Age-related macular degeneration (AMD) is the most common irreversible cause of visual loss within the developed world. The neovascular form of AMD accounts for 10% to 20% of the total patients with macular degeneration and is associated with choroidal neovascular (CNV) membrane formation below the retina and the release of blood and fluid distorting central vision.1 Severe visual loss occurs in up to 48% of patients with the neovascular form.2 Its impact on the quality of life and psychological stability of geriatric patients has been studied extensively; recent reports have highlighted the high rate of depression among patients with AMD.
Over the past decade, a variety of introduced therapies had variable success to treat the neovascular form of AMD. The Macular Photocoagulation Study (MPS) found that focal laser photocoagulation treatment for leaking blood vessels benefited visual outcomes,3-5 however, lesions found to be amenable to treatment had to meet strict criteria. Few lesions met the criteria and subfoveal treatment resulted in an immediate permanent loss of central vision.

Furthermore, the treatment delayed or reduced severe visual loss but did not improve vision. Photodynamic therapy (PDT) using verteporfin (Visudyne; Novartis, East Hanover, NJ) for selective photochemical thrombosis of neovascular vessels showed better results in the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) study and the Verteporfin in Photodynamic Therapy (VIP) trials.6, 7 In these trials, treatment reduced visual loss, but only a few patients improved vision and some patients remained ineligible for treatment based on lesion characteristic.7

The Role of VEGF in Angiogenesis, AMD
Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein that induces angiogenesis, vascular permeability and lymphangiogenesis and may also act as a survival factor for endothelial cells by preventing apoptosis. VEGF is upregulated by hypoxia. There are several major isoforms that are produced by alternative exon splicing of the VEGF gene: VEGF121, VEGF165, VEGF189, and VEGF206. Minor isoforms include: VEGF145, VEGF148, VEGF162, VEGF165b and VEGF183.

All isoforms contain a plasmin cleavage site and may be cleaved by plasmin to generate a smaller, diffusible, bioactive form — VEGF110. VEGF165 is the most abundantly expressed isoform and most pathologic.

VEGF was suspected as a potential target in AMD due to examination of excised CNV membranes and autopsy specimens.8-12 Studies reported that retinal pigment epithelial cells overexpressed VEGF, and high levels of VEGF were found in excised AMD-related CNV membranes.9 Presence of VEGF is regardless of the CNV’s angiographic subtype. Animal studies have also supported the role of VEGF in the pathogenesis of AMD.

In rats, the injection of a subretinal recombinant adenovirus vector expressing VEGF led to new blood vessel growth from the choriocapillaris, the formation of breaks in Bruch’s membrane and CNV formation in the subretinal space.12 This evidence has lead to the research and development of strategies to block VEGF’s effects.

Pegaptanib sodium
Pegaptanib (Macugen; OSI Eyetech, New York, NY/Pfizer New York, NY) is a pegylated aptamer that consists of an RNA oligonucleotide ligand that binds human VEGF165 with high affinity and specificity. Pegaptanib does not bind other VEGF isoforms.

The VEGF Inhibition Study In Ocular Neovascularization (VISION) trial examined the efficacy and safety of pegaptanib in patients with subfoveal neovascular AMD. This randomized, controlled, double-masked, multicenter, dose-ranging trial found that 70% of patients receiving a 0.3 mg intravitreal injection every 6 weeks lost <3 lines of vision versus 55% of control patients receiving sham injection in all types of CNV at 12 months.13

Furthermore, the clinical benefits were maintained after 102 weeks for pegaptanib-treated patients. There was a 45% relative difference at the end of 2 years. Data released from the same trial demonstrated enhanced efficacy associated with earlier treatment in a small subset of study patients. The researchers found that 12% to 20% of pegaptanib-treated patients gained ≥15 letters of visual acuity versus 0% to 4% who received usual care.14

The Federal Drug Administration (FDA) approved pegaptanib in December 2004 with a broad label that includes treatment of all neovascular AMD, regardless of lesion composition.

Ranibizumab
Ranibizumab (Lucentis; Genentech, San Francisco) is an affinity matured fragment antigen binding (FAb) of a recombinant, humanized, monoclonal antibody directed toward all isoforms of VEGF. It was engineered to allow for greater retinal penetration and short half-life to avoid systemic absorption.

Ranibizumab was tested in the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the Treatment of Neovascular AMD (MARINA) study, which demonstrated that ranibizumab was a safe and effective treatment for minimally classic and occult with no classic CNV lesions.20 Study results indicated that 95% of ranibizumab-treated patients experienced <3 line loss of vision compared with 62% of sham-treated patients after 12 months (P<.0001).

Patients treated with ranibizumab experienced a mean improvement in vision and a large proportion had a 15-letter increase in vision, something rarely found in studies with pegaptanib.

ANCHOR trial
The Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) study also showed the efficacy in of ranibizumab in treating predominately classic CNV lesions when compared with PDT. Approximately 94% to 96% of ranibizumab-treated patients had <3 line loss of vision compared with approximately 64% of patients treated with PDT during the first 12 months of the 24-month study (P<.0001).21

Patients treated with ranibizumab also had a mean improvement in vision. Studies are underway to evaluate alternative dosing regimens instead of every 4 weeks. Ranibizumab is currently undergoing review by the FDA.

Bevacizumab
Bevacizumab (Avastin; Genentech) was approved by the FDA in February 2004 for the treatment of colorectal cancer.15 It is a full-length, recombinant, humanized, monoclonal antibody against all VEGF isoforms. Based on the positive results of the ranibizumab studies — and since bevacizumab was available — Rosenfeld et al16 began to test the use of systemic bevazicumab in patients with exudative AMD.

The results of their off-label prospective trial with systemic bevacizumab were positive with improvement evident on angiographic, optical coherence tomography (OCT) and visual acuity. Elevation of systolic blood pressure and the potential for systemic thromboembolic events were concerning, however.17 To limit systemic side effects, Rosenfeld et16 al administered intravitreal bevacizumab injections.

Historically, bevacizumab was thought to be too large of a molecule to cross into the subretinal space.18 In the summer 2005, Rosenfeld reported the first patients treated with intravitreal fractionated doses of bevacizumab with impressive results.19 Current widespread adoption of this therapy is seen; bevacizumab is readily available and inexpensive. Studies are ongoing to evaluate the safety and efficacy of bevacizumab in the treatment of AMD.

There is considerable debate over the role of bevacizumab in light of its off-label status and unknown safety profile. How does it compare with ranibizumab or pegaptanib, and what will happen when ranibizumab is approved? Because ranibizumab consists of a FAb fragment and not the full-length monoclonal antibody, the half-life is considerably less than bevacizumab, thus decreasing systemic exposure.

Ranibizumab is less likely to cause postinjection complement-mediated inflammation because it lacks the fragment cristallizable (Fc) region of an antibody. Finally, the reconstitution and formulation of bevacizumab for intravitreal raises questions of sterility and stability. Thus, ranibizumab may be a better drug. At this time, bevacizumab and the examinations and procedures associated with its delivery are not reimbursed. This may soon change as more studies are performed. It is unclear how bevacizumab will fit in when approval of ranibizumab occurs.

VEGF-Trap
VEGF-Trap (Regeneron Pharmaceuticals, Tarrytown, NY) is a high-affinity, recombinant, fusion protein consisting of the immunoglobulin binding domains from VEGF receptor 1 and 2 fused to the Fc of human Immunoglobulin G (IgG).

Previous work has shown that VEGF-Trap induced regression in established tumors and metastases, inhibited growth of xenografted tumors, and limited the formation of malignant ascites.22 The initial phase 1 clinical trials using VEGF-Trap for the treatment of AMD evaluated systemic delivery. These studies were halted because of dose-dependent hypertension among treated patients. Patients showed evidence of efficacy and a dose-dependent decrease in retinal thickness with treatment, and it was decided to continue VEGF-Trap development with intravitreal delivery. Phase 1 and 2 studies are currently enrolling patients to evaluate the safety and efficacy of intravitreal administration of VEGF-Trap. Results are to be expected in mid-to-late 2006.23

Future Agents
RNA interference is based on a natural cellular process where small double-stranded RNA fragments cause activation of protein complexes that selectively degrade the messenger RNA (mRNA) of target genes. This has distinct advantages over the previously mentioned therapies. First, it allows for a more complete blockade by targeting the intracellular transcript that forms VEGF.

Second, because a single mRNA codes the formation of multiple protein copies of VEGF, small-interfering RNA (siRNA) based therapy theoretically could result in a greater suppression of VEGF. Several companies are currently developing siRNAs targeting the VEGF cascade including Acuity Pharmaceuticals (Cand5; Philadelphia), Alnylam Pharmaceuticals (ALN-VEG01; Kulmbach, Germany) and Sirna Therapeutics (Sirna-027; San Francisco). Both Cand5 and Sirna-027 are in phase 1 and/or 2 testing.
Another area of VEGF targeting beginning clinical studies is the inhibition of tyrosine kinases (TKI). These agents are critical in the downstream cascade of signaling that occurs after VEGF binds with its receptor and have shown considerable promise in preclinical studies.24-26 Several companies are evaluating TKI for the management of CNV using delivery modalities.

A revolution for AMD
The development of anti-VEGF drugs has revolutionalized our approach to the treatment of AMD. Hopefully, the implementation of such pharmacologic developments will lead to better clinical outcomes and result in an improved quality of life for our patients.
Although many studies demonstrate the safety and efficacy of intravitreal therapy for AMD, clinicians should emphasize the realistic facts about these therapies to patients. First, outcomes for most patients are stable vision or a slower decline than the natural course of the disease. Second, patients may need a minimum of 1 to 2 years of therapy before seeing benefit or changing course to other therapies.

Patients who were treated with other modalities may not experience as much visual improvement because of the damage incurred previously or delayed institution of therapy. Frequent injections (every 4 to 6 weeks) for an indefinite period of time may be expected. Long-term efficacy and safety of these medications — for bevacizumab in particular — are unknown and should be disclosed to patients.

Future randomized clinical studies with head-to-head comparison of these medications would be helpful in determining the best modality in this devastating disease. 

Peter K. Kaiser, MD, and Rishi P. Singh, MD, are from the Cole Eye Institute, Cleveland Clinic, Cleveland. Dr. Kaiser disclosed that The Cole Eye Institute has received research grant support from Alcon Laboratories, Allergan, Eyetech Pharmaceuticals, Genentech, Regeneron, Novartis, QLT and Sirna Therapeutics. Dr. Kaiser disclosed that he is a member of the scientific advisory boards and/or a consultant for Alcon, Allergan, Bausch & Lomb, Genentech, Regeneron, Novartis, Occulogix, QLT and SIRNA Therapeutics. Dr. Kaiser may be reached at pkkaiser@aol.com or 216-444-6702.

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