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 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 4  |  Issue : 1  |  Page : 3-8

Antivascular endothelial growth factor therapies for neovascular age-related macular degeneration: Search for the optimized treatment regimen


Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Date of Web Publication4-Mar-2014

Correspondence Address:
Aki Kato
Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuhocho, Mizuho-ku, Nagoya, Aichi 467-8601
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.1016/j.tjo.2013.12.003

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  Abstract 


Age-related macular degeneration is the leading cause of irreversible visual loss in elderly patients. After photodynamic therapy, therapy targeting vascular endothelial growth factor (VEGF) therapy has become the gold standard for treating neovascular age-related macular degeneration. Although monthly intravitreal injections of anti-VEGF agents are the most promising treatment to improve and sustain vision, as-needed treatments were administered based on the monthly examinations mainly because of costeffectiveness. However, as-needed treatments are considered reactive treatments that burden patients and doctors with required monthly examinations and potentially decrease the improved vision. To address this, the treat-and-extend regimen, a proactive treatment, has been advocated as individualized medicine. This article reviews the characteristics of currently available anti-VEGF agents and treatment strategies.

Keywords: aflibercept, age-related macular degeneration, pegaptanib, ranibizumab, vascular endothelial growth factor


How to cite this article:
Kato A, Yasukawa T, Ogura Y. Antivascular endothelial growth factor therapies for neovascular age-related macular degeneration: Search for the optimized treatment regimen. Taiwan J Ophthalmol 2014;4:3-8

How to cite this URL:
Kato A, Yasukawa T, Ogura Y. Antivascular endothelial growth factor therapies for neovascular age-related macular degeneration: Search for the optimized treatment regimen. Taiwan J Ophthalmol [serial online] 2014 [cited 2020 Apr 6];4:3-8. Available from: http://www.e-tjo.org/text.asp?2014/4/1/3/203922




  1. Introduction Top


Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in elderly patients and the most common cause of legal blindness in developed countries.[1] In Asia, regional studies have indicated that the prevalence rates of early AMD range from 5.6% to 9.2% and those of advanced AMD range from 0.7% to 1.9% in elderly individuals.[2],[3],[4],[5],[6],[7],[8] The prevalence of AMD in Asian populations is increasing.[2],[3],[4],[5],[6],[7],[8]

Treatment options for AMD have improved dramatically over the past 15 years. In April 2000, the US Food and Drug Administration (FDA) approved the first treatment for wet AMD: photodynamic therapy (PDT) with intravenous administration of verteporfin (Visudyne; Novartis International AG, Basel, Switzerland). When PDT is applied, 689-nm laser irradiation activates verteporfin, a photosensitizer, in the eye and closes the abnormal blood vessels. Although the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) study group proved the effectiveness of PDT,[9],[10],[11],[12],[13],[14],[15],[16],[17] its use slowly declined after the more effective therapies targeting vascular endothelial growth factor (VEGF) therapies were approved.

VEGF-A, generally referred to as VEGF, is the most important member in the VEGF family and plays an important role in vascular homeostasis, vascular permeability, and growth of new blood vessels.[18],[19],[20] The VEGF-A gene is organized into eight exons on chromosome 6p21. Alternate gene splicing can generate nine isoforms, the most prevalent of which are VEGF121 and VEGF165. VEGFA is a dimeric glycoprotein that interacts with two tyrosine kinase receptors, VEGFR-1 and VEGFR-2, located primarily on the endothelial cells. Intravitreal injection of a VEGF-A inhibitor is currently the primary treatment for neovascular AMD.

The first FDA-approved anti-VEGF agent for neovascular AMD was pegaptanib (Macugen, OSI Pharmaceuticals, Farmingdale, NY, USA/Pfizer, New York, NY, USA). The FDA approved ranibizumab (Lucentis; Genentech Inc., South San Francisco, CA, USA; Novartis International AG) in June 2006. Bevacizumab (Avastin; Genentech) was launched in 2004 for treating metastatic colon cancer and has been used off-label to treat neovascular AMD. More recently, aflibercept (Eylea; Regeneron, Tarrytown, NY, USA; Bayer AG, Leverkusen, Germany) was approved in November 2011.

This review summarizes the anti-VEGF treatment options and current treatment strategies.


  2. Drugs Top


2.1. Pegaptanib

Pegaptanib, a ribonucleic acid aptamer that inhibits only the pathologic VEGF-A165 isoform, was the first anti-VEGF agent to gain approval for treating neovascular AMD. The VEGF Inhibition Study in Ocular Neovascularization (VISION), that included two concurrent, prospective, randomized, double-masked, dose-ranging, controlled Phase III clinical trials, showed that intravitreal pegaptanib administered at 6-week intervals for 48 weeks reduced the risk of moderate and severe visual loss in patients with neovascular AMD regardless of the angiographic subtype of choroidal neovascularization (CNV).[21],[22],[23] In the group treated with 0.3 mg of pegaptanib, 70% of patients lost fewer than 15 letters of bestcorrected visual acuity (VA), compared with 55% in the control group. The patients treated continuously with intravitreal pegaptanib during the 2nd year of the VISION study had less frequent decreases in vision than those treated discontinuously with pegaptanib or with PDT. Although intravitreal pegaptanib was effective, it was replaced by monoclonal anti-VEGF antibodies.

2.2. Bevacizumab

Bevacizumab is a full-length, recombinant, humanized, monoclonal antibody with two VEGF-A binding sites.[20] In 2004, the FDA approved the drug because of its antiangiogenic effects for treating metastatic colon cancer. Bevacizumab was designed originally to have a long systemic half-life for use in cancer treatment, although it has not been approved for intraocular use.[24] Despite the lack of clinical research to support its safety and efficacy, anecdotal evidence has led to its worldwide use because the drug has a target specificity similar to that of ranibizumab and is less expensive.[25],[26],[27],[28]

To address the safety and efficacy concerns about bevacizumab for treating neovascular AMD, the National Eye Institute commissioned the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT). The 1-year results of the CATT study[29] and the Inhibition of VEGF Neovascularization (IVAN) study[30] reported the noninferiority of bevacizumab and the risk of cerebrovascular events compared with ranibizumab.

2.3. Ranibizumab

The introduction of ranibizumab in 2006 was one of the most exciting advances in the treatment of neovascular AMD. The drug is an antibody fragment that binds to and inhibits all identified VEGF isoforms and was designed specifically to treat wet AMD.[18],[19],[20],[31] Ranibizumab was engineered to have a 100-times higher binding affinity than bevacizumab, despite having one binding site. Given the absence of the Fc segment, the antibody fragment was designed to have a shorter systemic half-life, improved retinal penetration, and a possible decreased Fc-related inflammatory reaction compared to bevacizumab.[32]

The FDA approved ranibizumab after two large clinical trials showed its effectiveness for treating neovascular AMD.[31],[33] The Phase III Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) [31] evaluated the efficacy and safety of ranibizumab for treating minimally classic or occult with no classic CNV associated with AMD. In this 2-year, prospective randomized, double-masked, sham-controlled trial, the patients received monthly intravitreal injections of ranibizumab. In Month 12, 94.5% of patients treated with 0.3 mg of ranibizumab and 94.6% of patients treated with 0.5 mg ranibizumab lost fewer than 15 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. The mean increases in the ETDRS VA from baseline to Month 12 were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group [Table 1]. The Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR)[33] trial was also a multicenter, randomized double-blind trial that compared the efficacy and safety of ranibizumab and PDT with verteporfin in patients with predominantly classic CNV associated with neovascular AMD. In Month 12, 94.3% of patients in the 0.3-mg group and 96.4% in the 0.5-mg group lost fewer than 15 letters from baseline compared with 64.3% in the verteporfin group. The mean increases in the ETDRS VA from baseline to Month 12 were 8.5 letters in the 0.3-mg group and 11.3 letters in the 0.5-mg group; the verteporfin group had a mean loss of 9.5 letters [Table 1]. Both trials had low rates of serious ocular or systemic adverse events.[34],[35]
Table 1: The results of various treatment regimens for anti-VEGF therapies in the treatment of neovascular AMD.

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In these trials, ranibizumab was injected intravitreally on a monthly basis [Figure 1] over 2 years and resulted in a significantimprovement in the mean VA. To minimize the time and cost burden of monthly injections, the interval between injections was extended to lower costs and decrease the injection frequency. In the Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled PIER[36] and EXCITE[37] studies, the efficacy and safety of ranibizumab were studied in patients with subfoveal CNV with or without classic CNV secondary to AMD; patients were treated monthly with intravitreal ranibizumab for the first three injections and every 3 months thereafter. The mean changes from the baseline VA at 12 months were −16.3 letters, −1.6 letters, and −0.2 letters in the sham, 0.3-mg, and 0.5-mg groups in the PIER study and the changes were 4.9 letters, 3.8 letters, and 8.3 letters in the 0.3-mg quarterly, 0.5-mg quarterly, and 0.3-mg monthly groups in the EXCITE study, respectively. The outcomes were better than the control group; however, the treatment effects were inferior to those of the monthly regimen in the MARINA and ANCHOR studies. Subsequently, the Prospective OCT Study with Ranibizumab for Neovascular AMD (PrONTO) study, an open-label, prospective, single-center, uncontrolled clinical study, in which optical coherence tomography (OCT) was used, showed that a variable dosing regimen could achieve visual outcomes as good as the original trials with an average of 5.6 injections in the first study year[38] and 9.9 total injections over the 2-year study.[39] Patients received three consecutive monthly intravitreal injections of ranibizumab 0.5 mg and were retreated based on the monthly examinations when any of the retreatment criteria were met: a VA loss of more than five letters, increased retinal thickness >100 μm seen on OCT, new macular hemorrhages, a new area of classic choroidal neovascular membranes, and persistent fluid. Pro re nata (PRN) dosing was administered [Figure 1]. The study showed a mean improvement in VA of 9.3 letters in Month 12 and 11.1 letters in Month 24 [Table 1].[39]

The CATT Study Group[29] conducted a large prospective trial that compared a PRN regimen with monthly dosing and ranibizumab with bevacizumab. In this multicenter, single-blind, noninferiority trial, patients were randomized into one of four groups: ranibizumab monthly, bevacizumab monthly, ranibizumab PRN, and bevacizumab PRN. In the PRN groups, injections were administered only when active neovascularization persisted. The 1-year study results showed that monthly bevacizumab was equivalent to monthly ranibizumab, with means of 8.0 letters and 8.5 letters gained, respectively. Bevacizumab PRN was equivalent to ranibizumab PRN, with 5.9 letters and 6.8 letters gained, respectively [Table 1]. Ranibizumab PRN was equivalent to monthly ranibizumab, although the comparison between bevacizumab PRN and monthly bevacizumab was inconclusive. The mean number of injections was 6.9 for ranibizumab PRN and 7.7 for bevacizumab PRN. The IVAN study reported similar results in Great Britain[30] in a randomized head-to-head comparison of the efficacy and safety of bevacizumab and ranibizumab, with monthly and PRN dosing evaluated to treat neovascular AMD. In that study, the comparison at 1 year showed that the VA results were equivalent between the bevacizumab and ranibizumab groups with monthly and PRN injections.
Figure 1: Treatment regimens for neovascular age-related macular degeneration using antivascular endothelial growth factor.

Click here to view


Recently, in the HARBOR study[40] evaluated the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and as needed in treatment-naive patients with subfoveal neovascular AMD. The results of this Phase III, double-masked, multicenter, randomized, active treatmentcontrolled study showed that at month 12, the ranibizumab 2.0-mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5-mg and 2.0-mg PRN groups did not meet the prespecified noninferiority comparison. All treatment groups achieved clinically meaningful visual improvements of +8.2 ± 10.1 letters. The PRN groups required about four fewer injections (6.9 or 7.7) than the monthly groups (11.2–11.3; [Table 1]).

In the CATT and IVAN studies, the PRN regimen started immediately after the first injection, but in the HARBOR study, the PRN regimen started after three initial monthly (loading dosing) injections [Figure 1]. In both groups, there were no significant differences between the PRN and monthly groups. We previously compared a loading regimen of ranibizumab with a single-dose regimen for treating neovascular AMD[41] and found that the single-dose regimen was associated with equivalent functional and morphologic retinal improvement with fewer injections compared with the loading regimen [Figure 2], fewer injections during the first 3 months, and less frequent additional treatments during subsequent months [Figure 3]. These results suggested that the loading regimen might not be essential to the starting treatment.
Figure 2: The mean changes in the best corrected visual acuities and mean number of injections in single-dose and loading-dose regimens. (A) Neither regimen is associated with a significant difference in the best corrected visual acuities at any time points. (B) Significantly fewer injections are administered in the single-dose regimen compared with the loading dose regimen. M = months. Note. From “Effect of a single-dose regimen of intravitreal ranibizumab in the treatment of neovascular age-related macular degeneration,” by S. Ikemori et al, 2012, J Clin Exp Ophthalmol 3, p. 221. Copyright 2012, S. Ikemori et al. Reprinted with permission.

Click here to view
Figure 3: The relationship between the number of injections administered during the first 3 months and the frequencies of additional treatments administered in the 1 + pro re nata group. The fewer the number of injections that were administered during the first 3 months, the fewer additional treatments were administered during subsequent months. M = months. Note. From “Effect of a single-dose regimen of intravitreal ranibizumab in the treatment of neovascular age-related macular degeneration,” by S. Ikemori et al, 2012, J Clin Exp Ophthalmol 3, p. 221. Copyright 2012, S. Ikemori et al. Reprinted with permission.

Click here to view


The PRN regimen required monthly visits to the ophthalmologist, fundus examinations, and OCT examinations, which also were considerable burdens to patients, caregivers, the health care system, and doctors. The need for continuous management with the PRN regimen has the potential risk of delaying PRN (reactive)treatment and subsequent decreases in the once-improved vision. To address these issues, Spaide[42] recently advocated the treat(inject)-and-extend regimen, which is designed to minimize the number of office visits, ancillary testing, and intravitreal injections and perform reactive rather than proactive treatment. Specifically, patients received an injection at each visit independent of the exudative changes. The interval between each visit (injection) was extended by 2 weeks if the macula was dry or shortened if the macula remained exudative [Figure 1]. Several retrospective studies have reported the results with this regimen,[43],[44],[45],[46] and [Figure 4] shows the effect of the treat-and-extend regimen in a case. Toalster et al[47] conducted a recent [Table 1] prospective, multicenter, nonrandomized trial and found that the treat-and-extend protocol is safe and efficacious for treating neovascular AMD.
Figure 4: The treatment responses of a patient who was switched to the treat-and-extend regimen. With the pro re nata regimen, this patient had regular recurrences at intervals of 10–14 weeks. Therefore, the treat-and-extend regimen was adopted with the initial dosing interval of 10 weeks. At the visit immediately prior to the next injection, the macula remained dry. Treatment was performed proactively and the dosing interval was extended to 14 weeks. However, because a recurrence was observed 14 weeks later, the dosing interval was shortened. Thereafter, the macula became dry again and the dosing interval was extended step by step. CRT = central retinal thickness; IVR × 1 = one injection of intravitreal ranibizumab; IVR × 2 = two injections of intravitreal ranibizumab; IVR × 3 = three injections of intravitreal ranibizumab; M = months; MV = macular volume; T and E = treat-and-extend.

Click here to view


2.4. Aflibercept

A fourth anti-VEGF drug, aflibercept, was recently approved. This is a fully human, recombinant fusion protein comprised of the immunoglobulin (Ig) binding domain of VEGFR-1 and VEGFR-2 fused to the Fc portion of human IgG1. The drug works by binding tightly to three isoforms of growth factors (VEGF-A, VEGF-B, and placental growth factor).[48] Aflibercept has a long half-life in the vitreous cavity, and is thus expected to be more effective and long-standing, resulting in fewer injections. VIEW 1 and VIEW 2 (VEGF Trap-Eye, Investigation of Efficacy and Safety in Wet AMD)[49] were double-masked, multicenter, parallel-group, activecontrolled, randomized trials that compared monthly and every-2month administration of intravitreal aflibercept injections with monthly ranibizumab injections. Patients with active subfoveal CNV were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8; [Figure 1]), or ranibizumab 0.5 mg monthly. The results showed that all aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab injections for the primary endpoint. The 2q4, 0.5q4, and 2q8 regimens were effective in 95.1%, 95.9%, and 95.1% of patients in the VIEW 1 study, and effective in 95.6%, 96.3%, and 95.6% of patients in the VIEW 2 study, respectively, whereas monthly ranibizumab was effective in 94.4% of patients in both studies [Table 1]. The ocular and systemic adverse events were similar across the treatment groups. By halving the number of monthly visits, the every-2-month regimen of aflibercept may decrease the treatment burden. Less frequent injections also may increase the ocular safety. Although the VIEW studies were not powered to identify differences in rare but serious intraocular and systemic complications, fewer injections may substantially decrease the cumulative population risk of such events.[50]


  3. Conclusion Top


The current evidence-based treatment strategy for managing neovascular AMD supports the use of bevacizumab, ranibizumab, or aflibercept. However, the optimal treatment regimen, especially in the maintenance phase, remains controversial. For individualized therapy, an adequate regimen should be chosen and, if necessary, during long-term management, switched to a more effective regimen such as monthly/every-2-month fixed dosing regimens, the PRN regimen, the treat-and-extend regimen, or alternative strategies such as PDT.

Acknowledgments

The authors received support from a Grant-in Aid for Scientific Research (B) from the Japan Society for the Promotion of Science and a Grant-in Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan.

Conflicts of interest: The authors have no financial relationships with any organizations.



 
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    Figures

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