Whats New in AMD - 2012

What’s New in AMD
Rick Trevino, OD, FAAO
School of Optometry
University of the Incarnate Word

What’s New in AMD

10. Drug Pipeline

“It is difficult to make predictions, especially about the future.”

Drug Pipeline
• Geographic Atrophy
– Fenretinide (ReVision)
• Visual cycle modulator, Phase 3 clinical trial
– ACU-4429 (Acucela)
• Visual cycle modulator, Phase 2 clinical trial (ENVISION
Clarity Trial)
– POT-4 (Potentia/Alcon)
• Complement-3 inhibitor (anti-inflammatory), Phase 2 clinical
trials
– NT-501 (Neurotech)
• Ciliary neurotrophic factor (neuroprotection), Phase 3 clinical
trials

Drug Pipeline
• NT-501 (Neurotech)
– Ciliary neurotrophic factor (CNF) is a potent
neuroprotective agent that affects the survival of
cells in the nervous system, including retinal cells
– Human cells genetically modified to secrete CNF
are placed within a semipermiable capsule which
is then implanted within the vitreous
– The sustained release capsule will deliver CNF to
the retina for a year or longer

neurotechusa.com

Ciliary neurotrophic factor is delivered to the retina via encapsulated cell technology
(ECT). ECT implants consist of human cells that have been genetically modified to
produce a specific therapeutic protein and encapsulated in a semi-permeable hollow
fiber membrane. The cells continuously produce the therapeutic protein which
diffuses out of the implant at the target site.

Drug Pipeline
• Zhang (2011)
– Multicenter, 1yr, double-masked, sham-controlled
dose-ranging, phase 2 study
– CNTF treatment resulted in a dose-dependent
increase in retinal thickness
– Average change in VA
• 0.8 mean letter gain in the high-dose group
• 9.7 mean letter loss in the combined low-dose/sham group
– VA stabilization rates (loss of <15 letters)
• 96.3% high-dose, 83.3% low-dose, 75% sham group

Zhang K, Proc Natl Acad Sci U S A. 2011;108:6241-5

Effect of intraocular
CNTF on visual acuity
stabilization.

(A) Percentage of subjects
losing <15 letters from
baseline over 12 mo.

(B) Significant effect of
CNTF on visual acuity
stabilization in the
high-dose group with
baseline BCVA at 20/63
or better.

Drug Pipeline
• Conclusion
– “These findings suggest that CNTF delivered by the
encapsulated cell technology implant appears to
slow the progression of vision loss in GA, especially
in eyes with 20/63 or better vision at baseline”

Zhang K, Proc Natl Acad Sci U S A. 2011;108:6241-5

What’s New in AMD

9. Implantable Miniature Telescope
10. Drug Pipeline

Implantable Miniature Telescope
• The FDA approved the Implantable Miniature
Telescope (IMT) in 2010 to improve vision in
patients 75yrs and older with stable severe-to-
profound vision impairment (20/160 to
20/800) caused by bilateral end-stage AMD
• IMT produced by VisionCare Ophthalmic
Technologies and marketed as CentraSight

The housing measures 3.6 mm in diameter and 4.4 mm in length in a PMMA carrier
with haptics measuring 13.5 mm in diameter designed to be implanted “in the bag”

• IMT is implanted into one eye only, as
determined by patient and doctor (typically the
non-dominant or poorer seeing eye)
• Functions as a fixed
focus 2.2x or 2.7x
telescope system
(2 models available)
• Generates a 20° to
24° field of view
(depending on mag)

• The size of the device requires a 12 mm limbal
incision and is closed with 10.0 nylon sutures
• Most common
adverse event is
persistent vision-
impairing corneal
edema (9.2%
5-year cumulative
probability)


Implantable Miniature Telescope Professional Use Information, FDA-approved product labeling.

• Partial contraindications list:
– Active CNV or tx for CNV within the past 6 mos
– Previous intraocular or cornea surgery
– Peripheral vision loss in the fellow eye
– Central anterior chamber depth (ACD) <3.0 mm
– Myopia > 6.0 D or hyperopia > 4.0 D in the operative eye
– Presence of corneal guttata
– Failure meet the minimum age (75 yrs) and endothelial cell
density requirements
• Age 75-84: 2000 cells/mm2
• Age ≥85: 1800 cells/mm2


• Requirements prior to surgery:
– Evidence of visually significant cataract (>Grade 2)
– Confirm geographic atrophy or disciform scar with
foveal involvement in both eyes
– Undergo training and assessment with low vision
specialist in the use of an external telescope for
the patient to make an informed decision
– Agree to participate in post-operative visual
training with a low vision specialist.

• IMT Treatment Program
STEP 1: Patient Diagnosis and Management : Retina
Specialist
STEP 2: Evaluation (Low Vision Assessment/Eye
Selection): Low Vision Optometrist
STEP 3: Implantation: Cornea/Cataract Surgeon
STEP 4: Visual Training/Rehabilitation: Low Vision
Optometrist and Occupational Therapist
– All providers must receive training before becoming a
CentraSight program provider

centrasight.com

• Patient selection
– Management of goals and expectations
– Visual function questionnaires, cognitive
evaluation, and depression screens
– Mobility evaluations
• Eye selection
– Worse eye: Less risk if procedure fails
– Better eye: Improved functioning if procedure
successful

Primo SA. Optometry. 2010;81:86-93

• Summary
– Supplements conventional low vision aids for
persons with end-stage bilateral AMD
– Significant surgical complications and post-
operative adverse events can lead to profound
vision loss
– Strict pre-operative evaluation protocols designed
to select those candidates most likely to succeed
with IMT

What’s New in AMD

8. Aspirin
10. Drug Pipeline

Aspirin & AMD
• Four major pharmacologic properties of
acetylsalicylic acid (ASA)
– Analgesic: Inhibits pain via multiple mechanisms
– Antipyretic: Lowers body temperature of persons with
fever
– Anti-inflammatory: Inhibition of
prostaglandins, generation of
lipoxins
– Antiplatelet: Decreases the
aggregability of platelets and
the formation of intra-arterial
thrombi

Schror K. Aspirin Update. International Press Workshop 2008

Aspirin & AMD
• Aspirin for the primary prevention of disease
– Prevent of cardiovascular events, reduce the risk of
some cancers, reduced risk of Alzheimer's disease
– Approximately 36% of adults take aspirin regularly for
primary prevention of disease
• Adverse effects of aspirin
– Gastrointestinal hemorrhage,
worsen hypertension, renal failure,
aggravate asthma, hemorrhagic
stroke
– Each year 16,500 deaths are
related to aspirin and NSAID use

Seshasai SR, et al. Arch Intern Med. 2012;172:209-16

Aspirin & AMD
Harmful Effect No Effect
• Feman (1972) • MPS Group (1986)
• Bloome (1978) • MPS Group (1990)
• Kingham (1988) • Klein (1991)
• Lewis (1988) • Hirvela (1996)
• AREDS (2000) • Klein (2001)
• de Jong (2012) • Douglas (2007)
Protective Effect • Rudnicka (2010)
• Christen (2001)
• Christen (2009)

Aspirin & AMD
• Antiplatelet effect
– Enhance circulation and decrease the risk of
vascular events could decrease the risk of AMD
– Risk of macular hemorrhage associated with use
of anticoagulants and aspirin
• Anti-inflammatory effect
– Aspirin could decrease the risk of AMD through
though its anti-inflammatory effects

Christen WG. Ophthalmology. 2009; 116: 2386–2392.

Aspirin & AMD
• Christen (2009)
– Effect of ASA use on AMD development
prospectively studied in a randomized, double-
masked, placebo-controlled trial of 39,876 healthy
adult women over an average of 10 years
– Low-dose aspirin had a non-significant 18%
reduced risk of visually-significant AMD compared
to women assigned to placebo (hazard ratio, 0.82;
95% CI, 0.64 to 1.06).


Aspirin & AMD
• de Jong (2012)
– Study AMD development in 4691 participants
aged 65 years and older in the population-based
cross-sectional European Eye Study in 7 European
communities
– Frequent aspirin use was associated with early
and wet late AMD, and the odds ratios rose with
increasing frequency of consumption

de Jong, et al. Ophthalmology. 2012;119:112–118

de Jong, et al. Ophthalmology. 2012;119:112–118

Aspirin & AMD
• Summary
– Biologically plausible basis for protective effect
(improved circulation, anti-inflammatory)
– ASA use does not increase the risk of macular
bleeding, but if bleeding occurs it may be more
severe if anticoagulants or ASA are being used.
– Studies to date do not clearly demonstrate either
a beneficial or harmful effect of low-dose ASA use
on the development or progression of AMD

What’s New in AMD

7. Lifestyle
8. Aspirin
10. Drug Pipeline

Lifestyle & Behavioral Factors
• Modifiable risk factors related to lifestyle that have
been associated with AMD
– Smoking
– Physical activity
– Diet
• AMD has been associated with
chronic diseases or conditions which
can be modified by lifestyle choices
– Cardiovascular disease
– Diabetes & Hypertension
– Obesity
– Elevated markers of inflammation

Mares JA, et al. Arch Ophthalmol. 2011;129:470–480

• Smoking
– Smoking is the most significant modifiable risk factor
for AMD
– Estimated that 29% of all AMD cases can be attributed
to smoking
– Dose-response: Increased risk with more pack-years
– Reversibility: Risk declines following smoking
cessation, but does not return to baseline
– Exposure to environmental (second-hand) smoke has
not been associated with AMD

Chakravarthy (2010): Meta-analysis of studies assessing risk of advanced
AMD (combined atrophic and exudative) associated with smoking.
CC: case control, CS: cross-sectional, PC: prospective cohort

Warning label on cigarettes sold in Australia

• Obesity
– Most but not all studies have found a positive
association between obesity and AMD
– Obesity may have a role in the development of
AMD because of its associated hyperleptinemia-
induced oxidative stress
– Decreasing abdominal obesity results in a lower
risk for AMD. Suggests a role of weight loss in
preventing the development of AMD

Peeters A, et al. Arch Ophthalmol. 2008;126(11):1554-1560

AMD (combined atrophic and exudative) associated with BMI.

Risk of offending patients when obesity is discussed

• Exercise
– Physical activity lowers cardiovascular disease
risk, which is possibly predictive of AMD.
• Activity improves various risk factors associated with AMD
risk : adiposity and blood pressure.
– Seddon (2003): vigorous activity
associated with a 25% reduction in
progression to advanced AMD
– BDES (2006): Regular physical
activity reduced the cumulative
incidence of exudative AMD

Williams (2009)
Dose-response
relationship
Relative risk of
AMD by average
distance run per
day in 41,708
nondiabetic, no
nsmoking men
and women

What’s
Good for the Heart
Is also
Good for the Eye!
Don’t smoke
Lose weight
Exercise regularly

What’s New in AMD

6. Sunlight and Cataract Surgery
7. Lifestyle
8. Aspirin
10. Drug Pipeline

Sunlight & Cataract Surgery
• Photochemical damage occurs when low
wavelength light is absorbed by photoreactive
pigments in the retina, such as lipofuscin, causing
release of reactive oxygen species
• Speculate that chronic
exposure to low wavelength
light may overwhelm normal
defense and repair
mechanisms
• Inconsistent association with
AMD risk

Chalam KV, et al. Eye & Contact Lens. 2011;37:225–232

• Sunlight exposure
– Chesapeake Bay Waterman Study (1992): Subjects
exposed to long-term high doses of blue light were
found to have a higher incidence of advanced AMD
– BMES (1998): Persons with sun-sensitive skin (burning
rather than tanning) demonstrated increased risk of
neovascular AMD
– Hirakawa (2008): Greater total lifetime exposure to
sunlight as objectively measured using facial wrinkling
associated with greater risk of late AMD

Hirakawa M. Br J Ophthalmol. 2008;92:630-634

• BDES (2004)
– Ten-year follow-up of 2764 participants in the
Beaver Dam Eye Study
– Persons exposed to the summer sun for >5 hrs per
day in youth or at baseline were at higher risk of
early AMD than those exposed <2 hrs per day
– A protective effect of hat and
sunglass use was found for
those participants with highest
amount of sun exposure

Tomany SC., et al. Arch Ophthalmol. 2004;122:750-7

• Fletcher (2008)
– Population-based study of 4700 people in 7
European countries
– High sunlight exposure and low serum antioxidant
levels associated with 4-fold increased risk of wet
AMD
– Sunlight not hazardous if antioxidant levels are
adequate
– Risk greatest with low levels of zeaxanthin, vitamin
E, and vitamin C

Fletcher AE., et al. Arch Ophthalmol. 2008;126:1396-1403

• Cataract Surgery
– The adult lens absorbs nearly 100% of light below
400nm
– Following cataract surgery increased
exposure to short-wavelength
light may increase the risk of
photochemical damage to the
retina
– Inconsistent association with
AMD risk

Bockelbrink A., et al. Surv Ophthalmol 2008;53:359-367

• AREDS (2009):
– Found no clinically important increased risk of progression
to advanced AMD after cataract surgery
– AREDS is the only prospective study in which the severity
of AMD was documented before and after cataract surgery
in a large number of cases with more than 5 years of
regular follow-up
– Absence of any consistent pattern in the direction of harm
across models reinforces the conclusion that AREDS data
provide little evidence that cataract surgery increases the
risk of progression to late AMD.

Chew EY, et al. Ophthalmology 2009;116:297–303

AMD (atrophic and exudative) associated with cataract surgery.

• Blue-blocking IOL Controversy
– Most modern IOLs filter UV radiation below
400nm.
– The crystalline lens turns yellow with age, thereby
blocking some blue light, while most IOLs are
transparent
– Blue-blocking IOLs are designed to
simulate transmission characteristics of
the adult non-cataractous human lens
offering theoretical AMD protection

Wong IYH, et al. Int Ophthalmol. 2011;31:73–82

Turner (2008): Spectral sensitivity of photopic, scotopic and circadian (melatonin
suppression) photoreception

• Blue-blocking IOL Controversy
– Concerns have been raised that blue-blocking IOLs
attenuate visual performance under scotopic
conditions, have undesirable effects on color
perception, and disrupt circadian entrainment
– There is currently no evidence of any clinically
harmful effects of blue-blocking IOLs
– There is currently no evidence of any clinically
beneficial effects of blue-blocking IOLs

Henderson BA. Surv Ophthalmol 2010;55:284-289

• Summary
– There is some evidence that removal of a
cataractous lens may increase the risk of AMD
progression due to an increase in retinal short
wavelength light exposure
– This risk could possibly be mitigated if IOLs filtered
UV and short wavelength visible light
– The theoretical disadvantages of blue-light
filtering IOLs may be minimized by filtering only
violet light

What’s New in AMD

5. Lutein
7. Lifestyle
8. Aspirin
10. Drug Pipeline

Lutein
• Macular Pigment
– As the major components of macular
pigment, lutein and zeaxanthin are concentrated
at the macula suggesting a possible role in
preventing the onset and progression of macular
disease.
– Laboratory data suggest an important role for
these two carotenoids in protecting the neural
retina from photo-oxidative damage by absorbing
blue light and by quenching reactive oxygen
species through powerful antioxidant activity.

Lutein
• Weigert (2011)
– Dietary lutein supplementation can significantly
increase macular pigment optical density (MPOD).
– Patients with the lowest MPOD at baseline experience
the greatest increase
– Patients with high MPOD at baseline experience
almost no increase, suggesting that lutein
incorporation in the retina is saturable
– Increasing MPOD may be associated with
improvements in visual function (including improved
VA) due to decreased chromatic aberration

Weigert A, et al. Invest Ophthalmol Vis Sci. 2011;52:8174–8178

Normal Range

Weigert (2011): Correlation between MPOD at baseline and the change in
MPOD after 6 months of lutein supplementation.

Weigert (2011): Correlation between the change in MPOD and the change in
VA after 6 months of lutein supplementation.

Lutein
• Ma (2012)
– Meta-analysis of 6 longitudinal cohort studies
evaluating the relationship between dietary intake
of lutein and zeaxanthin and AMD risk
– Relative risk for early AMD: 0.96 (0.78-1.17)
comparing the highest with the lowest category of
lutein and zeaxanthin intake
– Relative risk for late AMD: 0.74 (0.57-0.97)
– Dietary intake of lutein and zeaxanthin may
decrease the risk of late but not early AMD

Ma L, et al. Br J Nutr. 2012;107:350-9.

Lutein
• Summary
– Lutein supplementation will improve MPOD in
patients with low levels of macular pigment, and
these patients will benefit visually from this
intervention
– It remains unclear to what extent lutein
supplementation or MPOD influences the onset
and progression of AMD
• This question is being investigated in AREDS 2

What’s New in AMD

4. Fish
5. Lutein
7. Lifestyle
8. Aspirin
10. Drug Pipeline

Fish
• Fish oil is rich in omega-3 long-chain
polyunsaturated fatty acids (LCPUFA).
– Docosahexaenoic acid (DHA) is the major dietary
and structural omega-3 LCPUFA of the retina
– Eicosapentaenoic acid (EPA) is a precursor to DHA
• LCPUFAs may protect against
oxygenic, inflammatory, and
age-associated pathology

Fish
• Chong (2008)
– Meta-analysis of 9 studies finds that consumption of
fish twice or more per week and foods rich in omega-3
fatty acids was associated with a reduced risk of both
early and late AMD.
• AREDS (2009)
– Participants reporting the highest consumption of fish
oil were approximately 30% less
likely to develop advanced AMD
than participants reporting
the lowest fish oil consumption

Fish
• Christen (2011)
– Prospective study of 38,000 females over 10 years
– Women who consumed 1 or more servings of fish
per week, compared with those who consumed
less than 1 serving per month, had a relative risk
of AMD of 0.58
– Strongest observational evidence to date in
support of a possible role for intake of omega-3
long-chain fatty acids and fish in the primary
prevention of AMD

Christen WG, et al. Arch Ophthalmol. 2011;129(7):921-929

Fish
Diagnosis of Visually Significant Age-Related Macular Degeneration
According to Categories of Fish Intake in the Women’s Health Study
Intake of Fish Relative Risk (95% CI) P
Total fish 0.58 (0.38 – 0.87) 0.001
Dark-meat fish (salmon, tuna) 0.56 (0.32 – 0.99) 0.01
Canned tuna fish 0.56 (0.40 – 0.80) 0.001
Shrimp / lobster / scallops 1.28 (0.77 – 2.13) 0.69
Other fish 0.72 (0.51 – 1.01) 0.06

Comparing risk associated with less than once per month consumption
to once per week or greater consumption. Visually significant AMD is defined
as AMD severe enough to cause a decline in visual acuity to 20/30 or worse

Christen WG, et al. Arch Ophthalmol. 2011;129(7):921-929

Fish
• Summary
– Strong and consistent observational evidence that
fish and omega-3 fatty acid consumption is
protective against early and late AMD
– Value of fish oil
supplementation in
slowing progression to
advanced AMD is being
tested in AREDS 2

What’s New in AMD

3. Anti-VEGF medications
4. Fish
5. Lutein
7. Lifestyle
8. Aspirin
10. Drug Pipeline

Anti-VEGF Medications
• Bind to VEGF preventing it from binding to its
target receptor on endothelial cells
– Decrease growth of and leakage from CNV
– Prevents moderate and severe vision loss
– Frequently leads to vision improvement
• Three anti-VEGF drugs FDA-approved for
AMD, plus one used extensively off-label
– Pegaptanib sodium (Macugen)
– Ranibizumab (Lucentis)
– Aflibercept (Eylea, VEGF-Trap)
– Bevacizumab (Avastin)

Vascular endothelial growth factor (VEGF) binds to its receptor
(VEGFR2) on the surface of vascular endothelial cells and triggers
a number of metabolic pathways that promotes and supports the
growth of new blood vessels, a process known as angiogenesis

Avastin: Humanized mouse anti-VEGF monoclonal antibody
Lucentis: Antigen-binding fragment modified to increase affinity for anti-VEGF

Anti-VEGF Medications
• Which is better, Lucentis or Avastin?
– Both drugs have the same mechanism of action, but
very different structures
– Lucentis is much more expensive than Avastin
• Lucentis costs $2000 per dose compared to $50 for Avastin
• Introduction to Eylea
– The newest drug to be FDA approved for
AMD, became commercially available in November
2011
– Primary advantage is that it’s recommended dosage is
q2mos, compared to q1mo for Lucentis

Avastin is the most popular drug used in the treatment of neovascular AMD,
but the vast majority of the cost is for the much more expensive Lucentis

CATT Study
• NIH-sponsored head-to-head comparison of
Lucentis and Avastin
• The safety and efficacy of Lucentis for wet AMD
has been established by clinical trials
• Because of it’s significant cost
advantage, Avastin has become
the most popular drug in the USA
for the treatment of wet AMD
despite the absence of any large-
scale clinical trials supporting it’s
use.

Martin DF, et al. N Engl J Med. 2011;364:1897–1908

CATT Study
• Methods
– Multicenter, single-blind, non-inferiority trial
– 1208 patients with neovascular AMD were
randomly assigned to receive intravitreal Lucentis
or Avastin on either a monthly schedule or as
needed (PRN) with monthly
evaluation x 1yr
– 4 study groups:
• Lucentis monthly, Lucentis PRN
• Avastin monthly, Avastin PRN


CATT Study
• Results: Visual Acuity
– Avastin administered monthly was equivalent to
Lucentis administered monthly, with 8.0 and 8.5
letters gained, respectively.
– PRN Avastin was equivalent to PRN Lucentis, with 5.9
and 6.8 letters gained, respectively
– PRN Lucentis was equivalent to monthly Lucentis
• 1.7 fewer letters on PRN dosing
– The comparison between PRN Avastin and monthly
Avastin was inconclusive
• 2.6 fewer letters on PRN dosing


CATT Study
• Results: Anatomy
– The mean decrease in central retinal thickness
was greater in the Lucentis-monthly group (196
µm) than in the other groups (P = 0.03)
– All other anatomic results also
indicate superior efficacy of
Lucentis
• Resolution of fluid on OCT (P < 0.001)
• Cessation of leak on fluorescien
angiography (P < 0.001)

A stronger effect on leakage by Lucentis might eventually
lead to actual differences in visual acuity outcomes over time

CATT Study
• Results: Safety
– The proportion of patients with serious systemic
adverse events (primarily hospitalizations) was higher
with Avastin than with Lucentis
• Avastin: 24.1% vs. Lucentis 19.0%
• Risk ratio, 1.29; 95% CI, 1.01 - 1.66
– Life-threatening or disabling events occurred in 3.51%
of the combined Lucentis and 5.61% of the combined
Avastin groups (P = 0.04)
– 1.5% of patients treated with Lucentis and 2.5% of
patients taking Avastin died


CATT Study
• Two plausible interpretations of CATT results
– Avastin is almost as good as Lucentis, and costs less
• The differences in efficacy are not statistically or clinically
significant
• The differences in safety signals may be attributable to
chance, or imbalances in baseline health status
– Avastin is not as good as Lucentis with more adverse
reactions
• In light of significant anatomic differences it is hard to justify
calling the efficacy equivalent
• Safety data contain some worrisome and important signals
which should not be minimized or ignored

Avastin Safety
• Ocular safety concerns
– Episodic severe uveitis (sterile endophthalmitis)
• Clusters of cases have been documented associated with
specific batches of Avastin in the USA, Canada and Japan
• Trace endotoxin contamination suspected
– Sustained IOP elevation reported much more
frequently after Avastin injection than Lucentis
• Etiology unknown.
• Possibilities include low-grade inflammatory reactions, direct
drug toxicity or mechanical obstruction of the trabecular
meshwork

Avastin Safety
• Systemic safety concerns
– Retrospective analysis of 146,942 Medicare records
• 11% higher risk in all-cause mortality and 57% higher risk of
hemorrhagic stroke with Avastin vs Lucentis
– BEAT-ROP study
• Higher mortality rate with Avastin than laser (6.6% vs 2.6%)
– Cancer deaths
• Compared with chemotherapy alone, the addition of Avastin
was associated with an increased risk of fatal adverse
events, with a relative risk of 1.46

Lim LS, et al. Am J Ophthalmol. 2011;152:329-31.

Avastin Safety
• Summary
– Significant safety concerns exist regarding off-label
intravitreal Avastin use
• Ocular toxicity, compounding
practice, systemic effects
– Awaiting 2-year results of
CATT for clearer evidence of
relative safety and efficacy of
Avastin and Lucentis
– In the meanwhile, intravitreal
Avastin should be used with
caution

Eylea
• The importance of dosing
– Lucentis pivotal clinical trials utilized a monthly
monitoring and dosing paradigm
• Monthly injections create a significant hardship for
patients
• Intravitreal injections are not risk free
– Attempts to reduce the frequency of injection by
employing extended dosing paradigms guided by
eye examinations and monitoring
• Clinical studies uniformly demonstrate decline in visual
acuity gains with less than monthly dosing

Monthly dosing: MARINA study
Rosenfield PJ, et al. N Engl J Med. 2006;355:1419-1431

Quarterly dosing: PIER study
Regillo CD, et al. Am J Ophthalmol 2008;145:239–248

As-needed dosing: SAILOR study
Boyer DS, et al. Ophthalmology 2009;116:1731–1739

The HORIZON study was a 24-month extension of the FOCUS, MARINA
and ANCHOR trials. Treated patients were switched from fixed monthly
dosing to as needed upon entering HORIZON. Three groups of patients
were always treated, never treated, and cross-over patients who were
initially untreated and later treated.

Eylea
• Need for a neovascular AMD treatment option that can
maintain visual acuity gains with less frequent
intravitreal injections
– Frequent office visits pose a
challenge for patients in terms
of travel and visit time
– Retinal practices are burdened
with frequent visits
• Need a wet AMD therapy that
can deliver consistent efficacy
with a more convenient,
predictable, less frequent
monitoring and dosing regimen

Heier J. Regeneron Investor Briefing. 2/13/2011

Eylea
• Aflibercept (Eylea, VEGF-Trap)
– Receptor decoy
– Recombinant chimeric
molecule
– Contains the VEGF-binding
elements from VEGF
receptors 1 and 2 fused to
human antibody.
– Eylea binds all VEGF-A
isoforms and placental
growth factor

Zampros I, et al. J Ophthalmol. 2012;2012:319728

Top. A key binding domain of VEGFR1 and a key binding domain of VEGFR2 (left) are fused
for tight binding affinity for both VEGF-A isomers and PlGF (center). Two dual-domain arms
are used for one aflibercept molecule to mimic the natural receptor (right).

Bottom. The Fc portion of IgG1 (left) is fused to the two dual-domain arms (center)
resulting in the engineered molecule of aflibercept (right).

Eylea
• Phase 3 clinical trials
– Two identical studies in different geographic
regions
• VIEW 1: USA and Canada
• VIEW 2: Europe, Latin America, and Japan
– Test two doses at monthly injection frequency and
higher dose at bimonthly frequency for 1 year
– PRN dosing, with a dose administered at least
every 3 mos (but not more often than monthly), is
being evaluated during year 2 of the study


Eylea
• Safety
– No significant difference in rates of ocular or systemic
adverse events when compared to Lucentis
• Conclusions
– All Eylea dosing groups were demonstrated non-
inferior to monthly Lucentis
– Eylea dosed every two months
was similar in efficacy and safety
to Lucentis dosed monthly
– Potential for a new, more
predictable and less burdensome
treatment paradigm


What’s New in AMD

2. Genetics
4. Fish
5. Lutein
7. Lifestyle
8. Aspirin
10. Drug Pipeline

Genetics
• Besides age, genetic background is the most
significant non-modifiable risk factor for AMD
– Smoking is the most significant modifiable risk factor
• The degree of heritability and the relative role of
genetic and environmental factors is still
unknown
• Seddon (2005): US Twin Study of AMD
– Genetic factors explain 46% - 71% of disease severity
– Environmental factors explain 19% - 37%

Genetics
• Genes associated with AMD
– Alternative complement pathway
• CFH, C2, CFB, C3, CFI
– ARMS2/HTRA1 region
• Function unknown
– High density lipoprotein (HDL) cholesterol pathway
• LIPC, ABCA1, CETP
– Extracellular matrix pathway
• TIMP3, COL10A1, COL8A1
– Angiogenesis pathway CFH and ARMS2/HTRA1
• VEGFA account for approximately
40% to 60% of the genetic
– Vitamin D pathway risks of AMD in whites
• CYP24A1

Yu Y, et al. Invest Ophthalmol Vis Sci. 2012 Jan 12. [Epub ahead of print]

60

50

AMD ODDS RATIO (%)
40

30

20

10 TT

GT
0 ARMS2
TT GG
TC
CFH CC

Risk of AMD based upon ARMS2 and CFH genotype
Rivera A, et al. Hum Mol Genet. 2005;14:3227-36

Genetics
• Risk modeling
– Mathematical models that attempt to predict the risk of
developing advanced AMD based upon
genetic, phenotypic and behavioral factors
• Pharmacogenomics
– Attempts to define the
genetic variants that
determine variable response
to medication.
– The ultimate goal is to
identify those who respond
best and avoid adverse
reactions

Risk Models
• Use of mathematical models to predict risk of
developing advanced AMD based upon genotype
and environmental risk factors
• A genetic test identifying individuals at high risk
of developing CNV holds
the promise for earlier
detection through risk-based
surveillance protocols and
improved outcomes from
more timely intervention

Genetic testing services are currently
available, including tests for AMD

Risk Models
• Two types of models
– Genetic only
• Risk factors are static through life and not subject to
misreporting
– Genetic plus other factors
• May include phenotype, behavioral and environmental
factors in the model
• Potential for improvement of short-term risk
assessment
• Unclear how to account for change over time (smoking
behavior, weight loss)

Risk Models
• Jakobsdottir (2009)
– Genetic only model using 3 SNPs
– AUC: 0.79 (a measure of how well a test can
distinguish between cases and controls)
• Seddon (2009)
– Joint gene–environment model using six-SNPs
– AUC: 0.81
– Can distinguish between “progressors” and “non-
progressors” and between non-disease controls from
patients with advanced AMD

Risk Models
• Hageman (2011)
– Genetics only model using 13 SNPs
– AUC: 0.80
– Achieves clinical performance comparable with
models with fewer SNPs that include self-reported
and/or non-static risk factors
• Klein (2011)
– Joint gene-environment model using two-SNPs
– AUC: 0.87

Hageman (2011): Probability of CNV using genetic-only model. Red bars
represent controls and blue bars represent patients with CNV.

Are you better
off knowing
genotype or
phenotype?
Demographics &
genotype known
Klein (2011):
Genetic
information
provides little
additional
Demographics & predictive
phenotype known value once
the
phenotype is
known

Risk Models
• Summary
– Using genetic information alone it is possible to
construct a model that achieves performance
comparable to models that include self-reported
and/or non-static risk factors.
– Once phenotype is known, genetic
information is of little additional
predictive value.
– Risk calculators can identify
high-risk individuals for more
frequent surveillance and clinical
interventions.

Pharmacogenomics
• CFH & AREDS Supplement
– Persons homozygous for the CFH high-risk allele (CC)
have a smaller treatment response to the AREDS
vitamin/mineral supplement than persons
homozygous for the CFH low-risk allele (TT)
– Supplementation was associated with a greater risk
reduction of AMD progression (68%) among those
with the low-risk TT genotype compared with those
with the high-risk CC genotype (11%)
– This is among the first pharmacogenetic studies to
suggest interaction between genotype and treatment
response

Klein ML, et al. Ophthalmology 2008;115:1019–1025

Response to the AREDS supplement is related to
CFH genotype

-Low risk
Low risk 23%
4%
Low risk

Persons homozygous for the CFH high-risk allele (CC)
have a smaller treatment response than persons
homozygous for the CFH low-risk allele (TT)

Pharmacogenomics
• CFH & Avastin
– 86 patients being treated with bevacizumab
(Avastin) were evaluated for associations between
treatment response and polymorphisms in the
genes CFH and ARMS2.
– Patients homozygous for both CFH risk alleles (CC)
had worse visual outcomes than those with the
CFH TC and TT genotypes.

Brantley MA, et al. Ophthalmology. 2007;114:2168-73

Pharmacogenomics
• CFH & Lucentis
– 156 patients receiving ranibizumab (Lucentis)
– Patients homozygous for both CFH risk alleles (CC)
had worse visual outcomes than those with the
CFH TC and TT genotypes
– These results suggest that determining patients'
CFH genotype may be helpful in the future in
tailoring treatment for exudative AMD with
intravitreal ranibizumab

Lee AY, et al. Br J Ophthalmol. 2009;93:610-3

Shastry BS. Discovery Medicine. Aug 2011

Pharmacogenomics
• Summary
– Genetic information may be used to tailor
strategies for predictive testing, treatment, or
prevention.
• Who should be treated and with which drug
– Concerns regarding loss of privacy, impact on
employment and insurance discrimination.
• Social, ethical, and economical issues such as genetic
discrimination needs to be addressed by regulatory
agencies.

Shastry BS. Discovery Medicine. Aug 2011

What’s New in AMD
1. Vitamins
2. Genetics
4. Fish
5. Lutein
7. Lifestyle
8. Aspirin
10. Drug Pipeline

Vitamins
• Vitamin D
– Has antiangiogenic, antioxidant and anti-
inflammatory effects
– Low vitamin D levels associated with AMD
• B vitamins
– Capable of significantly lowering serum levels of
homocysteine
– Elevated homocysteine levels are thought to
induce vascular endothelial dysfunction, and has
been associated with increased risk of AMD

Vitamin D
• Vitamin D has many diverse metabolic effects
– Bone mineralization and the regulation of Ca2+
and phosphorus
– Antiangiogenic, antioxidant and anti-inflammatory
effects
– Role in cellular proliferation, differentiation and
apoptosis
• Biologically plausible that vitamin D may
influence AMD risk

The 3 major sources of
vitamin D are:
• Sunlight
• Milk
• Supplements

Vitamin D
• Parekh (2007)
– Cross-sectional study of serum vitamin D and early
and advanced AMD from 7752 participants in NHANES
– Highest vs lowest quintile of serum vitamin D
• Early AMD: 0.64 (95% CI, 0.5-0.8) odds ratio
• Advanced AMD: 1.16 (95% CI, 0.5-3.1) odds ratio
– Milk intake ‘less than weekly’ vs ‘daily or more’
• Early AMD: 0.75 (95% CI, 0.6-0.9) odds ratio
– Vitamin D supplements protective against early AMD
only in individuals who did not consume milk daily
Parekh N, et al. Arch Ophthalmol. 2007;125:661-669

Vitamin D
• Millen (2011)
– Serum vitamin D levels were assessed 6 years prior to
AMD status in 1313 women aged 50-79 at baseline.
– In women <75 yo, having serum
vitamin D concentrations >38 nmol/L
was associated with a 48% decreased
odds of developing early AMD
– No association found between early
AMD and reported time spent outside
in direct sunlight

Millen AE, et al. Arch Ophthalmol. 2011; 129: 481–489

Vitamin D
• Morrison (2011)
– Cohort of 481 extremely phenotypically discordant siblings
• One sibling has wet AMD and other sibling has no AMD
– UV irradiance was protective of wet AMD
• Some UVB exposure, necessary for dermal vitamin D
synthesis, may be protective for AMD when the eyes are protected
– Serum vitamin D levels were higher in unaffected siblings
(not statistically significant)
– SNPs in CYP24A1 (enzyme in the vitamin D pathway)
increased AMD risk.
• First genetic association between vitamin D and AMD risk.

Morrison MA, et al. Hum Genomics. 2011;5:538-568

Vitamin D
• Summary
– Strong evidence that higher serum vitamin D levels
associated with reduced risk of early AMD
• Suggestion of protective effect for
neovascular AMD
– Increased consumption of milk
and vitamin D supplements may
decrease AMD risk
– Sunlight exposure may be protective
against AMD if eye protection is
worn (UV and blue blocker)

B Vitamins
• Among many other effects, B vitamins have the
ability to lower serum homocysteine levels
• Homocysteine is an amino acid that has been
found to promote inflammation and oxidative
stress in the body
• Elevated homosysteine levels have been
associated with
higher risk of
cardiovascular
disease and
stroke

Elevated homocysteine levels lead to increased oxidative stress, inflammation, and
increased thrombotic tendency. These all increase the risk of endothelial injury and
dysfunction.

B Vitamins
• Close relationship between AMD and CVD
– Common risk factors
• Smoking, Obesity, HTN, CRP
– Common antecedents:
• Inflammation, Oxidative stress, Vascular endothelial
dysfunction, Genetics
– Common interventions
• Fish oil, heart-healthy diet, exercise, weight loss
– Speculation: AMD and CVD are two manifestations of a
single underlying chronic inflammatory disease of aging
– Hypothesis: If Hcy is assoc with CVD, and if CVD is assoc
with AMD, then Hcy may be assoc with AMD

B Vitamins
• Observational evidence
– Studies finding AMD associated with elevated Hcy
1. Axer-Siegel (2004) wet AMD only
2. Nowak (2005) wet AMD only
3. Vine (2005) wet and dry AMD
4. Coral (2006) wet AMD only
5. Kamburoglu (2006) wet and dry AMD
6. Seddon (2006) intermediate or advanced AMD
7. Rochtchina (2007) advanced AMD in persons <75yo
8. Ates (2009) wet AMD only
9. Javadzadeh (2011) wet AMD only
– Studies not finding an association
1. Heuberger (2002) NHANES, few late AMD cases, non-fasting
2. Wu (2007) BMES, few late AMD cases

B Vitamins
• Christen (2009)
– RCT of 5205 women without AMD at baseline
randomized to receive folic acid or placebo for
7.3yr
• 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12
– Women assigned to B vitamin supplementation
had a statistically significant 35% to 40%
decreased risk of developing AMD

Christen WG. Arch Intern Med. 2009;169:335-341

Cumulative incidence rates of confirmed AMD (left) and visually significant
(VS) AMD (right). 137 cases of AMD appeared during follow-up, including 70
visually significant (20/30 or worse). After an average 7.3 yrs of follow-up
those women on treatment has a 35% lower risk of any AMD and a 40% lower
risk of visually significant AMD

B Vitamins
• Folic acid is the first identified means, other
than cigarette avoidance, to prevent the onset
of AMD
• Should I prescribe this to my patients?
– As with any prophylactic therapy, the risk, cost
and convenience of the treatment must be
weighed against the risk posed by the disease
– Should be avoided by cancer patients and those
on antifolate medications (eg. methotrexate)
Christen WG. Arch Intern Med. 2009;169:335-341

B Vitamins
• What should I prescribe?
– WAFACS supplement not commercially available
• 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12
– Maximum Hcy-lowering effect: 0.8mg (200% RDA)
• RDA: 0.4 mg (400 mcg)
– Tolerable upper intake of folic acid: 1mg
• From all sources (food, supplements)
• B12 not required if upper limit not exceeded
– Recommendation: ≥200% RDA folic acid plus
≥100% RDA B12 (2.5 mcg)

If you want to prescribe the WAFACS supplement: 5 pills/day

WAFACS: 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12

Recommendation
≥200% RDA folic acid
≥100% RDA B12

WAFACS: 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12

B Vitamins
• Summary
– Elevated serum homocysteine levels associated
with increased risk of neovascular AMD
– B vitamin supplements demonstrated to be
protective against developing AMD
– B vitamin supplementation
may be recommended
for normal patients seeking
to reduce their risk of
developing AMD

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