This document summarizes recent information on drug pipelines and treatments for age-related macular degeneration (AMD). It discusses several drugs in clinical trials that aim to treat geographic atrophy, including fenretinide, ACU-4429, and POT-4. It provides details on a phase 2 clinical trial of NT-501 (ciliary neurotrophic factor) that showed stabilization of vision for patients with AMD. The document also discusses topical pazopanib eye drops and the implantable miniature telescope as potential therapies.

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

2. What’s New in AMD
• Online slides
– slideshare.net/rhodopsin
• Online notes
– richardtrevino.net
• Email me
– rctrevin@uiwtx.edu
• Disclosures
– None

3. What’s New in AMD
10. Drug Pipeline

4. Geographic Atrophy
Drug Pipeline
• Fenretinide (ReVision)
– Visual cycle modulator
• ACU-4429 (Acucela)
– Visual cycle modulator
• POT-4 (Potentia/Alcon)
– Complement-3 inhibitor (anti-inflammatory),
• NT-501 (Neurotech)
– Ciliary neurotrophic factor

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

6. Ciliary neurotrophic factor is delivered to the
retina via encapsulated cell technology

7. Encapsulated Cell
Technology

8. Drug Pipeline
• Zhang (2011)
– Multicenter, 1yr, double-masked, sham-controlled
dose-ranging, phase 2 study of CNTF therapy
– 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

9. Effect of intraocular
CNTF on visual
acuity stabilization.
(A) Subjects losing
<15 letters
(B) Subjects losing
<15 letters with
baseline BCVA at
20/63 or better.

10. 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

11. Topical Pazopanib
• Topical eye drop for exudative AMD currently
in Phase IIb clinical trials
• Safety and efficacy of pazopanib is being
compared to Lucentis
• Pazopanib is a receptor tyrosine kinase
inhibitor that targets VEGF, platelet-derived
growth factor, and c-kit receptors
• Preliminary results find that patients with the
low-risk CFH genotype respond best
http://clinicaltrials.gov/show/NCT01134055

13. “This preliminary study suggests that
topical treatment with pazopanib 0.5% is
safe, well tolerated, and may have a role as
an alternative for the treatment of CNV.”
Amparo F, et al. IOVS 2013;54:537

14. Aiello LP. NEJM 2008;359:967

15. What’s New in AMD
9. Implantable Miniature Telescope
10. Drug Pipeline

16. Implantable Miniature
Telescope
• The FDA approved the Implantable
Miniature Telescope (IMT) in 2010 for
patients 75yrs and older with stable
severe-to-profound vision impairment
(20/160 to 20/800) caused by bilateral
end-stage AMD
• Marketed as
CentraSight

18. Implantable Miniature
Telescope

19. Implantable Miniature
Telescope
• Implanted into one eye only (typically
the non-dominant or poorer seeing eye)
• Two models
available 2.2x or
2.7x
• Generates a 20°
to 24° FOV

20. Implantable Miniature
Telescope
• Most common adverse event is
persistent vision-impairing
corneal
edema
• 9.2% over
5yrs

21. Endothelial cell loss following implantation of IMT leads
to vision-impairing corneal edema in about 9% of patients
Another 20% lost over time
Immediate 20% cell loss
Implantable Miniature Telescope Professional Use Information, FDA-approved product labeling.

22. Implantable Miniature
Telescope
• Partial contraindications list
– Tx for CNV within the past 6 mos
– Anterior chamber depth (ACD) <3.0 mm
– Myopia > 6.0 D or hyperopia > 4.0 D
– Presence of corneal guttata
– Failure meet the minimum age (75 yrs),
visually significant cataract and endothelial
cell density requirements
Implantable Miniature Telescope Professional Use Information, FDA-approved product labeling.

23. Patient Diagnosis (Retinal
Specialist)
Evaluation & Eye selection
(Low vision specialist)
Implantation
(Cornea/Cataract surgeon)
Visual Training & Rehab (Low
vision occupational therapist)

24. Implantable Miniature
Telescope
• 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

25. Implantable Miniature
Telescope
• 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 and are at lowest risk of adverse events

26. Retinal Prosthesis

29. What’s New in AMD
8. Aspirin
9. Implantable Miniature Telescope
10. Drug Pipeline

30. 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

32. 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)
• Klein (2012) • Douglas (2007)
• de Jong (2012) • Rudnicka (2010)
Protective Effect
• Christen (2001)
• Christen (2009)

33. Aspirin & AMD
• Christen (2009)
– Women’s Health Study: 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
Christen WG. Ophthalmology. 2009; 116: 2386–2392.

35. Aspirin & AMD
• de Jong (2012)
– European Eye Study: 4691 participants aged
65 years and older in the population-based
cross-sectional 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

36. More Associated
frequent with greater
ASA use AMD risk

37. Aspirin & AMD
• Summary
– Biologically plausible basis for protective
effect (improved circulation, anti-
inflammatory)
– The literature does not reveal any
consistent pattern of benefit or harm of
aspirin use on AMD
– No scientific basis to advise AMD patients
to start or stop ASA

38. What’s New in AMD
7. Lifestyle
8. Aspirin
9. Implantable Miniature Telescope
10. Drug Pipeline

39. 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
– Hypertension
– Obesity
– Elevated markers of inflammation
Mares JA, et al. Arch Ophthalmol. 2011;129:470–480

40. Lifestyle & Behavioral
Factors
• 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

42. Lifestyle & Behavioral
Factors
• 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 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

43. LOWER RISK HIGHER RISK
Chakravarthy (2010): Meta-analysis of studies assessing risk of advanced
AMD (combined atrophic and exudative) associated with BMI.

45. Lifestyle & Behavioral
Factors
• Exercise
– Physical activity lowers cardiovascular disease risk,
which is possibly predictive of AMD.
– 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

46. Williams (2009)
Dose-response
relationship
Found lower
risk of AMD
with greater
number of
kilometers run
each day
Relative risk of
AMD by average
distance run per
day in 41,708
nondiabetic,
nonsmoking men
and women

47. Lifestyle & Behavioral
Factors
• Mares (2011)
– Cross-sectional study of 1313 women aged 55-74
years in the Women’s Health Initiative Observational
Study
– Having a combination of 3 healthy behaviors (healthy
diet, physical activity, and not smoking) was
associated with 71% lower odds for AMD compared
with having high risk scores
– A combination of healthy lifestyle practices might be
more important in reducing AMD risk than a focus on
any given one

48. Lifestyle & Behavioral
Factors
What’s
Good for the Heart
Is also
Good for the Eye!
Don’t smoke
Lose weight
Exercise regularly

49. What’s New in AMD
6. Sunlight and Cataract Surgery
7. Lifestyle
8. Aspirin
9. Implantable Miniature Telescope
10. Drug Pipeline

50. 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

51. Sunlight & Cataract
Surgery
• BDES (2004)
– Ten-year follow-up of 2764 participants in the
Beaver Dam Eye Study
– Greater sun exposure was associated with higher
risk of early AMD
– 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

52. Sunlight & Cataract
Surgery
• Fletcher (2008)
– European Eye Study: Cross-sectional study of 4700
people in 7 European countries
– Sunlight not hazardous if antioxidant levels are
adequate
– High sunlight exposure and low serum antioxidant
levels associated with 4-fold increased risk of wet
AMD
– Risk greatest with low levels of zeaxanthin, vitamin
E, and vitamin C
Fletcher AE., et al. Arch Ophthalmol. 2008;126:1396-1403

53. Sunlight & Cataract
Surgery
• Sui (2012)
– Meta-analysis of 14 studies investigating sunlight
exposure as a risk factor for AMD
– Greater sunlight exposure was associated with
higher risk of AMD (pooled odds ratio: 1.379)
– AMD risk from sunlight exposure significantly
decreased as gross domestic product (GDP) per
capita increased (p=0.048)
– Latitude (p=0.21) was significantly associated with
risk
Sui GY, et al. Br J Ophthalmol. 2012 Nov 10. [Epub ahead of print]

54. Sunlight & Cataract
Surgery
• Cataract Surgery
– The adult lens absorbs nearly 100% of light below
400nm
– Cataract surgery results in increased exposure to
short-wavelength light and
this 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

55. Sunlight & Cataract
Surgery
• 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
Chew EY, et al. Ophthalmology 2009;116:297–303

56. LOWER RISK HIGHER RISK
Chakravarthy (2010): Meta-analysis of studies assessing risk of advanced
AMD (atrophic and exudative) associated with cataract surgery.

57. Sunlight & Cataract
Surgery
• Blue-blocking IOL Controversy
– All modern IOLs filter UV radiation below 400nm
but most do not filter any visible light
– 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

58. Concerns have been raised that blue-blocking IOLs attenuate visual
performance under scotopic conditions, have undesirable effects on
color perception, and disrupt circadian entrainment
Turner (2008): Spectral sensitivity of photopic, scotopic and circadian (melatonin
suppression) photoreception

59. Sunlight & Cataract
Surgery
• Blue-blocking IOL Controversy
– 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

60. Sunlight & Cataract
Surgery
• Summary
– There is some evidence that cataract removal may
increase the risk of AMD
– This risk could be mitigated if IOLs filtered UV and
blue visible light, but this could cause other
problems (impaired night vision)
– The theoretical disadvantages of
blue-light filtering IOLs may be
minimized by filtering only violet light

61. What’s New in AMD
5. Lutein
6. Sunlight and Cataract Surgery
7. Lifestyle
8. Aspirin
9. Implantable Miniature Telescope
10. Drug Pipeline

62. Lutein
• Macular Pigment
– Lutein and zeaxanthin are the major components
of macular pigment
– Macular pigment may
protect the retina
from photochemical
damage by absorbing
blue light and by
quenching reactive
oxygen species

64. Lutein
• Weigert (2011)
– Dietary lutein supplementation can significantly
increase macular pigment optical density (MPOD).
– Patients with low MPOD at baseline experience
the greatest increase
– Patients with high MPOD at baseline experience
almost no increase
– Increasing MPOD is 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

65. Normal Range
50% increase
with low
baseline MPOD
Weigert (2011): Correlation between MPOD at baseline and the change in
MPOD after 6 months of lutein supplementation.

66. Expect 3%
improvement
in VA with 50%
increase in
MPOD
Weigert (2011): Correlation between the change in MPOD and the change in
VA after 6 months of lutein supplementation.

67. Lutein
• Loughman (2012)
– Supplementation with
all 3 carotenoids (lutein,
zeaxanthin, and meso-
zeaxanthin) can produce
larger gains in MPOD
than supplements not
containing meso-
zeaxanthin
Loughman J, et al. IOVS. 2012;53:7871

68. Superior performance of supplement containing
meso-zeaxanthin (MZ)
Loughman J, et al. IOVS. 2012;53:7871

69. Lutein
• CARMA (2012)
– Randomized double-masked placebo-controlled
clinical trial of Ocuvite in 433 participants with early
AMD over 3 years
• Ocuvite: 12 mg lutein, 0.6 mg zeaxanthin, 15 mg vitamin E,
150 mg vitamin C, 20 mg zinc, and 0.4 mg copper
– Mean change in BCVA and macular pigment favored
the supplemented group
– Fewer eyes in the Ocuvite group demonstrated
progression of AMD compared with the placebo
group, but this did not reach statistical significance
Beatty S, et al. Ophthalmology. 2012 Dec 5. [Epub ahead of print]

70. Placebo
Ocuvite
Progression of AMD in the CARMA study. The eyes of participants in the active
treatment arm progressed at a slower rate than the placebo arm, but the difference
was not statistically significant

71. Lutein
• Ma (2012)
– Meta-analysis of 6 longitudinal cohort studies
– 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.

72. PROTECTION HARM
PROTECTION HARM

73. Lutein
• Summary
– Lutein supplementation will improve MPOD in
patients with low levels of macular pigment, and
these patients will benefit visually from this
intervention
– Effect of lutein supplementation on AMD remains
unclear
• Only beneficial against late AMD?
• Being investigated in AREDS 2

74. Lutein
• Eller (2012)
– First report of peripheral yellow corneal rings
secondary to carotenoid supplementation
– Not associated with deduced vision or corneal
dysfunction. Long-term implications unknown
– Carotenoderma: Also known as “xanthoderma,” is
a benign and reversible yellowish-orange
discoloration of the skin caused by increased
levels of carotenoids .
Eller AW, et al. Ophthalmology 2012;119:1011

75. Eller AW, et al. Ophthalmology 2012;119:1011

76. What’s New in AMD
4. Fish
5. Lutein
6. Sunlight and Cataract Surgery
7. Lifestyle
8. Aspirin
9. Implantable Miniature Telescope
10. Drug Pipeline

77. Fish
• Fish oil is rich in omega-3 long-chain
polyunsaturated fatty acids (LCPUFA).
– Docosahexaenoic acid (DHA)
– Eicosapentaenoic acid (EPA) is a precursor to DHA
• LCPUFAs may protect against
oxygenic, inflammatory, and
age-associated pathology
– Hyperlipidemia, coronary
disease, HTN, CVA, others

78. Fish
• Chong (2008)
– Meta-analysis of 9 studies finds that consumption
of fish twice or more per week reduced risk of
both early and late AMD.
• AREDS (2009)
– Participants reporting the highest consumption of
omega-3 LCPUFA were about
30% less likely to develop
advanced AMD

79. Fish
• Christen (2011)
– Prospective study of 38,000 females over 10 years
– Consumption of 1 or more servings of fish per
week associated with a 40% lower risk of
developing AMD, compared with those who
consumed less than 1 serving of fish per month
Christen WG, et al. Arch Ophthalmol. 2011;129(7):921-929

80. 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) 40% 0.001
Dark-meat fish (salmon, tuna) 0.56 (0.32 – 0.99) lower 0.01
Canned tuna fish 0.56 (0.40 – 0.80) risk 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 once per week or greater
consumption to less than once per month consumption.
Christen WG, et al. Arch Ophthalmol. 2011;129(7):921-929

81. Fish
• Christen (2011)
“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

82. Fish
• NAT2 Study (2013)
– Randomized, placebo-controlled, double-blind
study of 263 patients between age 55 and 85
years with early AMD in one eye and wet AMD in
the fellow eye assigned randomly to receive either
fish oil capsules or the placebo for 3 years
• 840 mg/day DHA and 270 mg/day EPA
– CNV incidence was significantly reduced in fish oil
supplemented patients showing a steadily high
EPA plus DHA index over 3 years.
Souied EH, et al. Ophthalmology. 2013 Feb 7 [Epub ahead of print]

83. PROTECTION HARM
CNV incidence was significantly reduced in fish oil
supplemented patients showing a steadily high EPA
plus DHA levels over 3 years.

84. 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

85. What’s New in AMD
3. Anti-VEGF medications
4. Fish
5. Lutein
6. Sunlight and Cataract Surgery
7. Lifestyle
8. Aspirin
9. Implantable Miniature Telescope
10. Drug Pipeline

86. 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

87. 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
Brechner RJ, et al. Am J Ophthalmol 2011;151:887

88. CATT Study: 2yr Results
• Methods
– 1208 patients with neovascular AMD were
randomly assigned to one of four study groups:
• Lucentis monthly, Lucentis PRN
• Avastin monthly, Avastin PRN
– At 1 year, patients initially assigned
to monthly treatment were
reassigned randomly to monthly or
PRN treatment, without changing
the drug
Martin DF, et al. Ophthalmology 2012;119:1388

89. CATT Study: 2yr Results
• Results: Visual Acuity
– Monthly Avastin was equivalent to monthly
Lucentis, with 7.8 and 8.8 letters gained,
respectively.
– PRN Avastin was equivalent to PRN Lucentis, with
5.0 and 6.7 letters gained, respectively
– Mean gain in vision was greater with monthly
dosing than PRN dosing for both drugs
• Switching to PRN dosing after 1 year of monthly
treatment, with either drug, produced a mean 2.2-
letter decrease
Martin DF, et al. Ophthalmol. 2012;119:1388–1398

90. At 104 weeks the visual acuity of both PRN dosing groups are
significantly lower relative to the monthly groups
Martin DF, et al. Ophthalmol. 2012;119:1388–1398

91. CATT Study: 2yr Results
• Results: Anatomy
– The mean decrease in central retinal thickness
was greater in the Lucentis-treated patients than
in the Avastin-treated patients (p=0.08)
– All other anatomic results also
indicate superior efficacy of
Lucentis
• Resolution of fluid on OCT (P < 0.0001)
• Cessation of leak on fluorescien
angiography (P = 0.002)
Martin DF, et al. Ophthalmol. 2012;119:1388–1398

92. Lucentis has a stronger effect on leakage than Avastin
Martin DF, et al. Ophthalmol. 2012;119:1388–1398

93. CATT Study: 2yr Results
• Results: Safety
– Serious systemic adverse events were more
frequent with Avastin than with Lucentis
• Avastin: 39.9% vs. Lucentis 31.7%
– Thromboembolic events occurred in 4.7% of the
combined Lucentis and 5.0% of the combined
Avastin groups (P = 0.89)
– 5.3% of patients treated with Lucentis and 6.1% of
patients taking Avastin died (P = 0.62)
Martin DF, et al. Ophthalmol. 2012;119:1388–1398

94. The cumulative proportion of patients with 1 or more systemic serious
adverse events by originally assigned dosing regimen and drug.
Martin DF, et al. Ophthalmol. 2012;119:1388–1398

95. CATT Study: 2yr Results
• Does too much anti-VEGF medication cause
geographic atrophy?
– Monthly Lucentis: 30% with GA at 2yrs
– Monthly Avastin: 20%
– PRN Lucentis: 16%
– PRN Avastin: 14%
The possible association of anti-VEGF therapy with
GA is “one of the most interesting outcomes” from
the entire CATT trial.
Retinal Physician. Nov 2012

97. 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

98. “Conclusion: In contrast to [Lucentis], current safety
data for [Avastin] are incomplete and not yet robust. If
the medical community remains committed to using
intravitreal [Avastin], it is critical to establish that it
has an acceptable safety profile, supported by
evidenced-based medicine. Considerable further
research is warranted to achieve this.”
Mitchell P. Curr Med Res Opin 2011;27:1465

99. Avastin Safety
• Analysis of 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 vs. 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.

101. Avastin Safety
• Complications may occur
due to compounding and
storage practices
– One study found Avastin
users were 12x more
likely to develop severe
intraocular inflammation
– Large particulate matter
can obstruct aqueous
outflow and lead to
prolonged elevation of IOP
Sharma S. Presented at the Am Soc Retina Specialists, 2010

102. Avastin Safety
• Summary
– Significant safety concerns exist regarding off-label
intravitreal Avastin use
• Ocular toxicity, compounding
practice, systemic effects
– Intravitreal Avastin should
be used with caution

103. 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
– Clinical studies uniformly demonstrate decline in
visual acuity gains with less than monthly dosing

104. 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.

105. 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

106. Heier J, et al. Ophthalmology 2012;119:2537

107. Heier J, et al. Ophthalmology 2012;119:2537

108. Heier J, et al. Ophthalmology 2012;119:2537

109. Heier J, et al. Ophthalmology 2012;119:2537

110. Eylea
• Safety
– No significant difference in rates of ocular or
systemic adverse events when compared to
Lucentis
• Conclusions
– Eylea dosed every two months
was similar in efficacy and
safety to Lucentis dosed
monthly
Heier J, et al. Ophthalmology 2012;119:2537

111. What’s New in AMD
2. Genetics
3. Anti-VEGF medications
4. Fish
5. Lutein
6. Sunlight and Cataract Surgery
7. Lifestyle
8. Aspirin
9. Implantable Miniature Telescope
10. Drug Pipeline

112. Genetics
• Risk modeling
– Attempts 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

113. Genetic testing services use risk models to calculate your
risk of contracting various disorders based on genotype

114. Risk Models
• Genetic only
– Genetic risk factors are static throughout life
• Genetic plus other factors
– May include phenotype, behavioral and
environmental factors in the model
– Better short-term risk
assessment
– May reflect change in risk
over time (age, smoking
behavior, weight loss)

115. Risk Models
# Genes Environment AUC
Jakobsdottir (2009) 3 No 0.79
AREDS (2009) 6 Yes 0.81
Hageman (2011) 13 No 0.80
Klein (2011) 2 Yes 0.87
The larger the AUC the greater the accuracy of predictions
.90-1 = excellent (A)
.80-.90 = good (B)
.70-.80 = fair (C)
.60-.70 = poor (D)
.50-.60 = fail (F)

116. Model predicts 85%
chance of having CNV
Model predicts 20%
chance of having CNV
50-50 chance of having CNV
0% 100%
Hageman (2011): Red bars represent controls and blue bars
represent patients with CNV.

117. Are you better
off knowing
genotype or
phenotype?
Demographics &
Worse genotype known
Genetic
information
provides little
additional
Value added by genetic
Demographics & info once phenotype and predictive
Better phenotype known demographics is known
value once the
phenotype is
known
Klein (2011)

118. Risk Models
• Summary
– 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.
– May be of greatest value early
in life prior to phenotype
manifesting itself

119. 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)
– This is among the first pharmacogenetic studies to
suggest interaction between genotype and
treatment response
Klein ML, et al. Ophthalmology 2008;115:1019–1025

120. Response to the AREDS
supplement is related to
CFH genotype
-Low risk
Low risk
Low risk 23%
4%
Persons homozygous for the CFH high-risk allele (CC)
have a smaller treatment response than persons
homozygous for the CFH low-risk allele (TT)

121. Pharmacogenomics
• CFH & Avastin (2007)
– Patients homozygous for both CFH risk alleles (CC)
had worse visual outcomes
• CFH & Lucentis (2009)
– Patients
homozygous
for both CFH risk
alleles (CC) had
worse visual
outcomes

122. Shastry BS. Discovery Medicine. Aug 2011

123. Pharmacogenomics
• CATT Study (2013)
– 834 (73%) of 1149 patients participating in the
CATT were genotyped for CFH, ARMS2, HTRA1,
and C3
– No statistically significant differences in response
by genotype were identified for any of the clinical
measures studied (VA, anatomic response, #
injections)
– Genotype did not predict response to anti–VEGF
therapy in the CATT trial

124. Pharmacogenomics
• Summary
– Determining patients' genotype may be helpful in the
future in tailoring treatment for exudative AMD
• Higher risk therapies may be suitable for patients with
higher risk genotypes if it can be predicted that they will not
respond to standard therapy
– 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

125. What’s New in AMD
1. Vitamins
2. Genetics
3. Anti-VEGF medications
4. Fish
5. Lutein
6. Sunlight and Cataract Surgery
7. Lifestyle
8. Aspirin
9. Implantable Miniature Telescope
10. Drug Pipeline

126. 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

127. 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

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

129. Vitamin D
• Parekh (2007)
– Cross-sectional study of 7752 participants
– Highest vs lowest quintile of serum vitamin D
• Early AMD: 0.64 odds ratio 36% lower risk!
• Advanced AMD: 1.16 odds ratio
– Milk intake ‘less than weekly’ vs ‘daily or more’
• Early AMD: 0.75 odds ratio 25% lower risk!
Parekh N, et al. Arch Ophthalmol. 2007;125:661-669

130. 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, high serum
vitamin D concentrations 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

131. 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
– Serum vitamin D levels were higher in unaffected
siblings (not statistically significant)
– Genetic link between the vitamin D pathway and
AMD risk (SNPs in CYP24A1 increased risk)
Morrison MA, et al. Hum Genomics. 2011;5:538-568

132. Vitamin D
• Summary
– Strong evidence that higher serum vitamin D
levels associated with reduced risk of early 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

133. 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

134. B Vitamins
• Close relationship between AMD and CVD
– Common risk factors (Smoking, Obesity, HTN)
– Common antecedents (Inflammation, Oxidative
stress)
– Common interventions (Fish oil, diet, exercise,
weight)
– Speculation: AMD and CVD are two
manifestations of a single underlying chronic
inflammatory disease of aging

135. Hypothesis
AMD
CVD
Homocysteine

136. 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

137. B Vitamins
• Christen (2009)
– Women’s Health Study: 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

138. Cumulative incidence rates of confirmed AMD (left) and visually
significant (VS) AMD (right). After an average 7.3 yrs of follow-up
those women on treatment had a 35% lower risk of any AMD
and a 40% lower risk of visually significant AMD

139. B Vitamins
• Conclusion
– “Folic acid is the first identified means, other than
cigarette avoidance, to prevent the onset of AMD”
Christen WG. Arch Intern Med. 2009;169:335-341

140. B Vitamins
• 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)

141. B Vitamins
• What should I prescribe?
– WAFACS supplement is not commercially available
• 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12
– Recommendation: ≥200% RDA folic acid plus
≥100% RDA B12 (2.5 mcg)
• 200% RDA provides maximum Hcy-lowering effect of
folic acid
• B12 helps to balance effect of folic acid

142. Recommendation
≥200% RDA folic acid
≥100% RDA B12
Take 2 pills per
day to get
recommended
dosage

143. B Vitamins
• Summary
– Elevated serum homocysteine levels associated with
increased risk of neovascular AMD
– B vitamin supplements demonstrated to be
effective in the primary prevention of AMD
– B vitamin supplementation
may be recommended
for normal patients seeking
to reduce their risk of
developing AMD in the
future

144. What’s New in AMD
1. Vitamins
2. Genetics
3. Anti-VEGF medications
4. Fish
5. Lutein
6. Sunlight and Cataract Surgery
7. Lifestyle
8. Aspirin
9. Implantable Miniature Telescope
10. Drug Pipeline

145. Thank You!