RETINAL UPDATE
| NEW TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION —George A. Williams,
MD, Clinical Professor of Biomedical Sciences, The Eye Research Institute of Oakland University, Rochester, MI,
and Chair, Department of Ophthalmology, William Beaumont Hospital, Royal Oak, MI
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| Developing epidemic: nearly 2 million people in United States have lost vision due to age-related macular degeneration
(AMD); >7.3 million patients at risk
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| History of therapies: Macular Photocoagulation Study showed photocoagulation benefited subgroup of patients
with limited well-defined disease; provided short-term benefit to patients with lesions near central fovea; however,
many patients in both groups eventually developed recurrence and visual loss; <10% of patients eligible for
thermal photocoagulation (“foveal amputation”) of subfoveal lesions
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 | Photodynamic therapy (PDT): first major breakthrough in management of subfoveal choroidal neovascularizations;
utilizes verteporfin; several studies have confirmed benefit in managing classic, minimally classic, and occult
lesions; many retinal surgeons add intravitreal triamcinolone to standard PDT
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| Photoablative therapies: PDT and laser therapy; guided by fluorescein angiography; based on anatomy of
neovascularization
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| Drug therapies: developed through improved understanding of pathobiology and molecular biology of choroidal
neovascularization; vasoactive therapies (pegaptanib [Macugen], bevacizumab [Avastin], ranibizumab [Lucentis])
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| Vascular endothelial growth factor (VEGF): one of several important growth factors involved in neovascularization;
increases vascular permeability; stimulates neovascularization; expressed in choroidal neovascular process;
target of anti-VEGF therapies
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| VEGF pathway: cell expresses protein in nucleus; protein activated to become VEGF, enters extracellular matrix,
and exerts effect after binding to target cell receptor; drug therapies block pathway at specific sites
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| VEGF antagonists: pegaptanib (Macugen)—pegylated RNA that binds to VEGF 165; first drug to be approved for
treatment of AMD; ranibizumab (Lucentis)—binds all VEGF isoforms (pan-VEGF inhibitor); consists of antibody
fragment; bevacizumab (Avastin)—also binds all isoforms of VEGF; monoclonal antibody currently
used to treat cancer; not approved for treatment of AMD; VEGF trap—new fusion protein currently in clinical
trials
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| Mechanisms of action: similar for all drugs; injected into vitreous, they “mop up” excess VEGF, preventing it
from binding to receptor site; effective as long as appropriate molar excess maintained; repeated injections
needed to maintain efficacy
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| Other products under development: binding of VEGF to receptor leads to degradation of basement membrane,
cell division, other processes resulting in neovascularization, and cell migration; new products in development
target these steps; examples—integrin antagonists; tyrosine kinase inhibitors
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| Clinical trials of pegaptanib: 70% of patients who received drug lost <15 letters (end point required by Food and
Drug Administration [FDA] as evidence of efficacy), compared to 55% of those receiving usual care; over 2
yr, control patients experienced slow but steady decrease in visual acuity; “somewhat ameliorated” by treatment,
but most patients still lost vision; only 33% of patients experienced any visual improvement; only 6%
realized substantial improvement; overall results similar to those achieved with PDT
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| Clinical trials of ranibizumab: by binding to all forms of VEGF, decreases vascular permeability and inhibits
choroidal neovascularization; binds more centrally than pegaptanib on VEGF dimer; Minimally Classic/ Occult
Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) demonstrated
actual visual improvement with ranibizumab; 95% of patients lost <15 letters; at 2 yr, after 24
monthly injections, >90% of patients lost <15 letters; one-third had gained 3 lines; >40% of patients had 20/40
vision or better; concerns about possible systemic effects of long-term intraocular inhibition of VEGF function;
no apparent increase in risk for hypertension or cardiovascular or thromboembolic complications (however,
patient population small); similar findings seen in smaller head-to-head comparison with PDT
(ANCHOR study; 40% of patients receiving ranibizumab improved by 3 lines); patients with classic lesions
respond best; ranibizumab first treatment to improve visual acuity in AMD; patients have 40% chance of visual
improvement and 40% chance of achieving at least 20/40 vision after 2 yr of treatment (“40-40 rule”);
FDA approved drug June 30, 2006; remaining questions—dosing; practice logistics; cost; Prospective Optical
Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Lucentis (PRONTO)
study—patients received 3 monthly injections of ranibizumab (0.5 mg), then had subsequent dose dictated
by findings on optical coherence tomography (OCT); single-center uncontrolled open-label trial of 40
patients over 12 mo; 18% needed only first 3 injections to improve; 20% needed only one more injection; only
5% required full year of therapy; 95% of patients lost <15 letters; 35% gained >15 letters
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| Bevacizumab for AMD: extensive international clinical experience with 100,000 patients shows encouraging results,
but no definitive data yet; multiple reports that bevacizumab penetrates retina and produces clinical effect
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| Current state of field: retarding visual loss “assumed”; new goal visual improvement; more safety data needed as
new therapies used by more people; ranibizumab “now the standard of care, but we have much to learn”; optimal
dosing regimen still unclear; also important to identify adverse predictive factors and test combination therapies;
consider cost and quality-of-life implications of any new therapy, and likelihood of obtaining good vision in eyes
with <20/400 vision; issues about retreatment and best use of imaging studies in conjunction with new drugs
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| ADVANCES IN THE TREATMENT OF DIABETIC RETINOPATHY —Jeffrey S. Heier, MD, Assistant Professor
of Ophthalmology, Tufts University School of Medicine, and Clinical Instructor of Ophthalmology, Harvard Medical
School, Boston, MA
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| Background: Results with new drugs for AMD have changed expectations in treatment of other retinal diseases;
stabilization of vision no longer adequate goal; “where we think it can be improved, we want to improve it”
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| Diabetic retinopathy: affects 16 million people in United States, of whom nearly 1 million have serious vision
loss; patients often in prime working years, leading to financial ramifications in lost wages and treatment costs;
treatment advances result of improved diagnosis, pharmacotherapy, and technology
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| Diagnostic technology: OCT major advance; now used by most retina specialists; “invaluable” for following retinal
thinning in diabetic patient; however, improved retinal thickening does not always correlate with improved vision;
patient may have significant edema, but good vision, and vice versa; influential factors include duration of
edema, retinal perfusion status, underlying problems (eg, photoreceptor damage, atrophy), and type of thickening;
Heidelberg retina tomography (HRT) combines reflectance, edema index, and thickness to provide 3-dimensional
map of retina showing degrees of edema
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| Challenge: simply preventing further vision loss insufficient; goal now to improve existing vision
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| Laser: best results seen in patients with focal edema; only approved therapy for diabetic retinopathy
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| Triamcinolone: shows promise in treating diffuse edema; efficacy short-term; associated with risk for increased intraocular
pressure; retina specialists may not be following patients long enough
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| Other treatments: implantable dexamethasone pellet (Posurdex); adverse effect possible change in macular thickness
(currently under study); panretinal photocoagulation (PRP) may worsen edema; in these cases, intravitreal
triamcinolone may help preserve (or even improve) vision; anti-VEGF drugs also may help; VEGF levels correlate
with disease severity; vitrectomy—study results vary
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| Proliferative diabetic retinopathy: several small series have shown complete regression of neovascularization
with bevacizumab treatment; allows doctor to perform PRP; also associated with resolution of iris neovascularization
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| Recommendations: if patient has failed conventional therapy, “think out of the box”; however, hold new studies to
same rigorous standards employed in older trials
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| TEARS OF THE RETINAL PIGMENT EPITHELIUM —David Sarraf, MD, Assistant Clinical Professor of Opthalmology,
Jules Stein Eye Institute, University of California, Los Angeles, School of Medicine
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| Rips or tears of retinal pigment epithelium (RPE): tears at level of RPE-Brooks complex; may occur spontaneously
or as adverse effect of treatment; most commonly, complication of exudative or neovascular AMD
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| Diagnosis: made on fundoscopy or angiography; see bare RPE that transmits fluorescence on angiography or shows
choroidal vessels on fundoscopy; RPE may retract and roll over itself; appears dark and scrolled; hemorrhage may
occur, breaking into vitreous if severe
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| Etiology: theories include accumulation of exudate under RPE that causes blowout; thinning of RPE, which leads to
tearing or dehiscence; development of traction under RPE, leading to pulling and tearing
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| Prognosis: poor, especially if hemorrhage or scarring have occurred (associated with severe permanent vision loss);
up to 80% of fellow eyes affected within several years
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| Development: occurrence of choroidal neovascular membrane most important event; causes RPE to detach, leading
to further exudation and fluid accumulation, putting RPE under pressure; fibrovascular ingrowth causes traction
on RPE and leads to tear; often develops at margin between flat and elevated RPE; often associated with choroidal
folds
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| Other causes: central serous retinopathy; trauma; proliferative vitreoretinopathy; retinal detachment; staphyloma;
all much rarer than tears associated with exudative AMD
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| Tears seen with AMD: 10% risk for tears with detachment of pigment epithelium and underlying occult choroidal
neovascularization (fibrovascular pigment epithelial detachment [PED]); can determine presence of choroidal
neovascularization through observation of heme or exudates associated with PED; may be notched or shaped like
kidney bean, or detachment may fill irregularly (suggesting underlying choroidal neovascular membrane)
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| Ranibizumab for RPE tears: current gold standard; treatment improves vision by 2 to 3 lines, whether membrane
classic or occult (natural history steady decline in vision); “a real revolution”; however, drug costs $2000/
vial (one injection), with up to 20 injections required per year; cost effectiveness is concern
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| Analysis of patients with RPE rips or tears associated with anti-VEGF therapy: patients often older than
average; tears frequently develop within few weeks of first or second injection (evidence for causation); risk factors
for spontaneous tears similar to those associated with anti-VEGF therapy (fibrovascular PED or PED with associated
underlying choroidal neovascular membrane [large elevated irregular PED with blood or exudate], or notch,
hot spot, or irregular filling of PED); incidence underestimated in literature due to population heterogeneity and diagnostic
difficulty
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| Why rips occur: rarely associated with serous PED (no underlying choroidal neovascular membrane formation);
traction probably important underlying factor; some believe rips part of natural history of PED; >40 published
cases relating incidence to anti-VEGF therapy; temporal association with therapy strengthens association with anti-
VEGF (treatment may accelerate natural history); shows that anti-VEGF therapy “not a panacea”; patients (especially
those with large fibrovascular PEDs) should be informed of potential risk
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Suggested Reading
Adamis AP et al: Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals.
Ophthalmology 113:23, 2006; Bakri SJ et al: Rapid regression of disc neovascularization in a patient with proliferative
diabetic retinopathy following adjunctive intravitreal bevacizumab. Eye 20:1474, 2006; Bakri SJ, Kitzmann
AS: Retinal pigment epithelial tear after intravitreal ranibizumab. Am J Ophthalmol 143:505, 2007; Bakri SJ, Patel
SP: Retinal pigment epithelial tear following intravitreal bevacizumab. Eye 21:424, 2007; Chang LK, Sarraf D:
Tears of the retinal pigment epithelium: an old problem in a new era. Retina 27:523, 2007; Emerson MV, Lauer
AK: Emerging therapies for the treatment of neovascular age-related macular degeneration and diabetic macular
edema. BioDrugs 21:245, 2007; Gragoudas ES et al: Inhibition study in ocular neovascularization clinical trial
group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351:2805, 2004; Heier JS et al:
Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1
results of the FOCUS study. Arch Opthalmol 124:1532, 2006; Kang SW et al: Macular grid photocoagulation after
intravitreal triamcinolone acetonide for diffuse diabetic macular edema. Arch Ophthalmol 124:653, 2006; Kim IK et
al: Effect of intravitreal injection of ranibizumab in combination with verteporfin PDT on normal primate retina and
choroids. Invest Ophthalmol Vis Sci 47:357, 2006; Ng EW et al: Pegaptanib, a targeted anti-VEGF aptamer for ocular
vascular disease. Nat Rev Drug Discov 5:123, 2006; Ronan SM et al: Retinal pigment epithelium tears after intravitreal
injection of becacizumab (avastin) for neovascular age-related macular degeneration. Retina 27:535, 2007; Rosenfield
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; Yanyali A et al: Bevacizumab
(Avastin) for diabetic macular edema in previously vitrectomized eyes. Am J Ophthalmol 144:124, 2007.
Educational Objectives
| The goal of this program is to improve management of retinal disease by increasing awareness of current vascular endothelial
growth factor (VEGF) antagonist therapy. After hearing and assimilating this program, the listener will be
able to:
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| 1. Discuss the history of the development of anti-VEGF agents as treatments for age-related macular degeneration
(AMD).
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| 2. Describe the action of VEGF.
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| 3. Explain the significance of ranibizumab in the treatment of AMD and other retinal diseases.
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| 4. List the new treatments for diabetic retinopathy.
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| 5. State the ways in which tears of the retinal pigment epithelium associated with anti-VEGF treatment differ from
tears associated with other causes.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Williams is a consultant
for Alcon and Allergan. Dr. Heier consults for, receives grant support from, and/or is on the Speakers’
Bureaus of Allergan, Eyetech, Genentech, Genzyme, Jerini, ISTA Pharmaceuticals, Novartis, Oxigene, Pfizer, Regeneron,
Bausch & Lomb, Genaera, VisionCare, Zeiss, and iScience.
Acknowledgments
Drs. Williams and Heier spoke at Retina: Separating Fact from Fancy, held September 15, 2006, in Boston, MA, and
sponsored by the New England Ophthalmological Society. Dr. Sarraf was recorded at the Jules Stein Eye Institute’s
Clinical and Research Seminar and University of California, Los Angeles (UCLA) Department of Ophthalmology Association
Meeting, held May 18-19, 2007, in Los Angeles, CA, and sponsored by the UCLA Department of Ophthalmology.
The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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