
Note
that
Bevacizumab
could
not
be
included
in
this
analysis
due
to
not
being
licensed
for
AMD
and
therefore
a
lack
of
data.
Therapeutic
Cost
Bevacizumab
£1.21
(a)
Pegaptanib
£514.00
Ranibizumab
£761.20
Table 1. net prices of the anti-angiogenic drugs3
. (a) Based on using the same dose
(500ug) as for ranibizumab.
Month
Fig 8. Mean changes in visual acuity against time for ranibizumab (0.5mg &
0.3mg) and sham injection. (From 23)

9. 9
Future
anti-­‐angiogenic
therapies
Fusion
proteins
These
proteins
are
formed
by
replacing
the
stop
codon
at
the
end
of
one
gene
with
the
DNA
from
another.
The
resultant
hybrid
gene
is
inserted
into
bacteria
and
the
protein
product
collected.
This
technique
has
been
used
to
combine
the
binding
domains
of
several
VEGF
receptors
with
human
Immunuloglobulin
G
to
produce
a
protein
that
will
tightly
bind
and
effectively
inactivate
VEGF12
.
This
therapeutic,
aptly
named
VEGF
Trap
produced
promising
results
in
phase
II
clinical
trials
(Fig
9.)
with
no
reported
adverse
effects6
.
Phase
III
Clinical
trials
comparing
VEGF
Trap
to
Ranibizumab
were
initiated
in
2007
and
are
due
to
be
completed
in
December
201129
.
Anti
VEGF
therapeutics
also
under
research
include,
Angiostatic
cortisenes,
RNA
interference
agents,
Aminosterols
and
further
anti
VEGF
antibodies.
Treatments
–
Drusen
Drusen
only
cause
visual
loss
If
they
are
larger
than
125um
or
are
present
in
extremely
large
numbers21
.
With
this
said,
they
are
present
to
some
degree
in
almost
all
patients
with
AMD
and
may
represent
an
early
part
of
a
more
complex
pathogenic
pathway
leading
to
GA
and
CNV.
Fig 9. Results from Phase II
Clinical trial comparing
VEGF Trap against laser
photocoagulation for
neovascular AMD (ref).
Graphs to show A.) Mean
change in visual acuity (Gain
in ETDRS letters) against
time in study. B.) Mean
change in central retinal
thickness against time in
study. (From 6)

10. 10
Complement
Drusen
contain
many
complement
and
complement
related
proteins,
research
has
therefore
targeted
this
pathway
to
try
and
determine
a
method
of
halting
their
development.
Many
complement
pathway
genes
have
since
been
linked
to
AMD.
These
include9
:
With
this
in
mind,
it
could
be
possible
to
stop
drusen
formation
by
designing
therapeutics
that
will
target
these
pathways.
Fig
10.
summarises
those
currently
in
development
• CFH
• CFB
• CFHR1
• C2
• CFHR2
• C3
Fig 10. A). The complement system. B). The actions of some of the many therapeutics
currently under development. Compstatin and eculizumab are currently in Phase 2 clinical
trials29
. (From 9)

11. 11
Treatments
–
GA
Due
to
progress
made
in
treating
the
“wet”
aspects
of
AMD,
research
into
therapeutics
for
geographic
atrophy
has
become
somewhat
overshadowed.
Although
there
are
currently
no
licensed
drugs
for
geographic
atrophy,
there
are
numerous
therapeutics
currently
undergoing
clinical
trials29
.
Drug
Mechanism
Clinical
trial
phase
Estimated
completion
Tandospirone
(AL-­‐8309B)
Neuroprotective
by
inhibiting
oxidative
stress
within
the
retinal
pigment
epithelium
(RPE)
III
February
2012
Alprostadil
Prostaglandin
E1
–
has
a
vasodilatory
effect
that
is
hoped
will
increase
blood
flow
to
atrophic
areas
and
slow/halt
disease
progression.
III
Terminated
as
study
was
under
powered.
Currently
re-­‐planning
Fenretinide
Retinol
metabolism
within
the
eye
creates
lipofuscin
and
A2E,
which
can
cause
damage
to
the
RPE.
Fenretindie
binds
Retinol
Binding
Protein,
decreasing
serum
retinol
concentrations.
This
reduces
retinol
uptake
by
the
RPE
and
therefore
damage.
II
June
2010
NT501
Implant
of
human
cells
genetically
modified
to
release
Ciliary
Neurotrophic
Factor
(CNTF),
a
neuroprotective
agent
shown
to
inhibit
photoreceptor
apoptosis.
II
unknown
Brimonidine
Neuroprotective
II
December
2011
OT551
Antioxidant,
anti-­‐inflammatory
and
anti-­‐
angiogenic.
Phase
II
results
are
encouraging
II
Completed
Conclusion
Much
progress
has
been
made
in
developing
therapeutics
for
this
potentially
sight
threatening
disease.
Drugs
targeting
drusen
and
GA
are
in
advanced
clinical
trials
and
with
the
new
anti-­‐VEGF
agents
we
are
now
in
a
position
to
give
real
benefit
to
patients
with
CNV.
The
prevalence
of
age
related
macular
degeneration
will
continue
to
increase
in
line
with
the
aging
population.
In
order
that
everyone
can
access
this
treatment
however,
pharmaceutical
companies
need
to
recognise
the
need
to
lower
their
prices.
Table 2. Summary of therapeutics for GA currently undergoing phase II and III clinical
trials29
.

12. 12
References
1.
Absent
from
final
version
2.
Avery
RL,
Pieramici
DJ,
Rabena
MD,
et
al.
Intravitreal
bevacizumab
(Avastin)
for
neovascular
age-­‐related
macular
degeneration.
Ophthalmology
2006;113:363-­‐
72
3.
British
National
Formulary
59
(March
2010).
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