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Contemporary Treatment Options for Dry and Wet ARMD
Steven Ferrucci, OD, FAAO
Chief, Optometry
Greater Los Angeles VA Healthcare System
Sepulveda VA Ambulatory Care Center
16111 Plummer St 112E
Sepulveda, CA 91343
(818) 891-7711 x 7744
Assistant Professor
Southern California College of Optometry
Fullerton, CA 92831
steven.ferrucci@ va.gov
Dry ARMD
Vitamins
 AREDS Study showed 25% decreased risk reduction in developing advanced ARMD in
categories 3 and 4 with antioxidants plus Zinc
 Other studies have also looked at role of lutein and zeaxanthin with promising results
 LAST Stud y
 AREDS II
 Many commercial preparations are available
Risk Factors
 Smoking has been shown to be a risk factor for both onset and progression of ARMD in
several studies
 Num ber one m odifiable risk factor
 Other risk factors include
 Increase BMI
 Higher level of dietary fat
 Increased red m eat consum ption
 Shown to be beneficial in several studies
 Increased fish intake, esp salm on (om ega 3s)
 Nuts (reservatol)
 Bananas
 Still considering
 Oral anti-inflamm atories
 Statins
 Alcohol
Rheophoresis
 Blood filtration system used to treat intermediate to late stage dry ARMD
 Proposed Mechanism:
 elim inates known risk factors and suspected pathoph ysiology relevant factors of ARMD b y
decreasing plasma viscosity
 m ay also have im pact on choroidal perfusion
 43 patients age 50 to 85
 Multi-centered, randomized, double-masked, placebo controlled trial
 Patients were assigned to receive either 8 rheophoresis or 8 placebo procedures over l0
weeks
 Primary Eyes
 m ean logMAR difference between rheophoresis and placebo was 1.6 lines at 1 year
 13% of rheophoresis vs 0% palcebo eyes had > 3 line increase in BCVA
 4% of rheophoresis vs 18% of placebo- control e yes had > 3 line loss in BCVA
 In eyes with baseline worse than 20/40
• mean logMAR difference between rheophoresis and placebo was 3.0 lines at 1 year
• 16% of rheophoresis vs 0% palcebo eyes had > 3 line increase in BCVA
• 5% of rheophoresis vs 29% of placebo- control eyes had > 3 line loss in BCVA
• 58% of rheophoresis vs 14% of placebo-controlled eyes improved to 20/40 or better
 No serious adverse events were observed
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Appears safe and well tolerated
Provides a statistically and clinically relevant improvement in BCVA
Provided an effect that was evident immediately post-treatment
The benefit remained stable throughout the year
Continuation of study is indicated with more patients and longer follow-up
Anecortave acetate
 Angiostatic steroid for the inhibition of ocular neovascularization
developed by Alcon as Retaane®
 Administered by juxtascleral injection with special cannula
 Newest studies looking at if AA is safe in arresting non-exudative ARMD in patients at highrisk for developing wet ARMD
 4 year study with 1500 patients
Laser Treatment
 Several studies throughout the years have looked at using low intensity laser prior to
development of CNVM
 Choroidal Neovascular Prevention Trial
 Suspended after 1 yr due to increase in CNVM in treated group
 Drusen Laser Study
 Also halted early due to excessive CNVM in treatm ent arm
 The Complications of Age-Related Macular Degeneration Prevention Trial (CAPT)
 Look s at whether low-intensity laser treatm ent to the retina can prevent the advanced
ARMD
 NEI/NIH sponsored study with over 1000 people
• After 5 yrs 20.5 % of treated and untreated eyes had lost 3 or more lines of acuity
• 20% of both treated and untreated pts progressed to advance ARMD
• NEI Released statement in Nov 2006 “Low intensity laser treatment is ineffective in
preventing complications of ARMD or loss of vision”
 The Prophylactic Treatment of ARMD Study
 Expansion from a sm all pilot stud y that showed that infrared diode laser m acular grid
photocoagulation in patients with dry ARMD reduced visible drusen levels and visual acuity
 Prelim inary results showed increased risk of CNVM in laser treated e yes
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Wet ARMD
Macular Photocoagulation
 Macular Photocoagulation Study 1986:
 In two trials, statistically significant, but m odest, im provem ent over natural progression of
disease
 Goal was to treat entire lesion, including 100 m icrons beyond the lesion with uniform white
lesions representing full thickness burns.
 189 eyes
 3 m onths 20/320 with treatm ent vs 20/200 untreated
 24 m onths 20/320 vs 20/400
• treated eyes decreased an average of 3 lines from baseline vs 4.4 with no treatment
• treated eyes however experienced an immediate 3 line decrease
 Long term modest benefit must be weighed against immediate loss of vision
Photodynamic Therapy (PDT)
 PDT is a two-step procedure
 IV adm inistration of a photosensitizing agent
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Activation with a laser light source
 FDA Approved late 1999/early2000
 Currently Verteporfin (Visudyne by Novartis is only FDA approved agent
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Power of 600 mW /cm2
 Duration of 83 seconds
 Spot size determined by FA
 m easure greatest linear dim ension of lesion
 add 100 m icrons
 m ust leave at least200 m icrons untreated tem poral to ONH
Classic CNVM
 At 24 months, significant benefit shown with predominately classic CNVM
 Moderate vision loss (3 lines of VA)
 41% with treatm ent vs 69% no treatm ent
 Severe Vision Loss (> 6 lines of acuity)
 15% with treatm ent vs 36% without
 Legal blindness
 44% with treatm ent vs 68% without
 1 year: No statistical difference
 2 years:
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Occult CNVM
Moderate Vision Loss (3 lines)
• 54% with treatment vs 67% without
Severe Vision Loss (> 6 lines)
• 30 % with treatment vs 46% without
Legal blindness
• 28% with treatment vs 48% without
Final Visual Acuity
• 20/126 vs 20/200
Anti-Angiogenic Agents
Macugen® (pegatanib sodium)
 Anti-vasoactive endothelial growth factor (VEGF) aptamer
 Developed by OSI Pharmaceuticals, co-marketed with Pfizer
 Delivered by intravitreal injection
 FDA Approved December 2004
 Comm ercially available February 2005
 VISION Study: Two concurrent double-blind, multi-center, clinical trials
 117 sites in US, Canada, Europe, Israel, Australia and South Am erica
 1186 pts > age 50 with CNVM and VA from 20/40 to 20/320 in stud y e ye and 20/800 or
better in other eye
 Patients randomly assigned to either sham injection or intravitreous injection of Macugen
 Intravitreous injections of 0.3 mg, 1.0 mg and 3.0 mg every 6 weeks for 48 weeks (8
injections)
 Primary endpoint is loss of less than 15 letters of visual acuity at 54 weeks
 Loss of less than 15 letters( primary endpoint)
 0.3 m g
70%
 1.0 m g
71%
 3.0 m g
65%
 Control
55%
 Maintain or gain vision
0.3 mg 33%
1.0 mg 37%
 3.0 m g
31%
 Control 23%
 Additional findings
 Effectiveness was evident after the first injection and increased over tim e
 No evidence that an y angiographic type of lesion, size of lesion, or acuit y at baseline
precluded treatment benefit
 Evidence of slowing in growth of lesion, size on CNVM lesion, and severit y of leakage on
FA at weeks 30 and 54
 Rate of discontinuation in Study only 1% in both treatment and sham group
 No system ic adverse effects
 Adverse events were mostly mild to moderate, and transient
 attributed to the injection procedure rather than the drug itself.
 Endophthalmitis
 1.3 % (12/890) of patients receiving injections
 m ost comm only happened when lid speculum not used
 Retinal detachment 0.08%
Traumatic lens injury 0.07%
 Macugen offers statistically significant and clinically meaningful benefit in a wide variety of
patients with neovascular ARMD
• regardless of CNVM subtype, size or baseline acuity
• potential injection-related complications are present, so deserve vigilance
• Every 6 weeks for 2 years
 Eight to nine injections / year m ay be indicated
• Cost: VA medication alone is $780. Most places $1200 med plus fees
Lucentis (ranibizumab)
 Antibody fragment which blocks VEGF activity
 Less specific than Macugen, so perhaps m ore efficacious
 Delivered by intravitreal injection
 Developed by Genentech and marketed by Novartis
 FDA Approved June 30, 2006
 ANCHOR Study (classic CNVM)
 2 Year Phase 3 random ized stud y
• 94% of pts treated with 0.3 mg had stable or improved vision vs 64% with Visudyne
• 36% had gain of 15 letters or more
• Avg acuity gain was 11.3 letters vs 9.5 letters lost with Visudyne at one year
• 31% had VA of 20/40 or better vs only 3% with Visudyne
 MARINA Study (minimally classic/occult)
 95% of treated pts vs 62% of controls had less than 15 letter loss
 25% treated vs 4.6% of controls had 3 line gain
 At 2 yrs, 6.6 letter gain with tx vs 14.9 letters lost without
 FOCUS: PDT alone vs PDT w/ Lucentis
 90% had less than 15 letters lost with both vs only 68% with PDT alone
 Gain of 15 letters: 24% with com bo vs 5.5% with PDT alone
 Avg gain of 4.9 letters with com bo vs 8.2 loss with PDT alone
 PIER Study: looking at alternative dosing
 Side effects
 Conjunctival hem orrhage
 Eye pain
 Vitreous floaters
 Increased IOP
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Intraocular inflammation
Serious adverse effects such as endophthlamitis, retinal detachments and traumatic
cataracts in less than 0.1% of patients
 Results are promising, with better results than Macugen
 Possible issue with systemic safety?
 Increase MI, CVA in studies
 Recommended injection every 4-6 weeks fro 2 yrs
 Cost: approx $2500 for medication alone
Avastin (bevacizumab)
 Drug currently FDA approved for the treatment of metastatic colorectal cancer (Genentech)
 Parent drug of Lucentis
 Being investigated as treatment for CNVM due to its anti-VEGF properties
 No large scale studies yet, but widely used off label
 Ophthalmology June 2005: SANA Study
 open label, uncontrolled single center study
 Bascom Palm er, Univ of Miam i
 9 patients with subfoveal CNV
 m ean age 78
 8 wom en, 1 m an
 20/80 VA
 3 infusions 5 m g/k g at 2 week intervals
 at 12 weeks
 no serious ocular or systemic events
 8 (89%) e yes with 1 line
 3 (33%) e yes with 3 line im provem ent
 1 e ye stable
 Decrease in retinal thickness on OCT
 Now being injected intravitreally off label for m yriad of ocular conditions
 CRVO, ARMD, BRVO, CSME
 Recent reports suggest it is the most effective agent, surpassing both Macugen and Lucentis
 Major advantage is COST
 $15-$50 per 0.3 m l injection
 Approx $1k for Macugen/$2.5K for Lucentis
 Role with PDR also being investigated
 Issue is there are no large prospective study to judge its efficacy and safety
 NEI recently announced it would fund study com paring Lucentis to Avastin
 System ic concern is thrombolytic events
• Amount used in vitreous is 300-400 fold lower than that administered IV
 Some controversy remains
 Still, continues to be used widely
 No studies yet to indicate proper dosing
 At VA, one injection/mos x 3 mos. Then repeat FA/OCT and evaluate for additional treatments
 Also, no h/o MI or CVA within 6 m os
 NEI announced plan to do head to head comparison of Leucentis vs Avastin
Squalamine
 Systemically administered anti-angiogenic drug
 Discovered in shark fin
 Developed b y Genaera Corporation
 Marketed as Evizon
 Adm inistered intravenously
 Phase 1 and II Trials
 Sm all trial, 13 patients
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Dosing was 4 weekly doses
• 97% had preserved or increased VA after 2 months
• 33% had at least a 3 line improvement in VA
 Study combining Evizon with PDT
 Systemic issues of concern
 Small study combining Evizon with PDT
 29 weeks slight im provem ent of vision
 90% stable vision throughout study
 Only 10% of those with Evizon and PDT needed retreatm ent vs 47% without Evizon
VEGF Trap
 Systemic VEGF inhibitor
 Binds tighter than either Macugen or Lucentis, so other growth factors besides VEGF are
blocked
 Administered IV, so side effects are of concern
 Unclear if can be injected into eye due to large size of molecule
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siRNA
 RNA factors which attempt to turn off growth factors at the source, rather than trying to inhibit
growth
 Currently in phase 1 studies
Triamcinolone Acetonide
 Steroids have anti-angiogenic properties as well as anti-inflammatory properties
Triamcinolone (kenalog)has been used in eye care for long time for treatment of CME secondary
to surgery or uveitis
 4 mg of triamcinilone injected intravitreal in 16 pts with VA 20/40 to 20/400 from ARMD
 at 6 m onths VA im proved 0.04 logMar units in treated eyes vs 0.39 decline in untreated
eyes
 Side effects included cataract form ation and IO P increase in 25% of patients, all c ontrolled
with ocular anti-hypertensive agents
 Therefore, appears promising
Anecortave acetate
 New angiostatic steroid for the inhibition of ocular neovascularization
 developed b y Alcon as Retaane®
 Administered by juxtascleral injection with special cannula
 No glucocortecoid activity, so no increase in IOP
 Long half-life, so can be injected in 6 month intervals
 Phase II results
 looked prim arily at classic CNVM
• at 6 mos, 88% of those treated had stable or improved VA vs 70% of controls
 18% gained 3 lines vs 0% am ong control
• at 12 mos, 79% of those treated had stable or improved VA vs only 53% of controls
• at 24 mos, 73% of those treated had stable or improved VA vs only 47% of controls
 15 m g dose work ed better than 3 or 30 m g dose
 Patients > 50yrs old
 VA 20/40 t0 20/320
 Predominately classic CNVM
 3 mg, 15 mg, and 30 mg juxtascleral injection
 In 15 mg injection group
 73% with tx vs 47% control dem onstrated less than 3 line acuit y loss
 6% vs 23% control had SVL(> 6 lines)
 on FA, lesion size was found to be reduced with tx
 no penetration of globe, so no endophthalm itis
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avg # of injections was 2/yr
 Retaane vs Visudyne study
Patients > 50 yrs old
20/40 to 20/400 acuity
 12 m os out
 45% of patients treated with Retaane had stable vision (> 3 line loss) vs 49% with PDT
 Therefore, Retaane alm ost as effective as PDT
 FDA approved in Australia for the Treatment of CNVM due to wet ARMD when there is a
classis component
 Currently being evaluated in US by FDA
Macular Translocation Surgery
 Designed to rotate the retina away from a CNVM lesion onto healthy RPE
 Initial reports were very favorable, with as much as six lines of increased VA
 More recent reports noted the unexpected rapid recurrence of GA under the translocated
fovea in 75% of patients and subsequent poor vision
 Currently, somewhat out of favor
Stem Cells
 Transplantation of fetal RPE cells has been performed in pts with CNVM and GA
 Reports feasibilit y of surgery, but high rate of rejection
 Autologous iris pigment epithelial cells have been evaluated
 have been shown to survive for up to 6 m os when transplanted in the subretinal space
 Very exciting as have potential to reverse vision loss from RPE disruption
 Many researchers feel widespread use may be decades away
Genetics
 Researchers have begun looking at genetic component of ARMD
 To im prove preventive efforts, diagnosis and treatm ent through better understanding of
disease
 To identif y those m ost at risk for advanced ARMD
 Many challenges arise
 Due to late onset of disease, only one generation is available to test
 Different types of ARMD may have different associated genes
 Role of environm ental factors and m odifiable risk factors com plicates inheritance patterns
 Apolipoproten E (APOE)
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Transporter of lipids and cholesterol in nervous system
 ABCA4
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Gene mutated in Stargardt’s disease
 HEMICENTIN-1 dystrophies
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Associated with other retinal
 PON1
 ELOVL4
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Also associated with Stargardt’s-like disease
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VLDLR
ACE (angiotensin.converting enzyme)
SOD2
CFH (Complement factor H gene)
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Associated with c-raective protein so inflammation may play role
 BF/C2 ( factor b /com plement component 2)
 PLEKHA1/LOC387715