NEOVASCULAR AMD SYMPOSIUM
| WET AMD THERAPY —Michael J. Cooney, MD, Practicing Surgeon, Vitreous Retina Macula Consultants of New
York
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| What lies ahead: incidence of age-related macular degeneration (AMD) expected to double during next 2 decades
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| Past therapies: laser photocoagulation/ macular photocoagulation study (MPS)—laser used to cauterize choroidal
neovascularization (CNV); resulted in damage to retinal photoreceptors and subsequent vision loss; only classic
lesions treatable with laser MPS (<20% of patients); high recurrence rate after treatment; photodynamic therapy
(PDT) with verteporfin (Visudyne)—initially approved by Food and Drug Administration (FDA) for predominantly
classic CNV; photoactive dye injected into vein, and laser used to selectively activate sites of CNV in subfoveal
region; efficacy studies (eg, Treatment for Age-Related Macular Degeneration with PDT [TAP]) divide
lesions into classic, minimally classic, and occult lesions, because PDT affects each type of lesion differently;
study showed PDT associated with superior efficacy, compared to observation; PDT with verteporfin associated
with significant treatment effect in smaller occult and minimally classic lesions; on average, patients required 3
treatments during first year of PDT, with overall requirement of 8 treatments
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| Antiangiogenesis agents: interfere with vascular endothelial growth factor (VEGF); VEGF upregulated in disease
states, eg, diabetic retinopathy, hypoxia, trauma; VEGF binds to cell receptor causing downstream signaling cascade
that can result in proliferation or increased permeability of blood vessels (VEGF also referred to as vascular
permeability factor)
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 | Pegaptanib (Macugen): chemically synthesized short strand of RNA or anti-VEGF aptamer; binds to VEGF and
prevents it from binding to cell surface receptors that activate cell signaling cascade involved in proliferation and
permeability of blood vessels; specifically binds to VEGF-165; study found treatment with pegaptanib at 6-wk
intervals for 1 yr resulted in decrease in rate of vision loss
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| Ranibizumab (RhuFab V2; Lucentis): recombinant anti-VEGF antibody fragment; binds to all VEGF isoforms
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| Registry trials—Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of
Neovascular AMD (MARINA) and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal
Neovascularization in AMD (ANCHOR); MARINA trial determined ranibizumab effective treatment in
wet AMD; looked at 2 doses (0.3-mg and 0.5-mg injections), given at 4-wk intervals for 1 yr, in patients with
minimally classic and occult CNV; 95% of patients maintained visual acuity over 1-yr treatment course, compared
to 64% of patients receiving pegaptanib or PDT; 30% of patients showed some improvement in visual
acuity during treatment; most common adverse events included subconjunctival hemorrhage from injection
and eye pain from “floaters”; serious adverse events occurred in <1% of patients (eg, ophthalmitis or uveitis);
ANCHOR trial found similar efficacy in patients with predominantly classic CNV; not associated with systemic
causes of mortality, eg, myocardial infarction; recommend giving patients 3 injections initially, then giving
injections as needed, based on stability of vision and presence or absence of changes seen on optical
coherence tomography (OCT) indicative of cystoid macular edema or subretinal fluid
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| Bevacizumab (Avastin)—full-length anti-VEGF antibody; FDA approved for systemic intravenous (IV) infusion
for colon cancer; study looking at off-label use of systemic IV infusion showed improvement in visual acuity and
OCT appearance at 12 wk; intravitreal injections penetrate retina; off-label use involves intravitreal injection
dose of 1.25 mg/ 0.05 mL; retrospective study looked at bevacizumab in patients who had failed other treatments
for wet AMD; study found 30% of patients had improvement in visual acuity
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| TREATMENT OF WET AMD: WHERE ARE WE GOING ?—David Boyer, MD, Associate Clinical Professor of
Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles
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| Criteria for new treatments: visual stabilization no longer benchmark for treatment; new treatments must improve
visual results, improve quality of life, or deliver medication with greater safety; cost may play role as well
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| Combination therapies: existing treatments—involve PDT and triamcinolone acetonide (Kenalog); studied in
VeriTAS (Verteporfin intravitreal Triamcinolone Acetonide Study); treatment beneficial, but safety may prove
problematic; other combinations and trials—PDT and pegaptanib (ongoing phase 3 trial); PDT and ranibizumab
(VeriTAS 2 trial; VeriTAS stopped because ranibizumab proven to have better anti-VEGF activity; FOCUS trial
showed that patients who received PDT and ranibizumab had improved visual acuity, while patients who got PDT
alone experienced loss of visual acuity); PDT and anecortave acetate; PDT with squalamine; rationale for combination
therapy—PDT stops growth of blood vessels by causing thrombosis and injury to endothelium, but also upregulates
VEGF-165, increases vascular permeability, and incites inflammatory response; addition of
triamcinolone or anti-VEGF therapy decreases upregulation of VEGF and reduces vascular permeability and inflammation
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| Anecortave acetate suspension: studies looking at ability to prevent formation of new blood vessels in patients with
semi-soft drusen and wet AMD in contralateral eye; studies also looking at anti-VEGF activity; not associated
with glucocorticoid activity and does not raise intraocular pressure or lead to cataract formation; inhibits proteolysis,
proliferation, and migration of vascular endothelial cells; phase 3 study showed anecortave acetate equally
effective as PDT, but did not meet 7% non-inferiority confidence interval required by FDA; delivered via posterior
juxtascleral depot, resulting in problems with reflux (may affect efficacy)
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| VEGF Trap: in phase 2 trials (Regeneron Pharmaceuticals); decoy; binds VEGF, not by using aptamers or monoclonal
antibodies, but by using soluble version of VEGF receptor to deactivate molecule; soluble receptors coupled
to Fc portion of antibody because of short half-life; intravitreal injection results in penetration through to
retina; preliminary results show intravitreal injection well tolerated and not associated with serious adverse
events or significant inflammation; 4-mg dose seems acceptable; binds with higher affinity than aptamers or antibodies
and also binds to placental growth factor (related to VEGF; implicated in pathologic angiogenesis);
elimination half-life 5.5 days; inhibits pathologic retinal neovascularization and CNV
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| AdPEDF: under development by GenVec; utilizes gene therapy to manipulate production of specific retinal pigment
epithelial protein product that has profound impact on ocular neovascularization; AdgvPEDF.11 adenovirus
vector designed to deliver gene coding for pigment epithelium-derived factor (PEDF); PEDF natural
regulator of blood vessel growth in eye and can inhibit ocular neovascularization; PEDF may protect photoreceptors
and retinal pigment epithelium; does not elicit inflammatory response
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| RNA interference (RNAi): intracellular mechanism of action; activates RNA silencing complex and leads to breakdown
in messenger RNA (mRNA), resulting in cessation of VEGF production or VEGF receptors; Sirna Therapeutics
study—involves injection of molecule that combines with RNA-induced silencing complex, causing
degradation of mRNA; targets VEGF receptor 1 (VEGFR-1); Acuity Pharmaceuticals study—directly targets
VEGF; combines silencing of protein that leads to inhibition of VEGF production; small interfering RNAs are
synthetic double-stranded RNAs that cleave and destroy mRNAs that make VEGF or VEGFR
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| Kinase inhibitors: VEGFR inhibitors that block activation of endothelial cells; eg, ruboxistaurin found to reduce macular
edema in some patients; current study looking at efficacy of oral preparation combined with PDT
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| Squalamine: aminosterol; synthesized chemically; results in endothelial cell inactivation, apoptosis, and vessel regression;
delivered systemically
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| New treatments for dry AMD: geographic atrophy—ciliary body neurotrophic growth factors delivered by implantable
device; study looking at antioxidant eye drops; prevention of progression to wet AMD—study looking at
anecortave acetate
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| ABLATIVE LASER TREATMENTS FOR EXUDATIVE AMD—Jennifer I. Lim, Associate Professor of Ophthalmology,
Doheny Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles
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| Role of laser treatment in wet AMD: considerations—location and type of CNV; risk for vision loss and
chances for vision improvement; patient compliance over multiple treatment visits (eg, systemic reasons, lack of
transportation); and cost-benefit analysis; types of CNV lesions—extrafoveal, juxtafoveal, and subfoveal; role for
thermal laser treatment in extra- and juxtafoveal lesions based on good data derived from phase 3 of MPS
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| Laser photocoagulation treatment of extra- and juxtafoveal CNV lesions: requires lesions with well-demarcated
borders; classic CNV responds best; can also use during other procedures, eg, feeder vessel technique and
indocyanine green (ICG) angiography-guided therapy; reduces risk for severe and moderate vision loss in patients
with extrafoveal CNV (high risk for persistence and recurrence of disease in these patients; recurrence possible in
≥50% of patients over 5 yr); no statistically significant benefit seen in treatment of juxtafoveal CNV; however,
when patients with hypertension excluded, only 38% of patients in treatment group had severe vision loss, compared
to 70% of patients in untreated group (study concluded hypertension affects treatment outcome); when classic
lesions alone studied, 54% of patients in treated group experienced severe vision loss, compared to 72% in
untreated group, irrespective of hypertension; persistence occurred in one third of patients, and recurrence seen in
47% at 5 yr; disadvantages of laser treatment include irreversible scotoma and possible thermal spread in areas adjacent
to treatment area (can lead to laser scar creep, causing atrophy and hyperpigmentation, with subsequent vision
loss)
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| Photodynamic therapy: mostly used in treatment of subfoveal CNV in patients with classic and minimally classic
lesions and recent disease progression; most patients do not experience improvement in vision; can result in acute
severe vision decrease in patients with occult CNV (loss of ≥20 letters 7 days after treatment; usually reversible);
requires venous access; can result in significant retinal pigment epithelium atrophy; extra- and juxtafoveal CNV—
consider PDT to treat juxtafoveal CNV lesions if laser treatment may ablate fovea (due to thermal spread or laser
scar creep); in study of 30 patients with predominantly classic juxtafoveal CNV lesions, 63% experienced vision
stabilization after 3 treatments ; in another study, patients with extrafoveal CNV had slight improvement in vision
loss, but patients with juxtafoveal CNV experienced decrease in visual acuity; subfoveal CNV lesions—classified
as predominantly classic, minimally classic, or occult lesions, with or without recent disease progression; role of laser
treatment includes treatment of feeder vessels or PDT for predominantly classic subfoveal CNV; consider PDT
in patients with small minimally classic or occult CNV lesions and recent disease progression; anti-angiogenesis
agents more effective in patients with large lesions, occult lesions, and predominantly classic lesions; consider PDT
in patients with subfoveal predominantly classic CNV if vision improvement not requirement of therapy; ranibizumab
superior to PDT in patients with subfoveal predominantly classic CNV; PDT not useful as adjunctive therapy
to ranibizumab in patients with minimally classic or occult subfoveal CNV; PDT with verteporfin more
effective than placebo in patients with smaller (<6 disc areas) minimally classic lesions; study found no benefit to
PDT in patients with occult lesions at 1 yr; subgroup analysis found that patients with small (< 4 disc areas) occult
lesions or who had better visual acuity (20/50 or better) received some benefit from PDT; conclusion—consider
PDT in patients with early predominantly classic subfoveal lesions with good visual acuity, especially if patient has
transportation issues that make multiple office visits problematic or has health issues that may contraindicate systemic
treatment
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| ICG-guided ablative therapy: used to treat extra- and juxtafoveal “hot spots” in patients with occult CNV lesions;
CNV resolved in two thirds of patients; however, recurrence common; treatment response better in patients
without pigment epithelial detachment (PED)
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| Feeder vessel technique: study looked at 170 patients with subfoveal occult CNV, using confocal scanning laser
ophthalmoscope (SLO) to identify feeder vessels and targeting CNV using dye-enhanced laser treatment; feeder
vessels identified in 37 patients; CNV resolved in 70%, and vision improved in 68%
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| Retinal angiomatous proliferation (RAP): study of 26 patients using intravitreal injections of triamcinolone
followed by ICG-guided PDT; cessation of fluid leakage occurred in 89% of patients; vision improved in 37% of
patients
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Suggested Reading
Azab M et al: Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular
degeneration: 2-year results of a randomized clinical trial. Arch Ophthalmol 123:448, 2005; Boscia F et al:
Combined surgical ablation and intravitreal triamcinolone acetonide for retinal angiomatous proliferation. Eur J Ophthalmol
15:513, 2005; Boyer DS et al: Subgroup analysis of the MARINA study of ranibizumab in neovascular
age-related macular degeneration. Ophthalmology 114:246, 2007; Fackler TK et al: Retrospective review of eyes
with neovascular age-related macular degeneration treated with photodynamic therapy with verteporfin and intravitreal
triamcinolone. Ann Acad Med Singapore 2006 35:701, 2006; Friberg TR et al: Prophylactic treatment of age-
related macular degeneration report number 1: 810-nanometer laser to eyes with drusen. Unilaterally eligible patients.
Ophthalmology 113:622, 2006; Ghazi NG et al: Retinal angiomatous proliferation with a cilioretinal artery anastomosis:
an unusual presentation. Graefes Arch Clin Exp Ophthalmol 243:493, 2005; Heier JS et al: Ranibizumab
combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of
the FOCUS Study. Arch Ophthalmol 124:1532, 2006; Kozak I et al: Phase I clinical trial results of verteporfin enhanced
feeder vessel therapy in subfoveal choroidal neovascularisation in age related macular degeneration. Br J
Ophthalmol 90:1152, 2006; Lim JI: Hastening choroidal neovascularization: the irony of prophylactic laser in unilateral
eyes with high-risk drusen. Am J Ophthalmol 141:354, 2006; Rosenfeld PJ et al: Ranibizumab for neovascular
age-related macular degeneration. N Engl J Med 355:1419, 2006; Spaide RF et al: Intravitreal bevacizumab
treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 26:383, 2006; 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.
Educational Objectives
| The goal of this program is to maximize the potential for treating wet age-related macular degeneration (AMD). After
hearing and assimilating this program, the clinician will be better able to:
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| 1. Appraise past therapies used to treat AMD.
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| 2. Evaluate the efficacy of anti-angiogenesis agents.
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| 3. Analyze the advantages and disadvantages of new combination therapies.
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| 4. Contrast the new anti-angiogenesis agents being used for wet AMD.
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| 5. Examine the current role of ablative laser therapy for exudative AMD.
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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. Cooney is a consultant for
Bausch and Lomb. Dr. Boyer is a consultant for Alcon, Genentech, Neurotech, Pfizer, QLT, and Novartis. Dr. Lim is on
the advisory boards for Genentech, EyeTech, Allergan, and Novartis and receives research grants from Genentech, Eyetech,
and Novartis.
Acknowledgements
Drs. Boyer and Lim were recorded on June 3, 2006, at the 2006 Ophthalmology Symposium, in Long Beach, CA,
sponsored by Kaiser Permanente. Dr. Cooney was recorded at the Annual Clinical Conference of the Kansas City Society
of Ophthalmology and Otolaryngology, in Kansas City, MO, sponsored by The Kansas City Society of Ophthalmology
and Otolaryngology and held January 5-6, 2007. The Audio-Digest Foundation thanks the speakers and the
sponsors for their cooperation in the production of this program.
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