The neovascular or wet form of age-related

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1 NEOVASCULAR AMD: WHAT DO COMPREHENSIVE OPHTHALMOLOGISTS NEED TO KNOW?* Dante J. Pieramici, MD ABSTRACT Characterized by new vessel formation and vascular leakage, the neovascular or wet form of age-related macular degeneration (AMD) accounts for 10% of all cases of AMD but 90% of cases in which there is severe vision loss. A key step in the pathogenesis of neovascular AMD is the production of inflammatory mediators and proangiogenic cytokines, including vascular endothelial growth factor (VEGF). Production of these substances promotes new vessel growth and vascular leakage, which in turn cause exudation and hemorrhage, discoid scar formation, and loss of central vision. This article discusses the treatment options for neovascular AMD from 1985 to the present, with special emphasis on anti-vegf therapies that directly target the underlying pathophysiologic mechanisms. The article presents recent data from clinical trials and other investigations evaluating the safety and efficacy of intravitreal injection with pegaptanib, ranibizumab, and bevacizumab. The important role of the comprehensive ophthalmologist with regard to early detection of the intermediate stage of AMD, patient education, follow-up strategies, and monitoring for signs of choroidal neovascularization is also addressed. (Adv Stud Ophthalmol. 2007;4(2):37-42) *Based on a presentation at a symposium held at the American Academy of Ophthalmology Annual Meeting in Las Vegas, Nevada, on November 12, Co-Director, The California Retina Research Foundation, Assistant Clinical Professor, Doheny Eye Institute, Partner, California Retina Consultants, Santa Barbara, California. Address correspondence to: Dante J. Pieramici, MD, California Retina Consultants, 515 East Micheltorena Street, Suite C, Santa Barbara, CA dpieramici@yahoo.com. The neovascular or wet form of age-related macular degeneration (AMD) is characterized by new vessel formation and vascular leakage of fluid and exudates. Often, there is a progressive loss of central vision with eventual disciform scar formation. In most cases, neovascularization begins in the choroid and grows into the retina. However, in some cases, neovascularization begins within the retina itself. Although neovascular AMD occurs in only 10% of all cases of AMD, it accounts for 90% of cases in which there is severe vision loss. 1 In the United States, there are an estimated to cases of neovascular AMD each year. 1 As with all forms of AMD, the pre valence of neovascular AMD increases exponentially with age, fro m 0.4/100 persons at ages 55 to 59 years to 1.1/100 persons at ages 70 to 75 years, 2.1/100 persons at ages 75 to 89 years, and 8.2/100 persons at age 80 years and o l d e r. 1 Other factors invo l ved in the development of AMD and its pro g ression to neovascular AMD include genetics, smoking, dyslipidemia, hypertension, obesity, endothelial inflammation, exc e s s i ve exposure to sunlight, light skin pigmentation, and nutrition. 2, 3 PATHOGENESIS OF NEOVASCULAR AMD Ne ovascular AMD is thought to develop when an older individual with a genetic predisposition to the disease process faces some environmental stress (eg, ox i d a- t i ve stress). This leads to the production of i n f l a m m a t o ry mediators and proangiogenic cytokines, which in turn causes the growth of abnormal blood ve s- sels in the choroid or retina, exudation and hemorrhage, disciform scar formation, and loss of central vision. Within this cascade of events in the pathogenesis of n e ovascular AMD, the stage at which inflammatory mediators and proangiogenic cytokines are pro d u c e d has become the focus of considerable re s e a rch in re c e n t Johns Hopkins Advanced Studies in Ophthalmology n 37

2 years, and these signaling molecules have been re c o g- n i zed as potential targets for therapeutic interve n t i o n. One important result of these investigations was the identification of vascular endothelial growth factor (VEGF) as a potential culprit in the pro g ression of AMD to choroidal neovascularization (CNV). 4-6 As demonstrated in animal and human studies, VEGF-A in particular promotes angiogenesis and vascular leakage 7 a n d is present in increased amounts in the ocular fluid of patients with AMD 8 and pro l i f e r a t i ve diabetic re t i n o p a- t h y. 9, 10 VEGF-A levels are also increased in patients with many other neovascular diseases of the eye, including diabetic macular edema, 11 retinopathy of pre m a t u r i t y, 12 iris neova s c u l a r i z a t i o n, 13 central and branch retinal ve i n o c c l u s i o n, 14 von Hippel-Lindau syndro m e, 15 and intraocular melanomas and re t i n o b l a s t o m a s. 16 TREATMENT OF NEOVASCULAR AMD The treatment of neovascular AMD has adva n c e d considerably since the 1980s, when laser photocoagulation was first used to ablate abnormal blood vessels in the choroid and retina. The approval of ve rt e p o rfin for use in photodynamic therapy (PDT) in 2000 ushere d in the second era of CNV therapy, and the approval of p e g a p t a n i b, the first anti-vegf therapy, in 2004 m a rked the beginning of the third era (Fi g u re 1). From its introduction until the 1990s, laser photocoagulation was the only option for treating CNV. T h e Macular Photocoagulation Study demonstrated that the technique was effective, particularly when the lesions we re extrafoveal or juxtafove a l. 1 7 Howe ve r, ophthalmologists we re appre h e n s i ve about lasering the fovea, and it was widely re c o g n i zed that better t reatments we re needed. As shown along the timeline in Fi g u re 1, va r- ious other therapies directed at eradicating abnormal blood vessels while trying to pre s e rve the n e u ro s e n s o ry retina (eg, submacular surgery, radiation, and other laser techniques) have been tried since the mid-1990s, with negative or mixe d results. For example, submacular surgery did not i m p rove or pre s e rve visual acuity over time. 1 8 and effective in clinical trials. 19 Ve rt e p o rfin is given syst e m i c a l l y, and thought to concentrate predominantly in c h o roidal neovascular vessels. After laser activation, the d rug acts to cause thrombosis of the new blood ve s s e l s. Data from the Treatment of Age-Related Ma c u l a r Degeneration with Photodynamic Therapy inve s t i g a- tion, which invo l ved patients with predominantly classic choroidal lesions, demonstrated that patients tre a t e d with PDT and ve rt e p o rfin lost less visual acuity at 5 years than untreated patients who we re switched to PDT after 24 months. 2 0 Howe ve r, even treated patients lost some visual acuity over time, albeit at a much slower rate than treated patients. Because the primary goal of CNV therapy is to improve visual acuity, not mere l y s l ow the rate of vision loss, any modality that does not result in improvement is less than ideal. PEGAPTANIB Pegaptanib is an anti-vegf aptamer that binds to the VEGF 165 isomer (one of several pathologic V E G F isomers in the circulation) and inhibits it from binding to the VEGF re c e p t o r. Pegaptanib is a chemically synt h e s i zed short strand of RNA and not an antibody, and is there f o re not immunogenic. Its selectivity for the VEGF 165 isomer alone may be one of its limitations. Pegaptanib has been evaluated in the V E G F Inhibition Study in Ocular Neovascularization, which comprised 2 concurrent, prospective, controlled, randomized trials in which patients received an intravitreal injection of the drug or a sham injection every 6 F i g u re 1. E volution of Treatment Options for CNV Since 1985 PDT WITH VERTEPORFIN Photodynamic therapy combines ve ry low intensity laser treatment with ve rt e p o rfin, the first d rug to be approved for CNV. Used together, PDT with ve rt e p o rfin has been shown to be safe CNV = choroidal neovascularization; sirna = small interfering RNA; TTT = transpupillary thermotherapy; VEGF = vascular endothelial growth factor. 38 Vol. 4, No. 2 n March 2007

3 weeks. 21 Three doses of pegaptanib were studied. The results were very similar to those seen with PDT and verteporfin. Although patients who received pegaptanib lost less visual acuity over time than those who received usual care (in this case, sham injections), they nonetheless continued to lose visual acuity. 22 OTHER ANTI-VEGF THERAPIES The purification and cloning of VEGF-A in led to the development of 2 important anti-vegf therapies: the anti VEGF-A monoclonal antibody bevacizumab, developed for cancer therapy, and after the crystal structure of VEGF-A was determined in 1997, 24 the anti VEGF-A monoclonal antibody fragment ranibizumab for AMD. Be vacizumab was developed to reduce malignant tumor growth by inhibiting angiogenesis. It is approve d for the treatment of metastatic colorectal cancer, but has been used off label by many ophthalmologists to tre a t CNV and has become a standard therapy for neova s c u- lar AMD. Howe ve r, the antibody fragment ranibizumab was specifically designed for AMD because it was felt that the full-length antibody beva c i z u m a b, a large molecule, might not penetrate the full thickness of the re t i n a to reach the choroid. In addition, ranibizumab is affinity maturated to increase binding of V E G F. Ranibizumab was approved for the treatment of AMD in June Data from clinical trials evaluating ranibizumab and clinical experience with bevacizumab are pre s e n t e d later in this art i c l e. RANIBIZUMAB Once phase I and II clinical trials had established that ranibizumab had a biologic effect on the diseased retina after intravitreal injection, 25 2 phase III, rand o m i zed, multicenter, double-masked, contro l l e d studies were designed: the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Age-Related Macular De g e n e r a t i o n (MARINA) 26 and the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choro i d a l Ne ovascularization in Age-Related Ma c u l a r Degeneration (ANCHOR) study. 27 MARINA randomized 726 patients with occult or minimally classic CNV in a 1:1:1 ratio to tre a t m e n t with intravitreal ranibizumab 0.3 mg or 0.5 mg or sham injection each month for 24 months. 26 ANCHOR rand o m i zed 423 patients with predominantly classic lesions in a 1:1:1 ratio to PDT with ve rt e p o rfin and sham injection, sham PDT and intravitreal ranibizumab 0.3 mg, or sham PDT and intravitreal ranibizumab 0.5 mg each month for 24 months. 2 7 The mean change in visual acuity over time thro u g h month 24 in each of the 3 MARINA study arms was a loss of 14.9 letters in patients receiving sham injections, F i g u re 2. Pe rcentage of Subjects Reaching the P r i m a ry Endpoint (Loss of <15 Letters from Baseline at Month 12) in the MARINA Study *P <.0001 versus sham. MARINA = Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Age-Related Macular Degeneration. Reprinted with permission from Rosenfeld et al. N Engl J Med. 2006;355: F i g u re 3. Pe rcentage of Subjects Reaching the P r i m a ry Endpoint (Loss of <15 Letters fro m Baseline at Month 12) in the ANCHOR Study *P <.0001 versus PDT.. ANCHOR = Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration; PDT = photodynamic therapy. Reprinted with permission from Brown et al. N Engl J Med. 2006;355: Johns Hopkins Advanced Studies in Ophthalmology n 39

4 a gain of 5.4 letters in those receiving ranibizumab 0.3 mg, and a gain of 6.6 letters in those re c e i v i n g ranibizumab 0.5 mg. 2 6 The primary endpoint was the p ro p o rtion of patients who lost less than 15 letters ( a p p roximately 3 lines) from baseline at month 12, as assessed with the Early Treatment Diabetic Re t i n o p a t h y Study chart, using standard i zed refraction and testing p rotocol at a starting test distance of 2 meters (Fi g u re 2). The loss of less than 15 letters of visual acuity at 1 ye a r is a measure of stability and, in that re g a rd, nearly 95% of MARINA patients who re c e i ved either dose of ranibizumab stabilized, compared to approximately 62% of patients who re c e i ved sham injections, a statistically significant difference (P <.001 for each dose vs sham). The secondary endpoint of the MARINA trial was the pro p o rtion of patients gaining 15 letters or more f rom baseline at month 12, a measure of notew o rt h y i m p rovement in visual acuity. 2 6 He re, too, significantly more patients treated with ranibizumab i m p roved than did patients receiving sham injections: 24.8% for ranibizumab 0.3 mg and 33.8% for 0.5 mg versus 4.6% for sham injections (P <.001 for each dose vs sham). Results of the ANCHOR study we re ve ry similar to those demonstrated in MARINA. 27 O verall, patients treated with PDT and ve rt e p o rfin lost visual acuity over time, with a mean loss of 9.5 letters by month 12. In contrast, approximately 95% of patients tre a t e d with either dose of ranibizumab reached the prim a ry endpoint, with a stable visual acuity at month 12, compared to 64% of those tre a t e d with PDT (Fi g u re 3; P <.001 for each comparison). In addition, 35.7% of patients who re c e i ved ranibizumab 0.3 mg and 40.3% of those who re c e i ved 0.5 mg gained 3 lines or m o re of visual acuity at month 12 versus only 5.6% of those treated with PDT (P <.001 for each comparison). Ocular and systemic adverse events at 24 months in the MARINA trial and at 12 months in the ANCHOR study are summarized in the Table. 26,27 Serious ocular adverse effects we re uncommon in both studies. Systemic adverse events, including those previously associated with systemically administered anti-vegf therapy (eg, hypertension and arterial thromboembolic events), occurred in both trials. Although the incidence of these events was similar across treatment and control groups in both trials, 12-month data from MARINA suggested a nonsignificant trend toward an increased incidence of thromboembolic events in the 239 patients who received ranibizumab 0.5 mg. 26 Postmarketing surveillance is ongoing to monitor for any increased risk of ocular or systemic adverse events associated with ranibizumab therapy. BEVACIZUMAB Currently, bevacizumab is approved by the US Food and Drug Administration for the treatment of metastatic colorectal cancer. The off-label use of bevacizumab for AMD was initially prompted by early reports of success from ranibizumab investigators, combined with a desire by some ophthalmologists to use anti-vegf therapy at a time when ranibizumab Table. Ocular and Systemic Adverse Events in the MARINA and ANCHOR Studies* Adverse MARINA 26 ANCHOR 27 Event Ranibizumab Sham Ranibizumab PDT (n = 477) (n = 236) (n = 277) (n =143) Presumed endophthalmitis 5 (1) 0 2 (0.7) 0 Uveitis 6 (1.3) 0 1 (0.4) 0 Retinal tear 2 (0.4) Vitreous hemorrhage 2 (0.4) 2 (0.8) 1 (0.4) 0 Lens damage 1 (0.2) Rhegmatogenous retinal detachment 0 1 (0.4) 1 (0.4) 1 (0.7) Hypertension 80 (16.8) 38 (16.1) 12 (4.3) 12 (8.4) Nonfatal MI 9 (1.9) 4 (1.7) 4 (1.4) 1 (0.7) Nonfatal stroke 9 (1.9) 2 (0.8) 1 (0.4) 1 (0.7) Death 11 (2.3) 6 (2.5) 5 (1.8) 2 (1.4) *Number of events (%) at 24 months in the MARINA trial and at 12 months in the ANCHOR study. Includes patients randomized to either ranibizumab dose (0.3 mg or 0.5 mg). As defined by the study investigator. ANCHOR = Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration; MARINA = Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Age- Related Macular Degeneration; MI = myocardial infarction; PDT = photodynamic therapy with verteporfin. Data from Rosenfeld et al 26 ; Brown et al Vol. 4, No. 2 n March 2007

5 was not yet available. Anecdotal reports of success with intravenous bevacizumab at first, and with intravitreal bevacizumab shortly thereafter, spread rapidly, and offlabel use of the drug followed. Recent experiments in a rabbit model have dispelled doubts about the ability of bevacizumab to penetrate the full thickness of the neurosensory retina at doses typically used in the human eye. 28 Although most of the clinical data on bevacizumab is anecdotal or from retrospective case series 29 or small prospective studies, results thus far have been promising. There are currently no phase III clinical trials or comparison data trials evaluating this drug in AMD, but a head-to-head study comparing ranibizumab and bevacizumab is being organized by the National Eye Institute. ROLE OF THE COMPREHENSIVE OPHTHALMOLOGIST As the primary eye care provider for most patients, the c o m p re h e n s i ve ophthalmologist plays a key role in AMD management by detecting the intermediate stage of the disease process and recommending appropriate follow - u p strategies. Compre h e n s i ve ophthalmologists must educate patients about the symptoms of neovascular AMD and teach them how to monitor their vision, one eye at a time, with the Amsler grid. In addition, they need to be able to detect signs of asymptomatic CNV and re f e r patients to retina specialists when this is indicated. Early detection is particularly important because effective anti-vegf therapies are now available to treat reversible changes that sometimes occur early in the natural history of AMD and to preserve or even i m p rove visual acuity. Howe ve r, once irre ve r s i b l e changes develop and the outer neurosensory retina is lost, visual acuity loss is permanent. In t e n s i ve monitoring with pre f e rential hyperacuity perimeter (PHP) testing is becoming incre a s i n g l y i m p o rtant and may be more effective than regular monitoring with the Amsler grid in detecting early CNV. One study showed that only 20% of regularly monit o red patients who developed CNV still had visual acuity of 20/40 or better. 3 0 By comparison, another study s h owed that 66% of patients who developed CNV but we re monitored by PHP had visual acuity of 20/40 or better at the time that the CNV was detected. 3 1 The signs of CNV may include subretinal blood, i n t r a retinal blood, subretinal fluid or fibrosis, subre t i n a l and/or intraretinal lipid, pigment epithelial detachment, and ye l l ow - g reen lesions. Because these warning signs may be subtle, they may be missed on funduscopic examination. T h e re f o re, fluorescein angiography, the gold standard for detecting CNV, is recommended if t h e re is any doubt as to whether CNV is pre s e n t. WHAT TO TELL PATIENTS ABOUT ANTI-VEGF THERAPY To avoid raising false hope and unrealistic expectations, ophthalmologists should give patients the topline data about anti-vegf therapy (ie, what the studies were designed to show and the proportion of patients reaching the primary efficacy endpoint). As demonstrated in MARINA and ANCHOR, patients receiving ranibizumab had a 95% chance of losing less than 3 lines of visual acuity over the course of treatment, 26,27 thus it may be appropriate to tell patients that their vision is very likely to be relatively stable with this therapy. On average, patients receiving the drug experienced some improvement in visual acuity, with 33% experiencing significant improvement and gaining 3 lines or more. However, many patients did not improve, and this should be pointed out. Patients should also be apprised that anti-vegf therapy is not a cure for AMD or CNV, repeat injections are necessary, and that treatment can be costly. In addition, they should be informed that while serious a d verse events we re uncommon in clinical trials, ongoing postmarketing surveillance might show a significant incidence of these events as more patients are treated. In addition to ocular adverse events, the potential for a d verse systemic events should also be noted. Another point to address is whether ranibizumab is better than, equal to, or inferior to bevacizumab. Patients should be told, clearly and simply, that the answer remains to be determined. CONCLUSIONS Ne ovascular AMD occurs in only 10% of all cases of AMD, but accounts for 90% of cases in which there is s e ve re vision loss. T h e re f o re, detection of the intermediate stage of AMD and early signs of CNV is cru c i a l. The identification of VEGF as a probable culprit in the progression of AMD to CNV led to the development of anti-vegf therapies that directly target the underlying pathophysiologic mechanisms of AMD. Anti-VEGF therapies represent a significant improvement over previously used modalities, such as laser photocoagulation, submacular surgery, radiation, and PDT with verteporfin. Johns Hopkins Advanced Studies in Ophthalmology n 41

6 Two major randomized controlled clinical trials, MARINA and ANCHOR, have demonstrated the efficacy of ranibizumab. In both studies, nearly 95% of patients lost less than 15 letters (approximately 3 lines) of visual acuity at 1 year, a measure of vision stabilization, and roughly 33% of patients had improved visual acuity, with a gain of 3 lines or more at 1 year. The compre h e n s i ve ophthalmologist plays a key ro l e in AMD by detecting the intermediate stage of AMD and early signs of CNV, recommending appropriate foll ow-up strategies, and educating patients about symptoms and self-monitoring. When discussing anti-vegf therapy with patients, the compre h e n s i ve ophthalmologist should present the main findings of any studies that may be pertinent to the medication that the patient is being treated with, explain how they relate to the patient, and address issues such as adverse events, cost, and the need for repeat injections. 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