AMD update

Wet AMD: New Theories and Treatments

In the final part of this two-part series, we explain how Anti-VEGF therapies are leading a growing list of promising new approaches.

ANDREW S. GURWOOD, O.D., F.A.A.O., Philadelphia AND JEFFRY D. GERSON, O.D., F.A.A.O., Shawnee, Kan.

The traditional treatment for symptomatic wet AMD begins with a referral to a vitreoretinal specialist, who uses intravenous sodium fluorescein angiography to confirm the diagnosis.^1-6 Also, current treatment planning — particularly the monitoring of treatment effects — is typically based on optical coherence tomography (OCT) findings. In cases in which hemorrhage and exudate obscure the angiogram or the fluorescein angiography poorly defines the choroidal neovascularization (CNV), indocyanine green angiography may offer help in determining whether treatment is feasible.

Limitations of laser therapy

The medical literature has revealed that laser photocoagulation is beneficial in reducing the risk of severe vision loss in patients who have classically definable subretinal neovascular membrane.^1-6 The Macular Photocoagulation Study (MPS) examined the efficacy of treating CNV with laser photocoagulation.^1-4 Although some benefit was seen in all treated groups, outcomes were not ideal, as many patients went on to have significant vision loss. Doctors still use this treatment for some patients who have extrafoveal lesions (greater than 200 μm from the fovea). Unfortunately, the rate of CNV recurrence following treatment is approximately 50%. Most recurrences develop within the first year of treatment, making a three-month follow-up schedule crucial.^{1-3, 5}

Since 2000, the mainstay of laser-related treatment for wet AMD has been photodynamic therapy (PDT) with verteporfin (Visudyne, Novartis). An M.D. administers verteporfin, a photosensitizing dye, intravenously. He then applies a nonthermal red-laser light at 689 nm for 83 seconds, fifteen minutes after the infusion.^46-49 The photo-activated medication seeks out low-density lipoproteins (LDLs) in the blood stream. Proliferating CNV has an affinity for LDLs, enabling the sensitized LDLs to form complexes that the developing CNV absorbs. The dye's activation causes the release of oxygen-free radicals, which produce endothelial damage and thrombus formation within the CNV. This results in CNV closure.

While PDT is effective in shutting down classic- and minimally occult CNV in diseases that produce CNV, such as AMD, use of this treatment results in the expression of vascular endothelial growth factor (VEGF).^{14, 46-50} This is one reason eyecare practitioners need either entirely new treatment modalities or adjunctive therapies with PDT. One such adjunctive therapy: the use of intravitreal triamcinolone acetonide.⁵¹ Research has revealed that patients who have used this combination therapy have required fewer re-treatments, improved visual outcomes and excellent CNV stabilizing effects. One such study revealed an improvement of 1.2 lines of visual acuity and a decrease in re-treatments to 1.2 in the first year of treatment compared with 3.5 with PDT alone.⁵²

Another wet-AMD treatment avenue that clinicians have explored is transpupillary thermotherapy (TTT). This is a novel technique for applying direct hyperthermic energy to numerous posterior segment disorders.^53-55 TTT is a low irradiance, large spot size prolonged exposure (long-pulse) method of applying infrared-laser photocoagulation. During the past decade, doctors have used it to manage benign and malignant ocular tumors, either as a sole therapy or in combination with other treatments, such a plaque radiotherapy, as well as for the management of CNV secondary to AMD.⁵³

Multiple trials have examined this treatment for the stabilization of CNV in AMD. Most of these trials, however, have produced equivocal results, at best, with no long-term positive effect.⁵⁶ For instance, in one study, the researchers couldn't find any statistical difference between the TTT group and the control groups at two years when they compared visual acuity and contrast sensitivity.⁵⁷ Because of such results, TTT isn't a mainstay of wet AMD treatment.

Targeting angiogenesis

As the pathogenesis of AMD and other CNV-inducing retinal diseases becomes more clear, the use of medications known to stop the growth of undesirable new blood vessels (angiogenesis) has emerged as a successful strategy.⁶⁴

Any pathological process that causes retinal pigment epithelium (RPE) and choriocapillaris injury has the potential to produce what appears to be a chronic inflammatory response within the choroid and Bruch's membrane. The result is the formation of an abnormal extracellular matrix, which induces altered diffusion of nutrients to the retina and RPE.^64-69 This pathway precipitates further RPE and retinal damage, causing altered RPE-choriocapillaris behavior, ultimately leading to an atrophy of the retina, RPE and choriocapillaris. This sets up conditions favorable to neovascularization/angiogenesis.⁶⁹

Angiogenesis depends on vascular endothelial cells (VEC) becoming stimulated by the abnormal release of factors such as VEGF and basic fibroblast growth factor (bFGF).⁷⁰ RPE, glial and endothelial cells produce VEGF in response to an ischemic environment. (Ironically, VEGF is also a necessary ingredient for normal vascular development.⁷⁰) Upon activation by one or more of these released factors, the VEC secrete proteinases designed to degrade the endothelial cell wall, promoting the migration of new cells into the extracellular spaces. This directly results in the formation of neovascularization.¹⁸ The common effect of all antiangiogenesis therapeutic agents is the interruption of this pathway at any one of several levels.⁷⁰

The new thinking involving angiogenesis centers on preventing CNV that is already present from progressing or not allowing CNV to grow in the first place.^68,70,71 The RPE seems to constitutively control angiogenesis beneath the retina.⁶⁷ The RPE produces VEGF, which can become overexpressed in ischemic situations, stimulating protease production, proteolysis, endothelial-cell proliferation, neovascularization, vascular permeability and inflammation.^67,70,72 Researchers have found high concentrations of VEGF along with VEGF receptors in the tissue and RPE cells surrounding CNV.⁶⁷ In particular, some researchers believe that the isoform VEGF¹⁶⁵ is of prime importance when dealing with AMD.

Pegaptanib sodium (Macugen, OSI Pharmaceuticals) is designed to target VEGF¹⁶⁵.⁷⁰ Pegaptanib is a chemically synthesized aptamer (polyethylene glycol oligonucleotide) that attaches to and inhibits the function of VEGF.⁷¹ It appears to offer a two-pronged approach to AMD with CNV, enabling control and diminution of leakage as well as suppression of CNV growth altogether.^70,71

M.D.s administer this drug via intravitreal injection. Because it's inhibitory in nature, ongoing therapy, at least theoretically, is required.

In the Phase III VEGF Inhibition Study in Ocular Neovascularization (VISION) clinical trials that led to its approval, subjects received injections every six weeks for two years. The patients treated with pegaptanib in the trials fared better than those receiving usual care, and the benefit wasn't restricted to any one classification of CNV. Approximately 70% of the pegaptanib-treated patients maintained vision (defined as less than 15 letters of visual acuity loss) compared with 55% of the control groups.⁷²

Ranibizumab injection (Lucentis, Genentech) is a monoclonal antibody that works by the same basic mechanism as pegaptanib.^37,73 Ranibizumab, however, binds to and inhibits all isomers of VEGF, not just VEGF¹⁶⁵. Results from the FDA Phase III clinical trials of ranibizumab revealed that up to 40% of patients treated with ranibizumab experienced vision improvement of at least three lines. Results were consistent among all subgroups.^86-87

To investigate whether a longer period between injections could be allowed, a subsequent trial, PIER, tested the effects of three monthly injections followed by quarterly dosing. The PIER approach was less effective than monthly dosing.

Eyecare practitioners have increasingly been using bevacizumab (Genentech, Avastin), a Food and Drug Administration (FDA)-approved drug for the treatment of colorectal and lung cancer, off-label as an intravitreal injection. Initially, practitioners didn't think the drug could penetrate the retina to the choroid, because it has a larger molecule than ranibizumab.⁷⁴ Although no large clinical trials of bevacizumab for AMD have been completed to date, numerous case series and small studies have suggested it's safe and effective for use in the eye.^75-77 The National Institutes of Health (NIH) is sponsoring a head-to-head comparison of the safety and efficacy of ranibizumab and bevacizumab. Enrollment for the trial, named CATT (Comparison of Age-Related Macular Degeneration Treatments Trials), began in January.

RPE cells produce pigment epithelial derived factor (PEDF), a 50-kDa protein that, in addition to neuroprotective effects, potently inhibits angiogenesis.⁶⁷ These PEDF characteristics suggest it, along with VEGF, may modulate the formation of subfoveal fibrovascular membranes, opening another avenue for treatment exploration.⁶⁷ AdPEDF (GenVec) is a pigment epithelial antiangiogenic protein factor under investigation.⁷⁸ Its administration into the eye, via intravitreal injection by way of an adenovector containing the PEDF gene, results in substantial inhibition of new vessel formation in the eyes of animals modeling human disease.⁷⁸ Clinical trials are underway to determine the safety and efficacy of this drug.

Researchers are investigating many other potentially effective antiangiogenic treatments for wet AMD. They include combrestatin A4 phosphate (CA4P, OXiGENE), Sirna-027 (Sirna), VEGF-Trap (Regeneron Pharmaceuticals) and ATG003 (Athenagen). ATG003 is formulated as an eye drop that appears capable of penetrating into the retina and choroid. Phase I trials have shown it to be safe, and the research program is ongoing.

The potential role of steroids

Because steroids exhibit both anti-inflammatory and antiangiogenic properties, they may be useful in the treatment of wet AMD. Several have shown promise when combined with other therapies, such as PDT and anti-VEGF agents.

In most AMD studies completed to date, researchers have administered steroids intravitreally, but sustained-release steroid implants may play a role in the future. The current interest in the use of steroid implants for the treatment of uveitis and diabetic macular edema is expanding to include wet AMD. One implant, which releases fluocinolone acetonide (Retisert, Bausch & Lomb), is already FDA-approved for the treatment of uveitis.^70-75 Others are making their way through clinical trials, including a different fluocinolone implant (Medidur, Alimera Sciences), a triamcinolone implant (I-vation, SurModics) and a dexamethasone implant (Posurdex, Allergan)^70-75.

In addition, anecortave acetate (Retaane, Alcon) is an angiostatic cortisene that inhibits the abnormal growth of blood vessels by working inside the endothelial cell to inhibit the signal for proteolysis — a first step in the process of new vessel growth.⁷⁰ Angiostatic cortisenes have angiostatic (antineovascular) potency but don't contain the chemical groups responsible for unwanted glucocorticoid effects, such as the development of cataracts and elevated intraocular pressure.⁷⁵ In theory, angiostatic cortisenes are able to block signals from multiple growth factors by acting downstream, independently of the initiating angiogenic stimuli.^70,75

Researchers have demonstrated that anecortave acetate is superior to placebo for preserving vision, preventing severe vision loss and inhibiting the growth of all lesion types in wet-AMD patients.⁷⁶ M.D.s administer anecortave acetate behind the eye every six months via a blunttipped, curved cannula. Last year, the FDA issued a letter to Alcon, which stated that approval would require additional clinical study. Alcon is continuing its Anecortave Acetate Risk-Reduction Trial (AART), which is evaluating the ability of anecortave acetate to reduce the risk of progression from dry to wet AMD.

Surgical modalities

Researchers have investigated the safety and efficacy of surgical procedures for the removal of subretinal neovascular membranes via the National Eye Institute's Submacular Surgery Trials (SST).^56,57 A total of 19 clinical centers collaborated to enroll 250 participants whom researchers followed for four years.

The SST involved patients with CNV not only from AMD, but also from histoplasmosis, among other causes. The SST researchers didn't recommend surgery for patients with CNV that resulted from AMD. Among patients with predominantly classic lesions, 44% of control eyes and 41% of eyes having surgery were stable or improved. In patients with CNV and blood hemorrhage approximately the same number of patients were stable regardless of surgery. At two years, however, the only patients who appeared to benefit from submacular surgery were those with CNV whose baseline vision was worse than 20/100.^58,59

Macular translocation is another potential surgical treatment for wet AMD. It's defined as any surgery that has the primary goal of relocating the central neurosensory retina or fovea intraoperatively or postoperatively specifically for the management of macular disease.⁶⁰ Investigators have found that limited macular translocation for the treatment of subfoveal CNV secondary to AMD is associated with improvement in visual acuity in almost 40% of eyes and enables complete laser photocoagulation of the neovascular complex with sparing of the sensory macula in approximately 60% of eyes.⁶¹ While the procedure is invasive, subjected retinas have shown remarkable resilience with at least one report documenting no alterations of retinal macrocirculation in the long-term.⁶² As with other procedures, persistence and recurrence of CNV are the common complications, which ultimately impacts the overall grade of success.⁶¹

Researchers have also examined pigment epithelial cell transplantation to restore damaged retinal infrastructure and pars plana gas injection with tissue plasminogen activator to evacuate subretinal blood and CNV as plausible treatments. The review of this data is ongoing, as the modalities are investigated in concert with existing or standalone procedures.⁸²

Emerging high-tech options for end-stage disease

Patients who have substantial bilateral loss of central vision and AMD deemed untreatable can derive some benefit from low-vision optical devices and vision-rehabilitation training. For example, Dr. Isaac Lipshitz, of VisionCare Technologies, has developed an Implantable Miniature Telescope (IMT).⁸² The implant functions like a telephoto camera lens, magnifying images onto the retina to help improve vision.

Also, efforts are under way to develop artificial vision. For example, The Boston Retinal Implant Project (BRIP), a collaboration of the Massachusetts Eye and Ear Infirmary and the Massachusetts Institute of Technology, is working on an epiretinal prosthesis for restoring vision in patients who have diseases of the outer retina, such as retinitis pigmentosa and AMD.^83-84

Current designs have the epiretinal prosthesis electrically stimulating the inner retina, bypassing the damaged photo-receptors, to produce meaningful vision.^83-84

While the IMT and artificial vision provide hope to patients who have AMD-induced vision loss where none existed before, they're not without significant pitfalls.

In addition to providing a potential obstacle for retinal examination and treatment, a significant learning curve exists for acquiring the eccentric viewing skills necessary for practical performance.⁸⁵

Researchers investigated this in relation to artificial vision and found that improvement is contingent on increased practice time.⁸⁵

Because there's such a large amount of effort and resources being applied in the area of wet AMD treatment, it's only a matter of time until the next treatment breakthrough occurs. OM

References for part 1 and part 2 are available at OM's Web site, which is www.optometric.com.