RETINAL UPDATE
| MACULAR DEGENERATION: WHAT TO TELL YOUR PATIENTS ABOUT THE NEW TREATMENTS—Edgar
L. Thomas, MD, Retina-Vitreous Associates Medical Group, Los Angeles
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| Anti vascular endothelial growth factor (VEGF) therapy: blocks effect of growth of blood vessels in or on retina; affects
permeability of retina; probably major role of VEGF in diabetic macular edema
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| VEGF (overview): naturally occurring protein; triggers permeability and angiogenesis; VEGF 165 thought pathologic;
probably breakdown product of other isoforms; angiogenic cascade—effects on endothelial cell wall; extracellular
activation of drug; enzymes dissolve basement membrane; starts to proliferate, migrate, and leak; tubules form and
loops of vessels; VEGF important in development of abnormal blood vessels (especially those under retina); present in
inner retina and pigment epithelium; may be supportive in choriocapillaris in maintaining retinal function; associated
with—choroidal neovascularization, vein occlusion, retinopathy of prematurity (ROP), corneal and iris neovascularization;
breakdown of cell wall and active leakage; receptors found in abnormal membranes
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| Pegaptanib (Macugen): blocks VEGF 165 (abnormal); therapeutic goal to block specific blood vessel
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| Bevacizumab (Avastin): systemic monoclonal antibody; nonselective drug (ie, one that affects all isoforms); side effects
of systemic administration—pulmonary hemorrhage; thromboembolic phenomena; hypertension; gastrointestinal
(GI) perforations and wound healing problems
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| Anti-VEGF aptamer: short strand of ribonucleic acid (RNA); goal to find protein “key” that sticks to target molecule
(like putting block in door keyhole so that door cannot be opened); molecule rendered biologically inactive; highly selective
(does not affect other proteins); Eyetech Study Group—anti-VEGF pegylated aptamer (small piece of nucleic
acid); polyethylene glycol stabilization component allows it to last longer; hope that affinity with antibody fragments
greater and more specific; aptamer easier to discover and more selective; relatively small (even when pegylated, only
50,000 Daltons) with no evidence of toxicity; potentially immunogenic (although humanized monoclonal antibody
may have less risk than previously thought)
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| Role of Macugen in targeting VEGF 165 (phase 3 trial)
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 | Parameters: primary endpoint whether patients lost 3 lines of vision on Early Treatment of Diabetic Retinopathy (ETDRS)
eye chart at 54 wk; secondary endpoints (mean vision; number of patients that gained lines of vision and number of lines
gained; severe visual loss [loss of ≥6 lines]); dose every 6 wk; 3 different doses compared to sham injection; subfoveal angiographic
lesions (verteporfin [Visudyne] study looked only at classic lesions; occult lesions minimally classic, therefore
excluded); large lesions up to 12 disc areas (half of lesion had to be active)
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| Findings: based on percentage of patients losing <15 letters, 0.3 mg looked like better dose; larger doses did not work
better; control ≈55% (high compared to Visudyne trials); mean change in visual acuity (good drop-off with sham-
treated group); some in sham-treated group gained lines; in most patients, not much gain in visual acuity; rate of severe
visual loss (large difference between sham-treatment group and patients that received Macugen); effect of
Macugen continued to 2 yr; in most studies (even Visudyne), treatment more efficacious if continued
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| Tin ethyl etiopurpurin (SnET2) photodynamic therapy: ongoing phase 3 clinical trials; attempting to show difference at 2-
yr end point; drop-off associated with discontinuation at 52 wk; needed to continue administration every 6 wk
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| Endophthalmitis: in trial, Vitrase (purified sheep hyaluronidase) injected into almost 3000 eyes with no endophthalmitis (probably
due to injection technique); prompted American Society of Retinal Specialists (ASRS) protocol for prepping and draping
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| Food and Drug Administration (FDA) approval for Macugen: end of 2004; drug available in early 2005
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| Photodynamic therapy (PDT): not cause for exclusion; 75% of patients never received PDT (during trial, PDT was rescue
therapy); group that had previous PDT small and consistent across subgroups; baseline similar; statistically, effect
of Macugen not enhanced by previous PDT
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| Treatment with nonselective VEGF (mouse model): drug similar to Avastin; eliminated VEGF; over time, loss of vascularity
in model (large areas where capillary bed missing); case—patient with large choroidal neovascular membrane (at
54 wk, not visible); seen in few patients treated with Macugen
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| Ranibizumab (formerly RhuFab; Lucentis)
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| Overview: human recombinant fragment antibody; monoclonal antibody (Lucentis); bevacizumab (Avastin) whole molecule
(Lucentis’ is fragment); in studies, drug did not penetrate intact animal retina (human retina with disease likely to let many
factors in because of leakiness of disease process)
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| Phase 1 and 2 trials: issues included whether proliferation and permeability sufficient to inactivate intraocular VEGF
nonselectively and whether elimination of all forms of VEGF injurious to eye; some isoforms eliminate VEGF for
short time; in study, changes reversible (no long-term sequelae; did not affect outcome); endophthalmitis and recurrent
uveitis remain issues (central vein occlusion also occurred); another issue whether drug immunogenic stimulus
(no new antibodies found); preliminary data—improvement in ETDRS letters at 210 days; prompted additional
studies
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| Minimally classic/occult trial of the anti-VEGF antibody ranibizumab in the treatment of neovascular AMD (MARINA)
study: occult or minimally classic lesions (<50%); predominantly classic (some with previous PDT); dose
comparison; control stabilization of <15 letters lost (62%); Visudyne down to 40s; difference in trials (some concern
timing of patients getting into studies); caution about controls in AMD studies (40% to 70% of sham or untreated
controls do well); with 2 dose levels, percent reduction in mid 90s); in past, Visudyne gold standard (only ≈70%;
with Lucentis, ≈25% increase in success in reducing visual loss at 12 mo); numbers of patients that gained 15 letters
up 40% and 33%; patients 20/40 or better up ≈40%; more patients in sham group 20/200 or worse; at 1 yr, 95% of
patients lost <15 letters (improvement in 25% to 34%)
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| FOCUS trial: RhuFab V2 Ocular Treatment Combining Use of Visudyne to Evaluate Safety trial; PDT vs addition of
Lucentis molecule (better effect with combination); results similar to MARINA trial (1-yr efficacy ≈90%); change in
lyophilized formulation seemed to make difference; more broad-spectrum anti-VEGF molecule and antibody seem
effective; safety of intraocular injection—no microinfarctions or cerebrovascular accidents (CVAs) reported
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| Data presented by Miller at 2004 ASRS meeting: high percentage of patients did not lose vision; Avastin approved in 2004;
100-mg dose (25 mg/mL); cost of Lucentis and Macugen ≈$1000/dose (compared to 60 to 70 doses of Avastin from
$500- or $600-vial)
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| Paper by Rosenfeld: cancer-delivery dose given systemically to patients with bilateral disease who had failed everything
else; case (large pigment epithelial detachment [PED]); diffuse disease in affected eye); advantage of intravenous
delivery (drug affects both eyes); at ≈12 wk, PEDs gone; macula looks good; in majority of patients, vision
improved in both eyes; short-term study
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| Off-label use of Avastin (case): patient’s father also had AMD; second eye started to deteriorate; initially, Macugen
used to treat peripapillary lesion; eye continued to worsen; large PED; subretinal fluid; after 3 doses, disease progressing
(vision decreasing); speaker had tried steroids (next step PDT; vision dropped); first intraocular injection of Avastin
(systemic administration not indicated; other eye beyond help); intraretinal and subretinal fluid; at 4 days, vision
20/70 (1.5 wk ago, 20/50); patient reading again; with systemic administration, some patients develop hypertension
(not with intraocular doses)
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| What to tell patients: speaker considers off-label use of Avastin only if patient has failed all other treatment and rescue
indicated; PDT—seems helpful; terrible results in animal studies, but some patients do very well with it; Macugen—
similar efficacy profiles; certain patients do very well (not many); in work by Spade, PDT and steroid combination better
(how much better not clear); steroid-induced glaucoma biggest worry; Lucentis—probably best efficacy; hopefully,
available soon; expensive; Avastin—speaker’s experience (of 35 patients, no one worse); all better visually and/
or on optical coherence tomography (OCT)
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| AMD RISK REDUCTION—David G. Telander, MD, Visiting Assistant Professor of Ophthalmology, Jules Stein Eye
Institute, David Geffen School of Medicine at the University of California, Los Angeles
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| Angiogenic cascade: target of new pharmacologic agents; angiogenic stimulus (often ischemia or injury) causes growth
factor secretion; vascular endothelial cells produce matrix metalloproteinase inhibitors; proteinase enzymes cause revascularization
of extracellular matrix; remodeling, endothelial cell migration and proliferation, and lumen formation
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| New treatment for wet exudative macular degeneration: Macugen and Lucentis target VEGF molecule; VEGF key
player in angiogenesis (especially ocular angiogenesis); anecortave—may target production of VEGF and matrix
metalloproteinase; may play role in stabilization of lumen and proliferation of endothelial cells
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| Background: with glucocorticoids, worry about ocular-hypertension glaucoma; with steroids, posterior subcapsular cataracts
(evidence for retinal toxicity); in study by D’Amico, atrophy associated with intravitreal injection; systemic steroid
use associated with tissue atrophy; anecortave—cortisol analogue with modifications of side chains specifically
engineered to avoid ocular side effects
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Anecortave
| ROP (rat model): evidence that VEGF production decreased by anecortave
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| In vitro: Mueller cells—probably primary producer of VEGF in retinal ischemia; with increasing doses of anecortave,
decreased production; so, anecortave may inhibit VEGF production; human retina on microvascular endothelial
cells—evidence for inhibition of proliferation (key in final cascade of angiogenesis); lumen formation (VEGF alone
stimulates cells for tube formation); at increasing dose-response curve, inhibition by anecortave; role in upstream and
downstream cascade
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| In vivo: much evidence in animal models that drug safe and effective in ocular angiogenesis; topical anecortave potent inhibitor
and safe (no cataract formation or increased intraocular pressure [IOP])
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| Drug delivery: juxtascleral depot—slightly different from standard sub-Tenon injection; therapeutic retinal and choroidal
drug levels up to 6 mo, so timing for treatment and dosing 6 mo; make conjunctival cut ≈8 mm from limbus;
blunted curve-tip cannula slightly different from standard needle (not sharp); cut down onto sclera itself (allows surgeon
to slide under conjunctiva and deliver depot in area of macula); positioning against sclera allows permeability
across sclera to macula; avoids risks associated with intravitreal injection (eg, retinal detachment and endophthalmitis);
procedure studied in >1700 patients; in 2 key trials, safety similar to placebo and controls
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| Latest trials: dose-response monotherapy study—comparing 3 different doses of anecortave to placebo in age-related macular
degeneration (AMD) patients; noninferiority study—comparing anecortave to PDT and Visudyne; prevention
study—role of anecortave in preventing conversion of dry macular degeneration to wet
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| Dose-response monotherapy study: parameters—predominantly classic lesions based on angiography; eyes randomized
into 3 groups (different dosages); patients followed at each 6-mo injection; visual acuity and lesion sizes about same in all
groups; findings—12-mo window showed statistically significant improvement in maintaining vision, compared to placebo;
15-mg dose had increased preservation of vision (same at 24 mo); less effective in other dose groups, but trending toward same
result; 73% receiving 15-mg dose lost <3 lines of vision, compared to 47% of placebo group; conclusions—anecortave superior
to placebo in maintaining vision; no significant side effects in clinical groups; weaknesses of trial—smallness of phase 2
trial; high dropout rate largely due to emergent availability of PDT; dose-response curve not clearly established
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| Noninferiority study: Visudyne vs anecortave; predominantly classic choroidal neovascular membrane; 15-mg dose vs
PDT alone (standard of care); findings—percentage of patients with <3 lines of vision loss (Visudyne vs 15-mg
anecortave); chi-square analysis shows statistical equivalence between 2 groups (similar efficacy); Treatment of Age-
Related Macular Degeneration with Photodynamic Therapy (TAP) study—different lesion characteristics (cannot
be compared head-to-head); more plastic choroidal neovascular membranes of smaller size
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| Prevention trial (ongoing): issue whether medical therapy can prevent conversion from dry to wet AMD; same injection
protocol (safety profile remarkable); injection once every 6 mo tolerable to patients; 15-mg and 30-mg doses compared to
sham; inclusion criteria—only patients at high risk enrolled; choroidal neovascular membrane with vision loss in one
eye (fellow eye is study eye considered at risk); according to studies from National Institutes of Health (NIH), if drusen
and retinal pigment epithelium (RPE) changes present, 50% risk for vision loss from choroidal neovascular membrane in
5 yr; within 3000 µ of fovea, ≥5 intermediate soft drusen and/or RPE hyperpigmentation, and must have reasonable vision
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Educational Objectives
| The goal of this program is to educate the listener about new treatments for age-related macular degeneration (AMD).
After hearing and assimilating this program, the clinician will be better able to:
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| 1. Describe the role of vascular endothelial growth factor (VEGF) in the development of AMD.
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| 2. Identify advantages and disadvantages of new medications for managing AMD.
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| 3. Describe recent research involving investigational therapies for managing AMD.
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| 4. Recognize the role of photodynamic therapy (PDT) in managing AMD.
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| 5. Describe recent studies of anecortave for managing and preventing AMD.
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Discussed on This Program
Anecortave acetate (investigational)
Bevacizumab [Avastin]
Ganciclovir intravitreal implant [Vitrasert Implant]
Lidocaine HCl with epinephrine [Octocaine, Xylocaine, Xylocaine MPF]
Pegaptanib sodium [Macugen]
RhuFab V2 [Lucentis] (investigational)
Tin ethyl etiopurpurin (SnET2; investigational)
Triamcinolone acetonide (several formulations and trade names)
Verteporfin [Visudyne]
Suggested Reading
[No authors listed]: Bevacizumab. Anti-VEGF monoclonal antibody. avastin, rhumba-VEGF. Drugs R D 3:28,
2002; [No authors listed]: New drug treats age-related macular degeneration. FDA Consum 39:4, 2005; Bandello F
et al: Verteporfin in photodynamic therapy: report no. 5. Ophthalmology 111:2144, 2004; Bressler NM et al: Verteporfin
therapy for subfoveal choroidal neovascularization in age-related macular degeneration: four-year results of an
open-label extension of 2 randomized clinical trials: TAP Report No. 7 Arch Ophthalmol 123:1283, 2005; Clarke
MS: Anecortave acetate. Ophthalmology 111:2316, 2004; Cunningham ET Jr et al: A phase II randomized double-
masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology
112:1747, 2005; D’Amico et al: Anecortave acetate as monotherapy for treatment of subfoveal neovascularization
in age-related macular degeneration: twelve-month clinical outcomes. Ophthalmology 110:2372, 2003;
Gragoudas ES et al: Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351:2805, 2004;
Michels S et al: Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-
week results of an uncontrolled open-label clinical study. Ophthalmology 112:1035, 2005; Rakic JM et al: Pegaptanib
and age-related macular degeneration. N Engl J Med 21:1720, 2005; Reichel E: Intravitreal bevacizumab for
choroidal neovascularization and cystoid macular edema: a cost-effective treatment? Ophthalmic Surg Lasers Imaging
36:270, 2005; Rosenfeld PJ et al: Maximum tolerated dose of a humanized anti-vascular endothelial growth factor
antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology 112:1048, 2005;
Rosenfeld PJ et al: Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin)
for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 36:331, 2005; Rosenfeld PJ et
al: Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema
from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 36:336, 2005; Schmidt-Erfurth et al: Anecortave
acetate for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration.
Eur J Ophthalmol 15:482, 2005; Taban M et al: Efficacy of verteporfin photodynamic therapy on laser-induced
choroidal neovascularization and the ancillary effect on diabetic microvasculopathy. Curr Eye Res 28:291, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. Dr. Thomas
has contributed to research conducted by Eyetech, Pfizer, and Genentech.
Dr. Thomas was recorded at the 4th Annual Downeast Ophthalmology Symposium, Practical Solutions in Ophthalmology
, presented September 23-25, 2005, in Bar Harbor, Maine, by the Maine Society of Eye Physicians and Surgeons;
Dr. Telander was recorded at the Jules Stein Clinical and Research Seminar 2005, presented May 20-21, 2005, by the
Jules Stein Eye Institute, David Geffen School of Medicine at University of California, Los Angeles. The Audio-Digest
Foundation thanks Drs. Thomas and Telander and the sponsors for their cooperation in the production of this program.
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