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1 Volume 1, Number 3 Spring 2008 THE OPHTHALMOLOGY Carl D. Regillo, MD, FACS Wills Eye Institute, Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania Guest Editor MARINA and ANCHOR Revisited Safety and Pharmacokinetics of Retinal Pharmacotherapeutics for Exudative AMD Optimizing Anti-VEGF Therapy for Neovascular AMD The Future of Neovascular AMD Therapy Selected Reports from the 25 th Annual Meeting of the American Society of Retina Specialists CONTINUING MEDICAL EDUCATION: 1.5 CREDITS AVAILABLE This activity is supported by an educational grant from Genentech, Inc.

2 Guest Editor: Carl D. Regillo, MD, FACS The opinions or views expressed in this publication are those of the authors and do not necessarily refl ect the opinions or recommendations of Genentech, Inc., Beam Institute, or the publisher, Direct One Communications, Inc. Please consult the full prescribing information before using any medication mentioned in this publication. This publication was made possible through an educational grant from Genentech, Inc. Copyright 2008 by Direct One Communications, Inc. All rights reserved. Printed in the USA.

3 Contents Volume 1, Number 3 Spring 2008 THE OPHTHALMOLOGY Selected Reports from the 25th Annual Meeting of the American Society of Retina Specialists Carl D. Regillo, MD, FACS, Guest Editor Wills Eye Institute, Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania 3 Introduction Carl D. Regillo, MD, FACS, Guest Editor 4 MARINA and ANCHOR Revisited Anita G. Prasad, MD Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio 10 Safety and Pharmacokinetics of Retinal Pharmacotherapeutics for Exudative Age-Related Macular Degeneration Rishi P. Singh, MD Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida 14 Optimizing Anti-VEGF Therapy for Neovascular Age-Related Macular Degeneration Mark A. Weisbrod, MD Duke University Eye Center, Durham, North Carolina 23 The Future of Neovascular Age-Related Macular Degeneration Therapy Adrienne W. Scott, MD C O N T I N U I N G M E D I C A L E D U C AT I O N : 1. 5 C R E D I T S A V A I L A B L E 2 About This CME Activity 31 CME Post Test and Evaluation 1

4 About This CME Activity Rationale and Purpose Not so long ago, ophthalmologists could only hope that their available therapies could slow the progressive blindness resulting from age-related macular degeneration (AMD) and associated choroidal neovascularization (CNV). Advances in our understanding of the role of vascular endothelial growth factor (VEGF) in CNV ushered in the era of anti-vegf therapy and the ability not only to halt the progress of CNV but also to restore visual acuity in a clinically meaningful fashion. This issue of The Ophthalmology Report, based on the 25 th Annual Meeting of the American Society of Retina Specialists in Indian Wells, California, explores the mechanisms of AMD and the pathogenesis of CNV, the crucial studies that established the value and safety of angiogenesis inhibition in the treatment of neovascular AMD, and current research attempting to defi ne the best anti-vegf agents, alone and in combination with other therapies; optimal, cost-effective dosing regimens; and the use of diagnostic tools to tailor AMD therapy to individual patients and to monitor its effect. The articles in this issue, written from the academic perspective of physicians in training at leading medical institutions, summarize the import of these new fi ndings and place them into clinical context. This activity has been developed and approved by a planning committee of nationally recognized thought leaders, under the direction of Beam Institute, to meet a perceived educational need to provide ophthalmologists and other physicians with strategies to help them perform their medical roles. Learning Objectives After reading this issue of The Ophthalmology Report, participants in this educational activity should be able to: Describe the results of important clinical trials of anti-vegf therapy in neovascular AMD. Discuss the issues surrounding the indications for treatment, dosing regimens, and safety that arose after publication of these important trials. Review approaches to quantify the impact of AMD treatment on vision-related quality of life. Understand how first-line therapy of neovascular AMD may affect the effectiveness of later treatment with a monoclonal antibody. Explain how to determine whether anti-vegf therapy should be continued in patients with neovascular AMD. Target Audience Ophthalmologists and other physicians signifi cantly involved in the diagnosis and management of patients with neovascular AMD should fi nd participating in this educational activity valuable. Accreditation This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Beam Institute and Direct One Communications, Inc. Beam Institute is accredited by the ACCME to provide continuing medical education for physicians. Faculty Disclosures In compliance with the ACCME s Standards for Commercial Support, any person who was in a position to control the content of this CME activity was required to disclose all relevant fi nancial relationships that created confl icts of interest. Beam Institute has identifi ed and resolved all confl icts of interest prior to the publication of this educational activity. All faculty have been offered a modest honorarium for their participation in this activity. Carl D. Regillo, MD, FACS, is Attending Surgeon, Retina Service, Wills Eye Institute, and Professor of Ophthalmology, Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania. He has received research support from and serves as a consultant to Genentech, Novartis, QLT, and Regeneron. Anita G. Prasad, MD, a Retina Fellow at Wills Eye Institute, Philadelphia, Pennsylvania, has nothing to disclose. Rishi P. Singh, MD, an Associate Staff Physician at Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, has nothing to disclose. Mark A. Weisbrod, MD, a Medical Retina Fellow at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, has nothing to disclose. Adrienne W. Scott, MD, a Vitreoretinal Surgical Fellow at Duke University Eye Center, Durham, North Carolina, has nothing to disclose. Continuing Education Credit The Beam Institute designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Disclaimer This activity is an independent educational activity under the direction of Beam Institute. The activity was planned and implemented in accordance with the Essential Areas and policies of the ACCME, the Ethical Opinions/Guidelines of the American Medical Association, the US Food and Drug Administration, the Offi ce of Inspector General of the US Department of Health and Human Services, and the Pharmaceutical Research and Manufacturers of America Code on Interactions With Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientifi c rigor, and objectivity. However, the planning committee, faculty, Beam Institute, Genentech, Inc., and Direct One Communications, Inc. shall in no way be liable for the currency of information or for any errors, omissions, or inaccuracies in this activity. Discussions concerning drugs, dosages, and procedures may refl ect the clinical experience of the planning committee or they may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Participants in this activity are encouraged to refer to primary references or full prescribing information resources. The opinions and recommendations presented herein are those of the faculty and do not necessarily reflect the views of the provider, producer, or grantors. Copyright Copyright owned by Direct One Communications, Inc. Copyright 2008, Direct One Communications, Inc. Contact Information We would like to hear your comments regarding this or other educational activities provided by Beam Institute. In addition, suggestions for future activities are welcome. Contact us at: Director of Continuing Education Beam Institute 11 West 19 th Street, 3 rd Floor New York, NY Phone: / Fax: beaminstitute@cmp.com Activity release date: April 11, 2008 Expiration date: April 11,

5 Introduction Selected Reports from the 25 th Annual Meeting of the American Society of Retina Specialists Carl D. Regillo, MD, FACS Wills Eye Institute, Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania T he past decade has been very exciting in the field of retina, with great developments in the diagnosis and treatment of age-related macular degeneration (AMD). Now that there are highly effective pharmacotherapeutics that can result in clinically meaningful visual improvement in many patients with neovascular AMD, much of the current research activity in this area is focusing on optimizing therapy. Optimizing therapy involves utilizing the best-available diagnostic and therapeutic tools to obtain the best visual outcome in the most rapid, convenient, safest, and cost-effective manner. On the diagnostic side, there is fluorescein angiography (FA) and optical coherence tomography (OCT) for detecting and guiding treatment of wet AMD. All the major prospective clinical trial data with anti-vascular endothelial growth factor (VEGF) agents that are currently available use fixed dosing regimens. Surveys indicate, however, that virtually all practitioners attempt to individualize therapy with these agents. We really don t know the best way to do this. The current trial data do not offer much guidance. What we do know is that early detection and good control of neovascular growth and leakage are important in obtaining the best long-term visual results. It appears that frequent OCT and selective use of FA in conjunction with close follow-up is the best way to keep on top of disease activity. The SAILOR (Safety Assessment of Intravitreal Lucentis for AMD) trial examines ranibizumab dosed on an as-needed basis, and we will learn much more about individualizing therapy as the results become available this year. What about the best anti-vegf agent? Most would agree that ranibizumab and bevacizumab have comparably good efficacy and represent the best monotherapy currently available. Pharmacokinetic studies of intravitreal administration of these drugs indicate a slightly longer vitreous half-life for bevacizumab, which suggests a possible longer duration of action, but there is also greater relative amounts of bevacizumab detected in the plasma. The latter could represent undesirable systemic exposure and possible unwanted systemic side effects. We will need to rely on the CATT (Comparison of AMD Treatments Trial) study to help determine the relative safety and efficacy of these two agents, but with the study just starting, the answer is still a few years away. How about combination therapy? There is much buzz about the promise of combining treatment modalities with different mechanisms of action to optimize neovascular AMD treatment outcomes. The leading candidates for combination therapy include anti-vegf agents, corticosteroids, and photodynamic therapy (PDT). Also back on the scene is radiation therapy. A relatively large number of papers recently published or presented suggest at least a reduction in the number of total treatments to achieve good short-term control of neovascular AMD. Visual outcomes appear similar to what can be achieved with monthly ranibizumab dosing, but nothing thus far seems to indicate better vision outcomes. A Dr. Regillo is Attending Surgeon, Retina Service, Wills Eye Institute, and Professor of Ophthalmology, Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania. number of trials are currently under way to answer whether or not dual- or triple-therapy combinations are of any added value compared with monotherapy. At this time, we cannot say anything with certainty, but there are enough pilot data to warrant putting the various combination treatment regimens to the test in large-scale clinical trials. What else is new for the immediate future? We should expect to see more on the relative potential benefits of the higher resolution spectral-domain OCT. We will know more about other anti-vegf agents, such as VEGF-Trap. We will learn more about AMD pathophysiology. We might have the telescopic implant available for clinical use soon. All of these expected developments, among others, will make the horizon in AMD management bright and exciting for years to come. 3

6 MARINA and ANCHOR Revisited Anita G. Prasad, MD Wills Eye Institute, Philadelphia, Pennsylvania Great strides have been made in battling visual loss secondary to neovascular age-related macular degeneration (AMD). The discovery of the crucial role of vascular endothelial growth factor (VEGF) in the pathogenesis of this disease has given patients and ophthalmologists renewed hope for preserving and even gaining vision lost from choroidal neovascularization (CNV). The effectiveness of intravitreal ranibizumab in the treatment of CNV was shown in the pivotal Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial and the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA). Later, the Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without Classic CNV Secondary to Age-Related Macular Degeneration (PIER) study investigated whether less frequent dosing was as effective as were monthly treatments given in the prior two trials. Further examination of the data may clear up concerns that arose since ranibizumab s approval by the US Food and Drug Administration in June T he effort to reverse or prevent visual loss secondary to neovascular age-related macular degeneration (AMD) continues. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and vascular leakage associated with choroidal neovascularization (CNV). 1 3 The use of recombinant humanized monoclonal antibodies directed against VEGF in treating CNV is based upon animal models. 1 3 The combined results 4 Dr. Prasad is a Retina Fellow at Wills Eye Institute, Philadelphia, Pennsylvania. of the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) 5 and the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial 6 confirmed the clinical relevance of VEGF isoforms that are neutralized by ranibizumab, an anti-vegf antigen-binding fragment used to treat neovascular AMD. Additional data from these trials and others continue to help investigators learn more about the workings of ranibizumab against AMD. During the 25 th Annual Meeting of the American Society of Retina Specialists, held December 1 5, 2007, in Indian Wells, California, leaders in the battle against CNV and AMD discussed various findings from MA- RINA, the ANCHOR trial, and other studies. As they tested ranibizumab, these researchers learned more about AMD-related CNV and delineated the usefulness of this monoclonal antibody and its safety. Overview of the Studies The simultaneously staged, phase III, multicenter, double-blind, sham-controlled, 2-year MARINA 5 and ANCHOR 6 trials established the effectiveness of intravitreal ranibizumab in treating CNV secondary to AMD. The ongoing Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without Classic CNV Secondary to Age-Related Macular Degeneration (PIER) 7 is testing the usefulness of less-frequent ranibizumab administration at different doses. MARINA MARINA examined patients with minimally classic or occult CNV who received monthly intravitreal injections of either 0.3 mg or 0.5 mg of ranibizumab for 24 months. 5 Approximately 95% of patients in the treatment arm lost fewer than 15 ETDRS (Early Treatment of Diabetic 4

7 MARINA and ANCHOR Revisited Retinopathy Study) letters of visual acuity, compared with approximately 60% of the sham group. Improvement in visual acuity by 15 or more letters, a previously unachieved goal, was experienced by approximately 30% of treated patients and 5% of the sham group. Patients in the treatment arm gained an average of approximately 7 letters, and those in the sham group lost approximately 10 letters. Improvement in visual acuity among the treatment group continued over the 2- year span of the study. ANCHOR Trial The ANCHOR trial yielded results similar to those of the MARINA. In this double-blind study, patients were randomized to receive sham ranibizumab plus photodynamic therapy (PDT) or ranibizumab (0.3 or 0.5 mg) plus sham PDT. 6 When compared with 64% of patients treated with PDT, 94% and 96% of the patients treated with 0.3 mg and 0.5 mg of ranibizumab, respectively, lost fewer than 15 ET- DRS letters. Ranibizumab-treated patients also enjoyed a benefit in visual gain, with 40% of patients given the monoclonal antibody and 6% of patients receiving PDT gaining 15 or more letters. The mean gain in visual acuity was 8.5 letters in those given 0.3 mg of ranibizumab and 11.3 letters in those given 0.5 mg of the drug, whereas patients randomly assigned to the PDT arm suffered a decrease of 9.5 letters. Thus, the ANCHOR trial clearly demonstrated the superiority of ranibizumab over PDT in treating AMDrelated, classic CNV. Further, both studies showed a low risk of serious ocular adverse effects, including endophthalmitis and severe uveitis, resulting from the use of ranibizumab (Figure 1). 8 PIER Figure 1 Study designs of the 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). PDT = photodynamic therapy. Adapted, with permission, from Regillo. 8 Sham injection (n = 238) MARINA Phase III, randomized, multicenter, double-masked, sham-controlled study Investigator identifies potential patients Reading center confirms angiographic eligibility Minimally classic or occult lesions with no classic lesions (n = 716) Randomization 1:1:1 Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240) The ongoing PIER study is assessing whether a lessfrequent dosing regimen of 0.3 or 0.5 mg ranibizumab is effective in preventing vision loss from AMD-related CNV. The protocol involves monthly injections of ranibizumab given for 3 months followed by injections every 3 months for a total of 24 months. In one analysis 7 performed at month 12, visual loss of less than 15 ETDRS letters was achieved in 90% of patients receiving ranibizumab and in 49% of those receiving sham injections. Controversies ANCHOR Phase III, randomized, multicenter, double-masked, active treatment controlled study Verteporfin PDT Sham injection (n = 143) Investigator identifies potential patients Reading center confirms angiographic eligibility Predominantly classic lesions (n = 423) Randomization 1:1:1 Sham PDT Ranibizumab 0.3 mg (n = 140) Sham PDT Ranibizumab 0.5 mg (n = 140) Multiple questions have arisen since results from the MARINA and ANCHOR trials were published. These questions mainly relate to dosing, the indications for treatment, and safety. Monthly intravitreal injections are burdensome to patients, physicians, and the healthcare system. Importantly, clear treatment guidelines are necessary if the monthly treatment protocols used in the MARINA and ANCHOR trials are not followed. For example, does anatomic success correlate with visual success? Can the results of anatomic studies guide treatment? Should baseline visual function determine whether or not treatment is initiated? How should patients who were initially treated with PDT be regarded? Can we predict which patients will benefit from prolonged therapy based upon early response? What are the implications of systemic absorption of anti-vegf for the fellow eye and for possible serious 5

8 Anita G. Prasad, MD thromboembolic complications? As seen below, some answers to these questions have been offered. Do Anatomic Characteristics Translate to Visual Outcomes? Most retinal ophthalmologists use fluorescein angiography (FA) and ocular coherence tomography (OCT) to guide the diagnosis and management of exudative AMD. These specialists rely heavily upon findings from FA and OCT, since they may help to determine the optimal dosing regimen of ranibizumab. Further, evaluation of patient response often is based upon both anatomic and visual improvement. ANCHOR Trial The 24-month anatomic outcomes from the AN- CHOR trial appeared to correlate with visual results of predominantly classic CNV that was treated with ranibizumab. 9 Evaluated fluorescein characteristics included the area of classic CNV component, the total CNV area, the total lesion area, and the total area of leakage (including progressive staining). Crucial OCT endpoints included the mean change from baseline central foveal thickness and the total retinal volume. At both 12 and 24 months, these anatomic outcomes were better for ranibizumab than for PDT and were statistically significant. The FA results showed an early and sustained reduction of CNV area in eyes treated with ranibizumab when compared with those treated with PDT. The number of patients followed with serial OCT testing was small; however, these individuals experienced a greater decrease in central foveal thickness following ranibizumab therapy than did those given PDT. All of the examined anatomic outcomes paralleled visual outcomes, further establishing the superiority of ranibizumab over PDT in treating exudative AMD. Which Eye to Treat? Further, in the ANCHOR study, 6 visual-function outcomes based upon quality-of-life (QOL) scoring were greater in patients treated with ranibizumab than in those who were treated with PDT. However, patient-reported binocular visual function based upon the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ- 25) depended upon whether patients received treatment in eyes with the best or worse vision. Although most ANCHOR patients were treated in the eye with worse vision, those treated in the eye with better vision enjoyed more significant, clinically relevant improvements. Similar findings were seen in the MARINA cohort. As expected, the eye with better vision determines visual QOL. However, withholding treatment from eyes with worse vision is not recommended. AMD is a bilateral condition, and the eye with worse vision may have the better vision in the future. PIER As previously described, this ongoing study is comparing the usefulness of a less-frequent dosing regimen of ranibizumab with monthly injections of the drug in managing exudative AMD. 7 Patients initially received three monthly injections followed by quarterly injections of 0.3 mg, 0.5 mg, or sham ranibizumab for a total of 10 injections. During the second year, the sham group is crossed over to the 0.5-mg ranibizumab group. At 24 months, the sham group showed statistically significant greater growth in classic CNV, total CNV, and total lesions than did either ranibizumab-treated group. However, there was no significant difference in change in leakage area between the three groups. Change in visual acuity did not seem to correlate with change in angiographic findings or OCT findings at 24 months 10 ; however, the final PIER data have yet to be released. Impact on Guidelines To help relieve patients and physicians of the burden imposed by monthly ranibizumab injections, guidelines are needed to extend treatment-free intervals and maximize the benefit-to-risk ratio of therapy. Toward that end, studies such as the PIER trial, the Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intra-Ocular Ranibizumab (PrONTO) study, and the Safety Assessment of Intravitreal Lucentis for AMD (SAILOR) are designed to help determine these guidelines. Fung at al 11 found similar visual results to those of the ANCHOR trial and the MARINA using an OCT-guided, variable-dosing regimen of ranibizumab in 40 patients enrolled in a 2-year, open-label, prospective trial. However, commonly used OCT parameters may not adequately relate to CNV activity. Qualitative measurements may be more useful and reliable than are quantitative measurements in assessing CNV activity and response to treatment. Also, high-resolution, spectral-domain OCT may be better than time-domain OCT in detecting subtle pathology and, therefore, preventing visual loss in patients. Detection of subtle morphologic changes appears to be important for maintaining vision in patients who do not receive treatment according to a monthly injection protocol. 12 Time Course and Predictability of Response to Ranibizumab The most important predictors of visual acuity outcomes in the MARINA cohort, in decreasing order of 6

9 MARINA and ANCHOR Revisited importance, were baseline visual acuity, CNV lesion size, and age. 13 However, another essential question regarding outcome was the predictability of long-term response based upon early reactions to monthly ranibizumab injections. In addition, the time course of visual acuity changes that may be expected after treatment begins also was important in determining treatment effect and, therefore, protocols. MARINA To evaluate the course of visual response in the MA- RINA trial, 14 investigators divided patients into four subgroups based upon change in visual acuity at 4 months when compared with those noted at baseline. The first subgroup gained at least 15 ETDRS letters (18%), the second gained 1 14 letters (53%), the third lost 0 14 letters (24%), and the fourth lost at least 15 letters (4%). Visual outcomes at 24 months in these subgroups did not show a consistent correlation between early and late responses. Specifically, a significant percentage of patients who had early loss of visual acuity (30% of group 3 and 11% of group 4) ended up gaining 1 14 ETDRS letters from baseline at 24 months. Further, 5% of patients in subgroup 3 and 11% of those in subgroup 4 gained at least15 letters from baseline at 24 months. Interestingly, early visual response could not be used to predict 2-year response with monthly injections of ranibizumab. The change in FA characteristics was stable in all four subgroups; therefore, it could not be used to predict long-term response. ANCHOR A subgroup analysis of the ANCHOR cohort explored the predictability of final responses based upon early reactions to monthly treatment with 0.5 mg of ranibizumab. 15 Patients were divided into subgroups as described above, based upon their response to therapy at month 4. As in the subgroup analysis of the MARINA patients, the results of this analysis suggested that early response did not predict late response, and patients in subgroups 3 and 4 had late vision gains from baseline. Interestingly, 28% of rapid responders eventually lost visual acuity; this likely was related to rips and/or atrophy of the retinal pigment epithelium. Subgroups 2 and 3 tended to improve the most by 24 months. Also similar to the subgroup analysis of the MARINA, improvement of FA findings was similar in all four ANCHOR subgroups; further, it did not predict 24-month visual outcome. However, the superiority of ranibizumab over PDT was seen by month 1; it increased until month 12 and was maintained at month Interestingly, 50 of the 143 patients in the PDT control group who crossed over to receive 0.3 mg of ranibizumab after receiving months of PDT had no significant visual gains at 2 months following crossover; instead, they maintained their pre-crossover visual acuity after receiving one to six ranibizumab injections. 16 Circulating Levels of Anti-VEGF Some patients treated with ranibizumab perceive a possible benefit to the fellow eye after receiving ranibizumab therapy. Theoretically, such a fellow-eye effect implies systemic absorption of ranibizumab. However, an uncontrolled, open-label, randomized study of escalating ranibizumab doses revealed the presence of noncirculating anti-ranibizumab antibodies in patients treated with up to 2 mg of ranibizumab. 17 One-year data from both the ANCHOR trial and the MARINA study showed no statistically significant change in fellow-eye visual acuity between treatment and sham groups, thereby supporting the theory of limited systemic exposure to ranibizumab. 18 Further, these findings reinforced the idea that systemic circulation of intravitreally administered ranibizumab either is nonexistent or at a concentration too low to be relevant for CNV secondary to AMD. However, systemic circulation of anti-vegf compounds led to concerns about cardiovascular adverse effects. Systemic anti-vegf compounds have real and theoretical risks due to the physiologic role of VEGF in healing and normal development. 19 Safety of Ranibizumab The pooled safety data from the MARINA and the ANCHOR trial showed a possible increased risk of myocardial infarction and stroke in patients receiving 0.5-mg monthly injections of ranibizumab when compared with groups receiving sham injections or 0.3 mg of the drug every month. However, these differences were not statistically significant. Furthermore, the 2-year MARINA results showed no increased risk of systemic vascular events among the three groups. 20 In addition, no increased mortality was noted among treated groups. However, non-ocular hemorrhage was reported in approximately 9% of treated patients versus 5% of controls. Serious ocular side effects occurred at a low rate secondary to the over 16,000 injections of ranibizumab that were given during the course of the MARINA and ANCHOR trials. Presumed endophthalmitis occurred in 0.5% of patients given the 0.3-mg dose, in 1.6% of those given the 0.5-mg dose, and in 0% of controls. Serious uveitis occurred in 0.8% and 1.1% of the 0.3-mg and 0.5-mg groups, respectively, as compared with 0% of controls (Table 1). 8 Longer-term (3-year) experience from the phase I/II ranibizumab trials in patients treated on a compassion- 7

10 Anita G. Prasad, MD Table 1 Serious Ocular Adverse Events in the MARINA and ANCHOR Studies MARINA + ANCHOR (combined) Year 1 (final study database) Year 2 (cumulative) Ranibizumab Ranibizumab Control * 0.3 mg 0.5 mg Control * 0.3 mg 0.5 mg (n = 379) (n = 375) (n = 379) (n = 379) (n = 375) (n = 379) Presumed endophthalmitis Culture-positive (0.3%) (0.3%) Culture-negative (0.5%) 0 1 (0.3%) 4 (1.1%) Culture not done 0 1 (0.3%) 1 (0.3%) 0 1 (0.3%) 1 (0.3%) Uveitis 0 2 (0.5%) 2 (0.5%) 0 3 (0.8%) 4 (1.1%) Rhegmatogenous 1 (0.3%) ll 1 (0.3%) 0 2 (0.5%) ll 2 (0.5%) 0 retinal detachment Retinal tear 0 1 (0.3%) 1 (0.3%) 0 1 (0.3%) 2 (0.5%) Vitreous hemorrhage 0 2 (0.5%) 1 (0.3%) 2 (0.5%) 3 (0.8%) 2 (0.3%) Lens damage (0.3%) (0.3%) * Sham injection-control for MARINA and active treatment-control with verteporfi n PDT for ANCHOR Defi ned as cases reported as endophthalmitis or uveitis in which intravitreal or systemic antibiotics were administered One case was reported as uveitis. One patient was reported as having two episodes of uveitis in the fi rst treatment year and was treated with systemic antibiotics for the fi rst episode; a vitreous culture was not done. One patient had two episodes of uveitis and was discontinued after the second episode. ll One patient had two episodes. MARINA = Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD; ANCHOR = Anti- VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD; PDT = photodynamic therapy Adapted, with permission, from Regillo 8 ate-use basis 21,22 showed a higher rate of both ocular and systemic complications than was reported during the phase III trials. A 4.1% rate of thromboembolic events occurred during the first year, although these events could not be causally or temporally correlated with ranibizumab treatment. 21 The most common side effects were hemorrhages at the injection site and reversible inflammation. 22 Vitritis occurred in 12% of patients treated with a lyophilized form of ranibizumab that no longer is used. Overall long-term treatment was well tolerated; it posed no new safety concerns, and some patients received up to 52 injections. 21 Conclusion Ranibizumab has revolutionized the approach to treating patients with exudative AMD. Ophthalmologists now have greater hopes that patients may maintain visual acuity and have a reasonable chance to gain vision. The nuances of intravitreal therapy given for a chronic disease such as AMD are still being elucidated. However, efforts to lessen the treatment burden have led to a greater understanding of the pathogenesis of CNV and response patterns to anti-vegf therapy. Concerns over the potential for systemic side effects will continue as physicians treat elderly patients afflicted with AMD. Nevertheless, the benefit-to-risk ratio of treating patients with ranibizumab remains high and likely will increase with the introduction of alternative dosing regimens. References 1. Shen J, Samul R, Silva RL, et al. Suppression of ocular neovascularization with sirna targeting VEGF receptor 1. Gene Ther. 2006;13: Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol. 2002;120: Reich SJ, Fosnot J, Kuroki A, et al. Small interfering RNA (sirna) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol Vis. 2003;9: Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina. 2006;26: Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. MARINA Study Group. N Engl J Med. 2006;355: Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. AN- CHOR Study Group. N Engl J Med. 2006;355: Ranibizumab prevents vision loss according to preliminary analysis of phase 3 study. P&T Community: The Online Resource for P&T Decision Makers Web site. June 2, Available at: ptcommunity.com/daily/dailydetail.cfm?chosen= Accessed January 25,

11 MARINA and ANCHOR Revisited 8. Regillo CD. Pivotal phase III trials of ranibizumab for age-related macular degeneration: overview of 2-year safety results of the MARINA and ANCHOR studies. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 9. Sadda SR. ANCHOR Ranibizumab (Lucentis) vs. photodynamic therapy in predominantly classic neovascular age-related macular degeneration: 2-year anatomic outcomes. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 10. Brown DM. Lucentis (ranibizumab) slows growth of CNV and CNV lesion in patients with neovascular AMD: 2-year angiographic results of the PIER study. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 11. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143: Brown DM, Regillo CD. Anti-VEGF agents in the treatment of neovascular age-related macular degeneration: applying clinical trial results to the treatment of everyday patients. Am J Ophthalmol. 2007;144: Boyer DS, Antoszyk AN, Awh CC, Bhisitkul RB, Shapiro H, Acharya NR. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. MARINA Study Group. Ophthalmology. 2007;114: Hariprasad SM. Time course of visual acuity changes with ranibizumab in the 2-year MARINA study of patients with neovascular age-related macular degeneration (AMD). Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 15. Morse LS. Time course of visual acuity changes with ranibizumab in the 2-year ANCHOR study of patients with neovascular age-related macular degeneration (AMD). Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 16. Ho AC. Visual acuity changes with ranibizumab: ANCHOR patients randomized to verteporfin photodynamic therapy (PDT) who crossed over to ranibizumab in year 2. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 17. Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N. Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology. 2006;113:623.e1 632 e Ciulla TA. Ranibizumab (Lucentis ) for neovascular age-related macular degeneration (AMD): one-year results for fellow eyes with neovascular AMD (MARINA, ANCHOR). Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 19. Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol. 2002;29(6 suppl 16): Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am. 2006;19: Boyer DS. Long-term (3-year) experience with Lucentis (ranibizumab) in patients with neovascular age-related macular degeneration in extension study Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 22. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006;113:642e1 642e4. 9

12 Safety and Pharmacokinetics of Retinal Pharmacotherapeutics for Exudative Age-Related Macular Degeneration Rishi P. Singh, MD Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio Nearly half of all patients diagnosed with the neovascular form of age-related macular degeneration (AMD) suffer from severe loss of vision and associated disintegration of quality of life and psychological health. During the 2007 Annual Meeting of the American Society of Retina Specialists, researchers discussed the pharmacologic characteristics of two monoclonal antibodies ranibizumab and bevacizumab that have shown promise in treating neovascular AMD. In addition, they described experiments in cell cultures and in animals that analyzed safety parameters and the pharmacokinetics of these biologic agents. Importantly, some of these experiments delved into associated changes when these drugs were used at different dosing levels or alone and with corticosteroids; they also investigated whether surgical removal of the vitreous humor affects characteristics of these drugs. Certainly, future reports will expand upon these findings and supply more information on how these drugs work in managing AMD. A ge-related macular degeneration (AMD) is the most common irreversible cause of vision loss among residents of developed countries. 1 The two forms of AMD, neovascular (wet) and non-neovascular (dry), are distinct. Over the years, we have learned certain facts and generalities about this disease. For example, the Beaver Dam Eye Study 2 found that the overall prevalence of early AMD was 12.1%. Dr. Singh is an Associate Further, the late, Staff Physician neovascular form of at Cole Eye AMD is present in Institute, Cleveland 10% 20% of all patients with macular Clinic Foundation, degeneration; it is Cleveland, Ohio. associated with the formation of neovascular membranes below the retina and the release of blood and fluid distorting central vision. Overall, severe vision loss occurs in up to 48% of patients with neovascular AMD. 1 Its impact on the quality of life and psychological stability of geriatric patients has been studied extensively; in fact, recent reports have spotlighted the high rate of depression among patients with AMD. 3,4 No cause for AMD has been proven; however, oxidative stress, immune hyperreactivity, and dietary deficiencies all may play a role in its etiology and progression. Age is the key risk factor, and heredity appears to play a role. During the 2007 Annual Meeting of the American Society of Retina Specialists, clinical investigators shared recent findings on new therapies for AMD. Equally important, however, were findings from experiments at the preclinical level, particularly those comparing important agents that target the vascular endothelial growth factor (VEGF). In particular, speakers discussed the safety, pharmacokinetics, and potential side effects of these new therapies given as monotherapy or as part of combination therapy. In addition, they reported on whether surgical removal of the vitreous humor affects the characteristics of these drugs. Targeting VEGF Examination of excised choroidal neovascular membranes and autopsy specimens resulted in the introduction of VEGF as a potential target in treating macular degeneration. 5 9 Retinal pigment epithelial cells on these membranes overexpress VEGF. Similarly, Frank and associates 6 found high levels of VEGF in excised 10

13 Safety and Pharmacokinetics of AMD Therapies membranes of this type in AMD patients. Interestingly, VEGF appears in choroidal neovascularization (CNV) regardless of angiographic subtype. Animal studies supported the role of VEGF in the pathogenesis of AMD. Rats injected with a subretinal recombinant adenovirus vector expressing VEGF exhibited new blood-vessel growth from the choriocapillaris, breaks in the Bruch s membrane, and CNV formation in the subretinal space. 9 Such evidence led to increased research and development of strategies to block VEGF s effects. Monoclonal Antibodies Bevacizumab was the first systemic, anti-angiogenesis therapy approved by the US Food and Drug Administration for use in the treatment of colorectal cancer. 10 Bevacizumab is a full-length, recombinant, humanized monoclonal antibody directed against all VEGF isoforms. Unfortunately, increases in systolic blood pressure and the risk of thromboembolic events that were associated with the drug s systemic infusion were among factors that limited its widespread use. 11 However, since Rosenfeld 12 first reported impressive results with intravitreal fractionated doses of bevacizumab in patients with neovascular AMD, off-label use of this drug began to spread among ophthalmologists. Ranibizumab is a monoclonal antibody fragment directed toward human VEGF; specifically, it is made up of the fragment antigen-binding (Fab) region that clings readily to VEGF-A. The idea of using a Fab fragment for ocular anti-angiogenic activity came from the belief that smaller molecules would penetrate the retina easier than would a full-length monoclonal antibody. 13 The Fab fragment for ranibizumab was developed from bevacizumab, which competitively binds to and inhibits the activity of many VEGF isoforms. There are distinct pharmacologic differences between ranibizumab and bevacizumab. Ranibizumab consists of a Fab fragment and not the full-length monoclonal antibody. Thus, its half-life is estimated to be considerably less than that of bevacizumab thus decreasing systemic exposure and raising the possibility of a need for more frequent injections. Ranibizumab has fewer binding sites for VEGF than does bevacizumab, but it offers several distinct advantages. For example, because ranibizumab lacks the crystallizable fragment region of the antibody, it is less likely to cause complement-mediated inflammation after injection. In addition, the bevacizumab formulation used intravitreally is administered on an off-label basis; the formulation may be too difficult for clinicians to obtain and may offer questionable sterility and stability. Comparing the Safety Profiles of Bevacizumab and Ranibizumab The safety of bevacizumab and ranibizumab has been a hot topic among ophthalmologists. Neekhra 14 and others compared use of bevacizumab alone with ranibizumab monotherapy in cultured retinal neurosensory cells (R28) and pigment epithelial cells (ARPE-19) to determine the drugs in vitro safety. The investigators exposed confluent ARPE-19 and R28 cell cultures to varying 1.25-, 2.5-, or 6.25-mg doses of bevacizumab or to 0.5-, 1.0-, or 2.5-mg doses of ranibizumab for 24 hours. They then determined early apoptotic changes by measuring the mitochondrial membrane potentials; they also performed the JC-1 assay to quantify the ratio of live to dead cells and investigated caspase-3/7 activity to assess the downstream apoptotic pathway. In both R28 and ARPE-19 cells, the mitochondrial membrane potential fell significantly in the cultures treated with 6.25 mg of bevacizumab when compared with cultures that were treated were ranibizumab or that remained untreated (P < 0.001). At the lowest and the middle doses, no significant difference between bevacizumab and ranibizumab was seen. Caspase-3/7 activity increased only in the cultures treated with 6.25 mg of bevacizumab when compared with untreated R28 cell cultures (P < 0.001). Cell viability was not reduced at any dose of drug when compared with controls in both cell lines. Further, clinical intravitreal doses of neither bevacizumab nor ranibizumab were toxic to retinal cells in vitro. Ranibizumab did not show any toxicity at doses up to 2.5 mg; however, higher bevacizumab doses caused early apoptotic changes in both cell lines at 0.5- and 1.0-mg doses and increased downstream apoptotic activity in R28 cells at the 2.5-mg dose. Comparing the Safety Profiles of Combination AMD Therapies In examining potential future targets for angiogenesis, researchers returned to the root causes of AMD and determined that this may not be strictly a vascular disease. The formation of choroidal neovascular membrane involves a complex interplay between genetic predisposition, hypoxia, inflammation, and oxidative stress shown by the presence of nonvascular components (eg, myofibroblasts, macrophages, and other inflammatory cells in AMD specimens). Drusen accumulation leads to localized tissue hypoxia, since it impairs nutrient transport from the choriocapillaris to the outer retinal tissues. Disregulation and mutations in complement factor 3 also have been causally related to an increased risk of CNV development 11

14 Rishi P. Singh, MD in patients with AMD. 15 Thus, therapy with two, three, or four different agents may be useful in treating this disease, and such combination therapies currently are being tested in numerous ongoing clinical trials. Comparing Corticosteroid/Monoclonal Antibody Combinations Kupperman 16 discussed his team s study of the safety of anti-vegf agent/steroid combinations in cultured neurosensory cells. They exposed cultured R28 cells to dexamethasone plus ranibizumab, dexamethasone plus bevacizumab, preservative-free triamcinolone acetonide (PFTA) plus ranibizumab, or PFTA plus bevacizumab. For 24 hours, the cells were exposed in culture to equivalent clinical intravitreal doses of the drugs (ie, 1.25 or 2.5 mg of bevacizumab, 0.5 or 1.0 mg of ranibizumab, 0.4 or 0.8 mg of dexamethasone, 4 or 8 mg for PFTA). They measured toxicity by assessing mitochondrial membrane potential, a hallmark of early apoptosis; further, they determined the ratio of live cells to dead cells using the JC-1 assay and performed cell viability studies using the trypan blue dye exclusion assay. The mitochondrial membrane potential fell significantly in the cells given 4 mg of PFTA plus 0.5 mg of ranibizumab or 4 mg of PFTA and any bevacizumab dose when compared with the groups given combined therapy with dexamethasone. However there was no significant difference between untreated R28 controls and groups given 4 mg of PFTA/0.5 mg of ranibizumab or 4 mg of PFTA/bevacizumab at 24 hours (P > 0.05). Similar results were seen in groups given 8 mg of PFTA/1.0 mg of ranibizumab or 8 mg of PFTA/bevacizumab. At both lower and higher doses, cell viability fell significantly in cell groups given PFTA with ranibizumab or bevacizumab when compared with those treated with dexamethasone combinations or left untreated at 24 hours. Thus, the combination of dexamethasone with pananti-vegf agents was significantly less toxic to retinal neurosensory cells in culture than was the combination of PFTA with pan-anti-vegf agents. In fact, combined use of dexamethasone with ranibizumab or bevacizumab showed a protective effect with respect to apoptosis. Bevacizumab and Ranibizumab Pharmacokinetics Given these differences between bevacizumab and ranibizumab, significant controversy exists in the ophthalmologic community about which drug offers the superior pharmacokinetic profile. Pharmacokinetics in a Rabbit Model Bakri 17 compared the pharmacokinetics of 0.5 mg of intravitreal ranibizumab with that of 1.25 mg of intravitreal bevacizumab in a rabbit model. The team intravitreally injected one eye of each rabbit with 0.5 mg of ranibizumab or with 1.25 mg of bevacizumab. Eyes were enucleated at days 1, 3, 8, 15, and 29. In addition, the team measured the level of intravitreal and retinal bevacizumab in the contralateral eye of animals injected in their primary eyes. Vitreous concentrations of ranibizumab declined in a monoexponential fashion, with a half-life of 2.88 days. Ranibizumab concentrations in the aqueous humor of the injected eye peaked 3 days after drug administration. Elimination of ranibizumab from the aqueous humor paralleled that from the vitreous humor (half-life, 2.84 days). No ranibizumab was detected in the serum or in the fellow eye. In comparison, the vitreous half-life of bevacizumab was 4.32 days; small amounts of the drug were detected in the serum and the fellow eye. Thus, as expected, the vitreous half-life of ranibizumab is shorter than that of bevacizumab. No evidence of ranibizumab leakage into the fellow eyes was found; however, systemic release of bevacizumab was indicated by transfer of the drug into fellow eyes. For comparison, more recent studies demonstrated that the half-life of VEGF-Trap is 4.5 days in the rabbit eye. Testing Pharmacokinetics and Penetration Loewenstein 18 presented data on the pharmacokinetics and serum bioavailability of intravitreal bevacizumab administered to rabbits. In this study, multiple dosing regimens used in clinical practice were given. Nine injections of bevacizumab and ranibizumab were given at 2-week intervals. Vitreous samples were taken 1, 2, 4, and 6 weeks post injection, and blood samples were taken 2 and 6 weeks after injection. Eyes were enucleated 1 and 3 days and 1 and 4 weeks after injection. The mean vitreal concentration of bevacizumab decreased by 37%, 62%, 70%, and 81% at weeks 1, 2, 4, and 6, respectively. Mean plasma concentrations of bevacizumab were pg/ml at 2 weeks post injection and 7.02 pg/ml at 6 weeks. The concentration of bevacizumab in the plasma and in the uninjected eye indicated that the drug circulates systemically following intravitreal administration. Steroid Pharmacokinetics in Posterior Segment Delivery Many studies have examined the combined use of anti-vegf agents, photodynamic therapy (PDT), and dexamethasone in AMD patients. Steroids are used against this disease for two reasons. First, application of 12

15 Safety and Pharmacokinetics of AMD Therapies PDT causes a natural inflammatory component effect that, if not suppressed, may lead to the release of growth factors and cytokines, possibly resulting in recurrent neovascularization. Second, steroids inherently have some anti-angiogenic properties mediated in VEGF and non-vegf pathways. Thus, using dexamethasone theoretically may lead to better outcomes. Any Difference with Vitrectomy? There is a theory that the half-life of dexamethasone is shorter in vitrectomized eyes, since the drug is cleared more rapidly in these eyes and not bound to vitreous humor. Welty 19 described an evaluation of the pharmacokinetics of dexamethasone in vitrectomized and nonvitrectomized eyes. Investigators administered 700 µg of dexamethasone via posterior segment implant device to rabbit eyes; concentrations of the drug were measured in the proximal retina, distal retina, vitreous humor, iris-ciliary body, and aqueous humor of rabbit eyes at multiple time points over 31 days. As expected, in both vitrectomized and nonvitrectomized eyes, dexamethasone concentrations were lowest in the aqueous humor and increasingly greater in the iris-ciliary body, the vitreous humor, the distal retina, and the proximal retina. For nonvitrectomized versus vitrectomized eyes, vitreous clearance was similar (51.9 vs 47.3 ml/d, respectively), as were retinal and vitreous maximal concentrations. The investigators concluded that vitrectomized and nonvitrectomized eyes showed similar retinal and vitreal posterior segment pharmacokinetics following intravitreal dexamethasone implantation of a posterior-segment drug delivery system. Conclusion Along with dramatic clinical results, important preclinical findings on the safety and efficacy of drugs developed against VEGF to manage neovascular AMD are being reported. These studies highlighted the important pharmacokinetic differences between ranibizumab and bevacizumab, the difference in retinal cell toxicities caused by the drugs when used with other agents, and the safety of combination therapy in cell cultures. Certainly, future reports will provide more insight into the clinical relevance of these studies. References 1. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. the Beaver Dam Eye Study. Ophthalmology. 1992;99: Walsh AW, Magargal LE, Wright F, Donoso LA. The early natural history of subfoveal neovascular membranes in eyes with agerelated macular degeneration. Ann Ophthalmol ;21: Rovner BW, Casten RJ, Tasman WS. Effect of depression on vision function in age-related macular degeneration. Arch Ophthalmol. 2002;120: Carabellese C, Appollonio I, Rozzini R, et al. Sensory impairment and quality of life in a community elderly population. J Am Geriatr Soc. 1993;41: Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1996;37: Frank RN, Amin RH, Eliott D, Puklin JE, Abrams GW. Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am J Ophthalmol. 1996;122: Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 1996;37: Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT. Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol ;81: Spilsbury K, Garrett KL, Shen WY, Constable IJ, Rakoczy PE. Overexpression of vascular endothelial growth factor in the retinal pigment epithelium leads to the development of choroidal neovascularization. Am J Pathol ;157: Reddy GK. The addition of bevacizumab to FOLFOX4 prolongs survival in relapsed colorectal cancer: interim data from the ECOG 3200 trial. Clin Colorectal Cancer. 2005;4: Barron H. Important drug warning. July US Food and Drug Administration Web site. Available at: gov/medwatch/safety/2004/avastin_deardoc_mod.pdf. Accessed February 4, Rosenfeld PJ. Avastin for AMD. Retina 2005: changing concepts and controversies. Presented at the 109 th Annual Meeting of the American Academy of Ophthalmology; October 15 18, 2005; Chicago, Illinois. 13. Mordenti J, Cuthbertson RA, Ferrara N, et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125 I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol. 1999;27: Neekhra A. A comparison of the safety profile of bevacizumab and ranibizumab on retinal cells in culture. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 15. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration: genetic factors in AMD study group. N Engl J Med. 2007;357: Kupperman BD. Comparative study of the safety profile of various combinations of anti-vegf and steroid therapies on retinal neurosensory cells in culture. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 17. Bakri SJ. Comparison of the pharmacokinetics of intravitreal ranibizumab and intravitreal bevacizumab. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 18. Loewenstein A. Ranibizumab and bevacizumab pharmacokinetic and penetration studies. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 19. Welty D. Dexamethasone posterior segment drug delivery system: pharmacokinetics in vitrectomized and non-vitrectomized eyes. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 13

16 Optimizing Anti-VEGF Therapy for Neovascular Age-Related Macular Degeneration Mark A. Weisbrod, MD Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida The hot topic and most discussed issue of the 2007 Annual Meeting of the American Society of Retinal Specialists was treatments that target vascular endothelial growth factor (VEGF). Many retina specialists recognize that anti-vegf therapy is useful in patients with neovascular age-related macular degeneration. Ophthalmologists seek better, safer, and longer-lasting treatments for their patients these goals stimulate therapeutic progression. Much of the current research on the retina is concentrated on improving treatments for macular degeneration, and many presentations delivered at this meeting focused on ways to extend and improve efficacies. One of the main conclusions of the presented research was that the adjunctive use of photodynamic therapy and intravitreal corticosteroids with anti-vegf agents may prolong therapeutic intervals and effects, all while maintaining safety and lessening side-effect risks. A ge-related macular degeneration (AMD), a prominent ocular disease, is the most common cause of severe vision loss among people 50 years of age and older in the developed world. Advanced disease affects 1.8 million Americans; with the increase in the aging population, AMD is projected to affect 2.9 million Americans by the year In fact, as the baby boomers grow older, they may well find that AMD will become the main cause of vision loss, as its prevalence is projected to surpass that of glaucoma and diabetic eye Dr. Weisbrod disease combined. 1 7 is a Medical No infallible measures are currently Retina Fellow at the Bascom Palmer Eye available to treat this Institute, disease; however, University several new therapies of Miami Miller School may help when they of Medicine, are combined with Miami, Florida. close observation and follow-up. During the 25 th Annual Meeting of the American Society of Retina Specialists, held December 1 5, 2007, in Indian Wells, California, the hot topic and most-discussed issue was the use of agents that inhibit vascular endothelial growth factor (VEGF). This treatment modality has been found to work quite well for neovascular AMD; presentations delivered during the meeting focused on the efficacy of anti-vegf agents, new treatment regimens in which to use these monoclonal antibodies, and the combined use of anti-vegf drugs with different therapeutic interventions. A History of AMD Therapy Neovascular AMD was once the bane of ophthalmologists and retina specialists in the developed world, as no effective therapies for the disease could be offered to patients. Approximately 30 years ago, thermal laser photocoagulation was first used to treat choroidal neovascular membranes (CNV) in neovascular AMD; this treatment modality offered some hope for managing the disease. Although this hot laser did destroy CNV, it did so nonselectively and at the expense of healthy retina. Unfortunately, this method and its resultant macular scars created little inspiration The late 1990s brought some promise with photodynamic therapy (PDT), which has largely displaced thermal laser photocoagulation as a treatment option. Patients who underwent thermal laser intervention tended to progressively lose vision; with PDT, however, vision was more apt to stabilize PDT selectively targets CNV lesions as it avoids the overlying retina; its use can slow and stabilize vision loss in patients with small and predominantly classic lesions. This technique represented both a breakthrough in AMD treatment and the first therapeutic option to offer hope to patients who were losing sight from this disease. However, the unfortunate aspect of AMD therapy still remained no treatment existed that could reliably 14

17 Optimizing Anti-VEGF Therapy improve vision. Fortunately, recent years have brought an increased understanding of the pathophysiology of neovascular AMD, particularly the factors involved in pathologic angiogenesis. This awareness led to the development of targeted pharmacologic approaches that improved upon the results achieved with PDT alone. VEGF The most important angiogenic contributor to neovascular AMD currently known is VEGF A great breakthrough in the history of ophthalmology the development of ocular anti-vegf therapy took place from 2004 to Using recombinant DNA technology, investigators refined biologic treatments to target and inhibit VEGF, thereby reducing CNV proliferation. By injecting these agents directly into the vitreous cavity of the eye, clinicians could deliver powerful doses to the source of morbidity while simultaneously reducing systemic side-effect profiles. Fortunately, these medications were found to work well. For the first time in the history of ophthalmology, physicians had an effective treatment that could stabilize, and even improve, vision in patients with neovascular AMD. Since then, anti-vegf therapy using pegaptanib, bevacizumab, and ranibizumab has become the mainstay for treating neovascular AMD, as well as other vascular ophthalmic diseases Does Treatment Prior To Ranibizumab Adversely Affect Results? Before ranibizumab became readily available for intravitreal use, other anti-vegf agents were used to treat neovascular AMD. Many clinical researchers have questioned whether treatment prior to ranibizumab adversely effects the results normally seen with ranibizumab monotherapy. Investigators presented research data regarding this important treatment issue. Ranibizumab After Alternative VEGF Inhibitors Ehlers 45 and his team sought to determine how previous anti-vegf therapy for neovascular AMD would affect later treatment with ranibizumab. Specifically, in a retrospective, consecutive-case study conducted over 2 years, they studied AMD patients who had previously received pegaptanib and/or bevacizumab and were then given ranibizumab. The researchers divided patients into a continuity group (70 patients for whom less than 12 weeks elapsed between previous anti-vegf therapy and ranibizumab treatment) and a rescue group (32 patients for whom more than 12 weeks elapsed between previous therapies). Patients were followed for an average of 15 weeks after initial injection of ranibizumab. In the continuity group, prior bevacizumab therapy resulted in an initial gain of 1.8 ETDRS (Early Treatment of Diabetic Retinopathy Study) lines of vision, whereas pegaptanib treatment resulted in a 1.9-line loss. After switching to ranibizumab, patients gained an average of 0.6 lines of vision. In the rescue group, however, patients previously given bevacizumab gained an average of 1.6 lines, whereas those who had received prior pegaptanib suffered an average loss of 2.2 lines. Overall, ranibizumab therapy resulted in an average additional gain of one line in both groups;, 31% experienced a vision gain of more than three lines, 3% experienced a gain of six lines, 94% of treated eyes experienced up to a three-line loss, and 3% of eyes showed a vision loss of more than six lines. The continuity and rescue groups received an averaged 3.0 and 2.7 ranibizumab injections, respectively. Interestingly, ranibizumab performed similarly in both the continuity and rescue groups. Thus, ranibizumab administration following alternative VEGF therapy resulted in stable vision in most patients. In addition, nearly 30% of patients had significant visual gains of over three lines. The authors concluded that ranibizumab appears to be effective against neovascular AMD following treatment with other VEGF inhibitors. Pegaptanib to Ranibizumab Before ranibizumab was approved by the US Food and Drug Administration (FDA) for intravitreal ophthalmic use in June 2006, pegaptanib was the mainstay of neovascular AMD treatment for many patients. Ravage 46 discussed his team s exploration of possible limited efficacy of ranibizumab therapy caused by prior pegaptanib use. The authors performed a retrospective chart review of 114 eyes of 113 patients given intravitreal injections of pegaptanib followed by ranibizumab for neovascular AMD. Patients previously treated with laser, PDT, bevacizumab, or fewer than three injections of pegaptanib or ranibizumab were excluded, leaving 34 eyes of 33 patients. These individuals had received a mean of 4.97 pegaptanib injections and a mean of 5.6 ranibizumab injections. The primary efficacy outcome measured was Snellen visual acuity measured 1 month after the last ranibizumab injection; the mean follow-up period was 56 weeks. After switching from pegaptanib to ranibizumab, 12 eyes (35%) gained at least three lines of vision, 16 eyes (47%) gained fewer than three lines, 2 eyes (6%) lost fewer than three lines, and 4 eyes (12%) lost three or more lines. In all, 78% of eyes that lost vision with pegaptanib treatment stabilized or gained vision after switching to ranibizumab, 15

18 Mark A. Weisbrod, MD and 88% of eyes lost fewer than three lines of vision. The authors concluded that previous pegaptanib treatment did not appear to reduce the efficacy of subsequent ranibizumab therapy in eyes afflicted with neovascular AMD. Therefore, patients switched from a selective anti-vegf therapy to a pan-anti-vegf therapy may show a tendency for further stabilization or improvement in visual acuity. Bevacizumab to Ranibizumab Approval of intravitreal ranibizumab by the FDA led many ophthalmologists to begin treating their neovascular AMD patients with this monoclonal antibody. Berinstein 47 explored whether prior treatment with a 1.25-mg, 0.05-mL dose of bevacizumab limited the efficacy of a subsequent 0.5-mg, 0.05-mL dose of ranibizumab. In all, data on 64 patients were analyzed; the main outcome measures included best corrected visual acuity (BCVA) and central retinal thickness (CRT) as measured using optical coherence tomography (OCT). The mean BCVA improvement in eyes receiving bevacizumab was (by logarithmic minimal angle resolution) to With ranibizumab treatment, patients who did not respond to bevacizumab treatment had an improvement in BCVA from to 0.878, whereas patients who did respond improved from to However, these results were not statistically significant. Results from this trial are shown in Table 1 and Figures 1 3. Eyes that did not respond to bevacizumab showed an increase in CRT; however, 60% of these eyes experienced a fall in CRT following ranibizumab treatment. The authors noticed a slight trend suggesting that patients who do not respond to bevacizumab initially may experience improved BCVA and CRT after ranibizumab therapy. Because they found no statistically significant difference in outcomes when patients were switched from bevacizumab to ranibizumab, they concluded that both bevacizumab and ranibizumab are effective in treating neovascular AMD. Testing Pegaptanib as Maintenance Therapy in Neovascular AMD Investigators affiliated with the ongoing, prospective, uncontrolled, open-label, phase IV Evaluation of Efficacy and Safety in Maintaining Visual Acuity with Sequential Treatment of Neovascular AMD (LEVEL) study presented interim data on their investigation of maintenance pegaptanib therapy to treat neovascular AMD. Friberg 48 reported on interim 24-week results in patients who experienced improvement of neovascular AMD after induction therapy with either bevacizumab or ranibizumab and maintenance therapy with pegabtanib. Table 1 Visual Acuity Results: Bevacizumab Followed by Ranibizumab in Neovascular AMD Final bevacizumab/ Baseline baseline ranibizumab Final Mean 20/157 20/124 20/115 Median 20/126 20/95 20/73 AMD = age-related macular degeneration Adapted, with permission, from Berinstein 47 Figure 1 Rate of visual acuity loss (< 15 ETDRS letters from baseline) among patients with neovascular age-related macular degeneration who were given bevacizumab before they began ranibizumab treatment and at fi nal follow-up after ranibizumab therapy. Adapted, with permission, from Berinstein. 47 Loss of < 15 letters (%) % Final bevacizumab/ baseline ranibizumab 86% Final Patients received booster/rescue therapy with anti-vegf medications at the discretion of the investigators. In all, 83 patients over 50 years of age whose exudative subfoveal AMD lesions responded to prior therapy with at least one, and as many as three, induction treatments days before the study are participating in this research. Pegaptanib maintenance therapy is given every 6 weeks for 48 weeks; patients then are followed through week 54. Principal efficacy measures are visual acuity and CRT. As illustrated in Figures 4 to 7, the interim results showed that mean visual acuity improved after induction therapy and remained preserved with pegaptanib treatment (ETDRS letters at study entry, 64.6; at week 24, 64.0 letters). Overall, 96% of patients lost fewer than three lines of visual acuity from the beginning of the 16

19 Optimizing Anti-VEGF Therapy Figure 2 Rate of visual acuity gain ( 15 ETDRS letters from baseline) among patients with neovascular age-related macular degeneration who were given bevacizumab before they began ranibizumab treatment and at fi nal follow-up after ranibizumab therapy. Adapted, with permission, from Berinstein. 47 Increase of 15 letters (%) 100 Figure 3 Percentage of patients with neovascular age-related macular degeneration having 20/40 vision or better in the treated eye at baseline, after bevacizumab therapy but before ranibizumab treatment, and after ranibizumab treatment. Adapted, with permission, from Berinstein. 47 Patients with 20/40 or better (%) % 32% % 12% 20% 0 Final bevacizumab/ baseline ranibizumab Final 0 Baseline Final bevacizumab/ baseline ranibizumab Final induction phase to week 24, whereas 82% gained at least zero lines, and 37% gained at least three lines. In terms of anatomical results, CRT was stable from study entry to week 24. Further, 41% of subjects required booster therapy; 76% of these patients required only one booster treatment by week 24. This interim analysis showed that pegaptanib maintenance therapy seems to preserve visual and anatomical stability in neovascular AMD patients who received induction therapy with bevacizumab or ranibizumab. Pegaptanib maintenance therapy may reduce patient exposure to nonselective anti-vegf agents while retaining visual gains. In particular, this study and its results may be especially important for patients at high risk for cardiovascular events. Combination Therapy for Neovascular AMD A topic of great interest is the attack of neovascular AMD from multiple directions using different treatment regimens. Recently presented research sought to answer some questions about these methods of therapeutic combination. PDT plus Dexamethasone and Possible Anti-VEGF Therapy Neovascular AMD is associated with broad-spectrum inflammation. Preliminary reports on the use of intravitreal triamcinolone acetonide in neovascular AMD patients are positive. However, combination therapies with PDT, intravitreal dexamethasone, and anti-vegf agents may provide longer term stabilization/regression of these lesions. Ray 49 reported on the use of intravitreal dexamethasone with PDT and the difference between intravitreal anti- VEGF combination strategies against neovascular AMD. With a minimum 4-month follow up, investigators in this retrospective, interventional, comparative case series followed 94 consecutive eyes. In all, 56 eyes were treated with PDT and intravitreal dexamethasone, followed by delayed (by at least 3 months) intravitreal anti-vegf injections as needed. On the other hand, 38 eyes received PDT and intravitreal dexamethasone followed by injection of intravitreal anti-vegf (less than 1 week later). Main outcome measures were Snellen visual acuity and retreatment rates. Of the 56 patients treated with only PDT and intravitreal dexamethasone, 82% required intravitreal anti-vegf 4 months (on average) later, 80% had a loss in visual acuity of fewer than three lines, 43% gained one or more letters, and 20% gained two or more lines. Of the 38 subjects treated with triple therapy, 95% lost fewer than three lines of visual acuity, 87% lost no letters, 58% gained two or more lines, 45% gained three or more lines, and 32% gained four or more lines. Final vision was 20/40 or better in 32% of subjects; this was 17

20 Mark A. Weisbrod, MD Figure 4 Proportion of subjects with neovascular age-related macular degeneration having optical coherence tomography results of 200 µm, µm, and > 225 µm after induction therapy with either bevacizumab or ranibizumab. Adapted, with permission, from Friberg. 48 Figure 5 Mean visual acuity over time in patients with neovascular age-related macular degeneration who received induction therapy with bevacizumab or ranibizumab and then received maintenance therapy with pegaptanib. Adapted, with permission, from Friberg. 48 Proportion of subjects Visual acuity (letters) % > 225 µm % 69% µm 200 µm (~20/100) 65.8 (~20/50) 62.5 (~20/50) Median duration of induction = 15 weeks Figure 6 Proportion of subjects with neovascular age-related macular degeneration who maintained or gained vision after beginning bevacizumab or ranibizumab induction to week 36 of pegaptanib maintenance therapy. Adapted, with permission, from Friberg. 48 Proportion of subjects % 90% Week Figure 7 Mean center-point thickness during pegaptanib maintenance therapy in patients with neovascular age-related macular degeneration previously given bevacizumab or ranibizumab induction therapy. Adapted, with permission, from Friberg. 48 Center-point thickness (µm) % Gaining 3 lines Gaining 0 lines Losing < 3 lines significant for the 5% of subjects in this group who had 20/40 vision initially. From these results, the authors concluded that intravitreal dexamethasone used with PDT is well tolerated. No significant adverse events were reported, and patients intraocular pressure rose above 25 mm Hg in only 8% of Week 36 18

21 Optimizing Anti-VEGF Therapy subjects. However, recurrences are not uncommon with dual therapy, and an additional anti-vegf agent may improve this recurrence rate. Therefore, triple combination therapy with PDT, intravitreal dexamethasone, and intravitreal anti-vegf therapy may lead to significant visual improvement. Ranibizumab With or Without PDT? Prünte 50 spoke on his group s investigation into the safety and efficacy of ranibizumab monotherapy compared with combined use of PDT and ranibizumab in patients with neovascular AMD. In this prospective, randomized, double-masked study, researchers examined two groups of 20 subjects. One group received initial PDT, and the other received sham PDT. Both groups then received 0.3-mg injections of intravitreal ranibizumab at monthly intervals for 3 months. Thereafter, both groups received ranibizumab injections only if disease activity was detectable based upon persistent retinal fluid as seen on OCT or with loss of at least five ETDRS letters in BCVA, increase in CRT of at least 100 µm, or signs of disease progression as confirmed by fluorescein angiography (FA). At the time of this report, the 6-month results were available; however, patients will be followed for up to 1 year. The primary outcome of the study is to determine the proportion of patients requiring retreatment at 6 months. Secondary endpoints include mean BCVA; proportion of patients gaining 5, 10, or 15 letters of BCVA from baseline; proportion of patients losing fewer than 15 letters of BCVA from baseline; mean change in CRT detected by OCT; and mean lesion area found using FA. Preliminary data show that ranibizumab monotherapy may be as potent as combined use of PDT and ranibizumab in terms of CRT measurements. Also observed, the early treatment benefits from combination therapy are limited, which is hypothesized to be due to inflammatory and/or adverse oxidative stress. However, no systemic or ocular safety concerns were noted. FOCUS Subanalysis: PDT Plus Ranibizumab vs PDT Monotherapy The RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety (FOCUS) trial was a 2-year, randomized, single-masked, controlled study of ranibizumab plus PDT versus PDT monotherapy. The study was performed with 162 patients diagnosed with subfoveal, predominantly classic CNV secondary to AMD. All patients received PDT at baseline and then quarterly, as needed. Thereafter, 106 of these patients received 0.5-mg monthly doses of ranibizumab, and 56 received sham injections. Patients participated whether or not they received previous therapy for their subfoveal CNV. Apte 51 discussed his team s subgroup analysis that evaluated FOCUS eyes given no previous therapy for subfoveal CNV. In all, 85 patients given no previous treatment in their study eye for subfoveal neovascular AMD were identified. In all, 58 subjects were randomized to ranibizumab plus PDT and 27 to PDT alone. Outcome measures included variations of visual acuity. At 24 months, visual acuity was better for the ranibizumab-plus-pdt group than for the group receiving only PDT. First, 28% of patients receiving dual therapy gained at least 15 letters compared with 7% of those given PDT only (P = 0.034). Further, loss of fewer than 15 letters occurred in 84% of those receiving the dual therapy and 70% of those given PDT monotherapy (P = 0.130). In addition, the overall mean change in visual acuity was a gain of 4.1 ETDRS letters for the dual-therapy group and a loss of 11.5 letters in the PDT group (P = 0.001). This subgroup analysis showed that treatment-naïve subjects who received ranibizumab plus PDT as their study regimen had better visual-acuity outcomes at 24 months than did those who received PDT alone. These results were consistent with those for the entire study population. Triple Therapy Augustin 52 reported on his team s evaluation of the safety and efficacy of combined verteporfin PDT, dexamethasone, and bevacizumab therapy given to individuals with CNV secondary to AMD. They employed a prospective, noncomparative, interventional case series design, following 104 patients with neovascular AMD every 6 weeks for a mean of 56 weeks. All patients were subjected to reduced-fluence PDT (42 J/cm 2 for 70 s); approximately 16 hours later, they were given 800 µg of dexamethasone and 1.5 mg of bevacizumab intravitreally. Main outcome measures were visual acuity and reduction in CRT by OCT. All 104 subjects received one cycle of triple therapy. Five patients needed a second triple treatment due to remaining CNV activity. The triple therapy was complemented in 23 patients (22%) by an additional intravitreal injection of bevacizumab. Results were statistically significant and promising the mean increase in visual acuity was 2.1 ETDRS lines, and the mean decrease in CRT was 195 µm. The authors found that most subjects experienced significant visual and anatomical improvement after receiving only one cycle of triple therapy. They concluded that this method may be beneficial, since it offers a good 19

22 Mark A. Weisbrod, MD Figure 8 Change in visual acuity from baseline to the time of last follow-up (mean, 54 weeks) after triple therapy. The increase in mean visual acuity was 2.1 lines (P P < 0.01). logmar = logarithmic minimal angle resolution. Adapted, with permission, from Augustin. 52 Figure 9 Change in retinal thickness from baseline to the time of the last follow-up (mean, 56 weeks) after triple therapy. The decrease in mean retinal thickness was 195 µm (P < 0.01). Adapted, with permission, from Augustin. 52 logmar /126 Retinal thickness (µm) Change in visual acuity = letters (P < 0.01) 400 Decrease in mean retinal thickness = 195 µm (P < 0.01) / Before triple therapy Last follow-up 100 Before triple therapy Last follow-up safety profile and a potentially lower cost to the patient and healthcare system when compared with therapies that must be administered more frequently. Also, triple therapy offers less frequent, more convenient dosing and may allow for drug holidays and a theoretical reduced risk of receptor upregulation. Quadruple Therapy Clinical investigators believe that pars plana vitrectomy (PPV) may help angiogenic factors diffuse from the retina more easily, leading to decreased concentrations of these factors and a drop in the formation of CNV membranes. Koch 53 described his team s study of the ability of PPV to aid triple therapy in patients with neovascular AMD. This type of quadruple therapy combines intravitreal injection of dexamethasone and bevacizumab, PDT, and core PPV. The team used a prospective study design to evaluate 50 patients with CNV diagnosed by FA. Patients underwent surgery with the Intrector (Insight Instruments; Stewart, Fla); this 23-G, sutureless pars plana vitrector features an extra port for sequential drug injection delivery during surgery and may offer more accurate drug dosing than possible with other drug delivery methods. Each patient was given 72 seconds of PDT on day 1. On day 2, they received a combined core PPV followed by sequential injections of 1.25 mg of bevacizumab and 800 mg of dexamethasone intravitreally. All eyes were followed every 6 weeks for 14 months; visual acuity was the main outcome measure. During the study period, symptoms worsened and OCT demonstrated recurrence of CNV in nine of these eyes, which were subsequently retreated with the quadruple procedure. Including these eyes, only 1 of the 50 total eyes showed recurrence of CNV by FA. On average, at 14 months, the mean visual acuity improved two lines from baseline. None of the 50 eyes regressed to pretreatment baseline visual acuity levels. The rate of retreatment at 14 months was 18%. The authors concluded that vitrectomy plus PDT, dexamethasone, and anti-vegf therapy play complementary roles. The theory of efficacy is threefold: vitrectomy can potentially aid anti-angiogenesis by lowering the concentration of angiogenic factors; by reducing the viscosity of the vitreous fluid, allowing for increased diffusion of angiogenic factors away from the retina; and by increasing the oxygenation of the vitreous cavity, thereby decreasing ischemia. A potential adverse affect of vitrectomy may be increased and faster clearance of intravitreal medications, which could blunt retreatment outcomes. Conclusion Many retina specialists recognize that anti-vegf treatment works well in patients with neovascular AMD. Much of the current research in the realm of the retina is concentrated on improving treatments for macular degeneration; many investigative teams are focusing especially on ways to extend and improve efficacies. In particular, 20

23 Optimizing Anti-VEGF Therapy an important finding of recent research is that adjunctive use of PDT and intravitreal corticosteroids with anti- VEGF treatment may help to prolong treatment effects and lengthen treatment intervals, all while maintaining safety and lessening side effects. This is an exciting time in the treatment of macular degeneration, as an effective treatment for this insidious disease finally exists. Certainly, future research, such as results from the SUMMIT (DENALI/MONT BLANC) trials, will supply even greater optimism for the visual health of our patients. References 1. Friedman DS, O Colmain BJ, Muñoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122: Javitt JC, Zhou Z, Maguire MG, Fine SL, Willke RJ. Incidence of exudative age-related macular degeneration among elderly Americans. Ophthalmology. 2003;110: Klein R, Klein BE, Knudtson MD, Meuer SM, Swift M, Gangnon RE. Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology. 2007;114: Klein R, Klein BE, Knudtson MD, et al. Prevalence of age-related macular degeneration in 4 racial/ethnic groups in the multi-ethnic study of atherosclerosis. Ophthalmology. 2006;113: Klein R, Peto T, Vird A, Vannewkirk MR. The epidemiology of age-related macular degeneration. Am J Ophthalmol. 2004;137: Mukesh BN, Dimitrov PN, Leikin S, et al. Five-year incidence of age-related maculopathy: the Visual Impairment Project. Ophthalmology. 2004;111: Salm M, Belsky D, Sloan FA. Trends in cost of major eye diseases to Medicare, 1991 to Am J Ophthalmol. 2006;142: Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: three-year results from randomized clinical trials. Arch Ophthalmol. 1986;104: Macular Photocoagulation Study Group. 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Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization verteporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001;131: Azab M, Benchaboune M, Blinder KU, et al. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: meta-analysis of 2-year safety results in three randomized clinical trials: Treatment Of Age-Related Macular Degeneration With Photodynamic Therapy and Verteporfin In Photodynamic Therapy Study Report no. 4. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group; Verteporfin in Photodynamic Therapy (VIP) Study Group. Retina. 2004;24: Bressler NM. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Arch Ophthalmol. 2001;119: Husain D, Kramer M, Kenny AG, et al. Effects of photodynamic therapy using verteporfin on experimental choroidal neovascularization and normal retina and choroid up to 7 weeks after treatment. Invest Ophthalmol Vis Sci. 1999;40: Miller JW. Photodynamic therapy for choroidal neovascularization. The Jules Gonin Lecture; September 1, 2002; Montreux, Switzerland. Graefes Arch Clin Exp Ophthalmol. 2003;241: Miller JW, Walsh AW, Kramer M, et al. Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin. Arch Ophthalmol. 1995;113: Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331: Krzystolik MG, Afshari MA, Adamis MP, et al. Prevention of experimental choroidal neovascularization with intravitreal antivascular endothelial growth factor antibody fragment. Arch Ophthalmol. 2002;120: Ng EW, Adamis AP. Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can J Ophthalmol. 2005;40: Aisenbrey S, Ziemssen F, Völker M, et al. Intravitreal bevacizumab (Avastin) for occult choroidal neovascularization in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2007;245: Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular agerelated macular degeneration. Ophthalmology. 2006;113: e Boyer DS, Antoszyk AN, Awh CC, et al. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2007;114: Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355: Chakravarthy U, Adamis AP, Cunningham ET Jr, et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group. Ophthalmology. 2006;113:1508.e Chen CY, Wong TY, Heriot WJ. Intravitreal bevacizumab 21

24 Mark A. Weisbrod, MD (Avastin) for neovascular age-related macular degeneration: a short-term study. Am J Ophthalmol. 2007;143: D Amico DJ, Masonson HN, Patel M, et al. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group. Ophthalmology. 2006;113: e Emerson MV, Lauer AK, Flaxel CJ, et al. Intravitreal bevacizumab (Avastin) treatment of neovascular age-related macular degeneration. Retina. 2007;27: Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina. 2006;26: Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143: Goff MJ, Johnson RN, McDonald HR, Ai E, Jumper JM, Fu A. Intravitreal bevacizumab for previously treated choroidal neovascularization from age-related macular degeneration. Retina. 2007;27: Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. N Engl J Med. 2004;351: Michels S, Rosenfled MJ, Puliafito CA, Marcus EN, Venkatraman AS. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005;112: Moshfeghi AA, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study. Ophthalmology. 2006;113: e Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular agerelated macular degeneration. Retina. 2006;26: Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355: Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am. 2006;19: Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina. 2006;26: Yoganathan P, Deramo VA, Lai JC, Tibrewala RK, Fastenberg DM. Visual improvement following intravitreal bevacizumab (Avastin) in exudative age-related macular degeneration. Retina. 2006;26: Ehlers JP. Ranibizumab for exudative age-related macular degeneration following previous treatment with alternative vascular endothelial growth factor inhibitors. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 46. Ravage ZB. Visual outcomes in eyes switched from pegaptanib to ranibizumab for neovascular age-related macular degeneration. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 47. Berinstein DM. Efficacy of intravitreal ranibizumab in patients with neovascular age-related macular degeneration previously treated with intravitreal bevacizumab. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 48. Friberg TR. The LEVEL study: maintenance therapy with pegaptanib sodium (Macugen ) in neovascular age-related macular degeneration. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 49. Ray SK. Combined photodynamic therapy with intravitreal dexamethasone for the treatment of neovascular age-related macular degeneration. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 50. Prünte C. A randomized double-masked study comparing Lucentis monotherapy and PDT combined with Lucentis therapy in patients with CNV secondary to AMD. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 51. Apte RS. Outcomes of FOCUS patients with previously untreated subfoveal wet age-related macular degeneration receiving Lucentis +verteporfin PDT or PDT alone. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 52. Augustin AJ. Triple therapy for the treatment of wet AMD. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 53. Koch FHJ. Quadruple therapy for AMD with significantly reduced retreatment rates at 14 months; vitrectomy may help angiogenic factors diffuse from the retina. Presented at the 25 th Annual Meeting of the American Society of Retina Specialists; December 1 5, 2007; Indian Wells, California. 22

25 The Future of Neovascular Age-Related Macular Degeneration Therapy Adrienne W. Scott, MD Duke University Eye Center, Durham, North Carolina The treatment paradigm for neovascular age-related macular degeneration (AMD) changed dramatically over the past decade. In the past, clinicians could only hope that available treatments would slow the progression of vision loss from AMD-related choroidal neovascularization (CNV). Inhibition of vascular endothelial growth factor (VEGF) plays a critical role in slowing the angiogenic cascade associated with CNV. The drugs recently introduced to treat CNV equipped clinicians with a new weapon against vision loss from AMD and provided AMD patients with the promise of immediate visual improvement. During the 25 th Annual Meeting of the American Society of Retina Specialists, experts presented novel therapeutic approaches and combination therapies for treating AMD-related CNV and examined methods to gauge and improve upon anti-vegf treatment. Ongoing clinical trials will provide further insight into the pathogenesis of AMD as researchers continue to improve upon and refine AMD therapies. M ore and more adults in the United States are reaching and surpassing the age of 45 years; in fact, by 2010, people 45 and older will comprise nearly 40% of the US population. 1 Age-related macular degeneration (AMD) remains a leading cause of vision loss among elderly individuals in the Western world. 2,3 Approximately 90% of patients have the non-neovascular (nonexudative or dry ) form of AMD; however, the neovascular (exudative or wet ) form causes the majority of severe vision loss associated with the disease. The economic burden of treating wet AMD poses a significant public health problem; therefore, earlier intervention with effective treatment strategies is needed to decrease the cost to society. 4 Recent dramatic breakthroughs in treating wet AMD have been achieved. Historically, therapies aimed at wet AMD sought to reduce severe vision loss or, at best, to stabilize visual acuity. Laser photocoagulation has been used to ablate the choroidal neovascular complex along with the overlying retina; however, this method is associated with a high risk of choroidal neovascularization (CNV) recurrence Photodynamic therapy (PDT) uses a nonthermal laser to activate verteporfin, a photoexcitable dye, to selectively destroy choroidal neovascular complexes. The Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) trial and the Verteporfin in Photodynamic Therapy (VIP) trial established the efficacy of PDT in treating characteristic CNV lesions; vision loss was prevented in eyes having predominantly classic CNV lesions or smaller 100% occult lesions (eg, less than four Macular Photocoagulation Study disc areas) The mechanisms underlying AMD are not entirely understood. However, inflammation has been identified as a key component. Single nucleotide polymorphisms in the complement factor H gene (CFH) have been linked to the development of AMD. 14 Further, vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of CNV associated with AMD During the 25 th Dr. Scott is a Vitreoretinal Surgical Fellow at Duke University Eye Center, Durham, North Carolina. Annual Meeting of the American Society of Retina Specialists (ASRS), held from December 1 5, 2007, in Indian Wells, California, experts described clinical trials testing various therapeutic approaches and combination therapies for treating AMD and related CNV. In addition, these investigators examined methods to determine the efficacy of anti-vegf therapies and tested devices that may offer promising results in patients with wet AMD. 23