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September 2009 Newsletter

My Two Cents: Health Care Reform And AMD

MyVisionTest is not a politically-oriented website, and that is not going to change. It is devoted to providing news and information of interest to the AMD community. Health care policy is clearly of vital interest to anyone coping with macular degeneration. With that in mind, I am going to provide an brief analysis of the health care reform debate in the context of how this may affect persons with AMD.

Having lived and worked as a doctor in Canada for a number of years, I am very familiar with that system. There are some important advantages to such a system that make it very attractive to those concerned about the problems of the uninsured. A universal health care system wipes out that problem completely, but creates a number of other much thornier problems. Of greatest concern to those with AMD is access to expensive drugs, such as Lucentis. Under a universal system, money must be carefully allocated by the government to where it will do the most good for the largest number of people. Lucentis was not available in most Canadian provinces for a very long period of time because of its high price tag. In the UK, it was not being used unless a person had already lost the vision of one eye to the disease. This policy resulted in horror stories that were so bad that public pressure eventually forced the government to scrap it. Unfortunately, we can expect very similar, if not identical, problems to arise every time a new, better, and yet more expensive drug becomes available.

Why do we not hear horror stories of people being denied Lucentis therapy in the United States? Because Medicare covers all medically-necessary, FDA-approved treatments. The government can afford to do this only because the Medicare system is subsidized by a large number of working-aged taxpayers who pay into the system but do not draw benefits from it. If the system were expanded to cover all Americans, it could no longer provide such generous benefits. So, one goal of reform is to protect the generous benefits of the current Medicare system, while making private insurance for working-age Americans more affordable. This could be accomplished by a program of tax credits and reforms in rules regarding pre-existing conditions. If all working-age Americans have access to affordable private health care coverage, Medicare can continue to provide state-of-the-art care to our seniors with AMD.

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Update On VEGF Trap-Eye Clinical Trials

VEGF Trap-Eye, an investigational drug, is being developed for the potential treatment of the neovascular form of age-related macular degeneration (wet AMD), DME, and CRVO.

Regeneron Pharmaceuticals announced that the first patient has been enrolled in the Phase 3 program of VEGF Trap-Eye for the treatment of central retinal vein occlusion (CRVO). Regeneron also announced that enrollment in the Phase 2 DA VINCI study of VEGF Trap-Eye in diabetic macular edema (DME) has been completed and data are expected during the first half of 2010.

The Phase 3 program in CRVO consists of two multinational, one-year clinical studies. The COPERNICUS study is being led by Regeneron and the GALILEO study is being led by Bayer HealthCare. Patients in both studies will receive six monthly intravitreal injections of either VEGF Trap-Eye or sham control injections. The primary endpoint of both studies is improvement in visual acuity versus baseline after six months of treatment. At the end of the initial six months, patients will be dosed on a PRN (as needed) basis for another six months. All patients will be eligible for rescue laser treatment. Results from both CRVO studies are expected in 2011.

In wet AMD, Regeneron and Bayer Healthcare are evaluating VEGF Trap-Eye in two ongoing Phase 3 studies, known as VIEW 1 and VIEW 2. Enrollment in these trials is expected to be completed by the end of 2009, and data are expected in late 2010.

WHAT IT MEANS TO YOU: VEGF Trap-Eye is a very promising long-acting anti-VEGF drug that is expected to become available in the US to treat wet AMD within the next few years. Its major attraction is that it may not need to be injected as frequently as currently available drugs, such as Lucentis.

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Scavenger Receptors Involved In CNV Development

A study involving mice finds that lectin-like oxidized low-density lipoprotein receptor type 1 (LOX-1) is involved in the formation of CNV and might thus be a novel therapeutic target for patients with neovascular AMD.

Recently, similarities have been suggested between the pathogenesis of AMD and atherosclerosis. During the progression of atherosclerosis, oxidized low-density lipoprotein (ox-LDL) and its specific receptors, so-called scavenger receptors (SRs), play a critical role. Lectin-like ox-LDL receptor type 1 (LOX-1) is a recently identified SR expressed by vascular endothelial cells that plays an important role in atherogenesis. It is suspected that LOX-1 might also contribute to the formation of CNV in patients with AMD.

In this study on laboratory mice, the expression of LOX-1 mRNA and protein after laser injury was analyzed. In wild-type mice, the relative expression level of LOX-1 mRNA compared with the control increased significantly 6 hours after laser injury and peaked 12 hours after laser injury. The induction of CNV formation following laser injury was significantly inhibited in LOX-1-deficient mice.

The present study revealed the upregulated expression of LOX-1 mRNA in the acute phase after laser injury to the retina. It was also found that the formation of CNV after laser injury is inhibited in LOX-1-deficient mice. This implies that LOX-1 plays an important role in the pathogenesis of CNV lesions.

In summary, the present study shows that upregulated expression of LOX-1 can be induced by laser injury. These results clearly indicate, for the first time, the involvement of LOX-1 and associated factors in the formation of CNV. Although further studies will be needed to clarify the significance of LOX-1 in the pathogenesis of AMD, this work suggests that the inhibition of SRs could be a novel therapeutic modality for AMD.

WHAT IT MEANS TO YOU: Many risk factors for AMD are also risk factors for cardiovascular disease. These include smoking, obesity, and hypertension. Furthermore, many measures that are benefitial for AMD are also benefitial for cardiovascular disease, including fish oil, folic acid, and exercise. So, it makes sense that common pathogenic mechanisms may be at work in both diseases. This study identifies one such common link between these two diseases: lectin-like oxidized low-density lipoprotein receptor type 1. Because LOX-1 appears to be required for the development of CNV, it is possible that knocking out this receptor could form the basis of new treatments for AMD.

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Lucentis And Nonocular Hemorrhage

The ANCHOR trial 2-year results report that the incidence of serious nonocular hemorrhage, such as bleeding stomach ulcers, was only slightly higher in the Lucentis (ranibizumab) group than in the control group, and that the pattern of these events in relation to the timing of the Lucentis injections did not suggest a causal association.

VEGF plays an important role in the healing of mucosal ulcers in the gastrointestinal tract (GIT). Indeed, VEGF has been shown to speed the healing of ulcers. Because ulcers can be present for some time before they bleed; the lack of a close temporal relationship of GIT bleeding to the administration of an anti-VEGF is not necessarily evidence supporting the safety of this therapy.

In the ANCHOR trial, a GIT bleed occurred in 11 of 277 Lucentis patients and 0 of 143 controls. This is a statistically significant difference and should not be dismissed as a slight increase. The occurrence of a spontaneous subdural hematoma in 2 of 277 Lucentis patients is not in keeping with the rarity of this condition in the general population.

The 2-year data from ANCHOR trial adds to the concern about an increased rate of serious nonocular hemorrhages occurring in Lucentis patients. It emphasizes the need to be vigilant with regards to post-marketing surveillance, particularly in reporting GIT hemorrhages and subdural hematoma in any patient who has had anti-VEGF treatment.

WHAT IT MEANS TO YOU: While no medical therapy is 100% safe, intravitreal anti-VEGF therapy has remarkably few adverse effects. One of the few safety issues that has been clearly identified is the occurrence of nonocular hemorrhage, including stroke and gastrointestinal bleeding. The rate of these occurrences is low, but they can be very serious, even life-threatening. It is therefore important that patients considering this treatment be made aware of this risk as part of the informed consent process.

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Blood Stem Cells Restore Vision To Blind Mice

University of Florida researchers were able to program bone marrow stem cells to repair damaged retinas in mice, suggesting a potential treatment for AMD.

"To our knowledge, this is the first report using targeted gene manipulation to specifically program an adult stem cell to become a new cell type," said Maria B. Grant,of UF's College of Medicine. "Although we used genes, we also suggest you can do the same thing with drugs - but ultimately you would not give the drugs to the patient, you would give the drugs to their cells. Take the cells out, activate certain chemical pathways, and put the cells back into the patient."

Scientists chose to build retinal pigment epithelial cells, which form the outer barrier of the retina. In addition to being very specialized and easy to identify, RPE cells are faulty in many retinal diseases, including AMD.

Researchers removed blood stem cells from the bone marrow of mice, modified the cells in cultures, and injected them back into the animals' circulatory systems. From there, the stem cells were able to home in on the eye injury and become retinal cells.

At 28 days after receiving the modified stem cells, mice that had previously demonstrated no retinal function were no different than normal mice in electrical measures of their response to light.

WHAT IT MEANS TO YOU: Stem cell therapy holds great potential for treating a wide varieties of disease, including macular degeneration. However, many people have ethical concerns about using fetal tissue for this purpose. This study, for the first time ever, demonstrates how it is possible to use stem cells from adults to replace damaged retinal cells. If this can replicated in humans, then this study could open the door to more widespread use of stem cell therapy.

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Avastin For Macular Edema

Several studies appeared last month in the scientific literature discussing use of intravitreal Avastin (bevacizumab) injection in the treatment of macular edema from various causes, including diabetic retinopathy, uveitis, and following cataract surgery.

A retrospective review of 115 diabetic patients with diffuse macular edema found that Avastin therapy provides stability or improvement in visual acuity and macular integrity after 24 months of follow-up. All patients were treated with at least 1 intravitreal injection of Avastin and followed for at least 24 months. The mean age of the patients was 59.4 years. The mean number of injections per eye was 5.8 (range, 1-15). Improvements in average visual acuity and central macular thickness were evident by the 1 month follow-up visit, and persisted through 24 months.

The next paper reports on a retrospective review of 27 patients that underwent Avastin therapy for macular edema arising from inflammatory eye disease and followed for at least 1 year. Mean logMAR visual acuity improved significantly from -0.59 at baseline to -0.42 at 1 year. Mean central macular thickness also improved significantly from 383.66 um at baseline to 294.32 um at 1 year. The investigators conclude that intravitreal Avastin is a useful and therapeutically beneficial agent in the treatment of refractory uveitic macular edema.

The final paper is a retrospective review of 31 patients successfully treated with Avastin for cystoid macular edema following cataract surgery. All patients received at least 1 injection of Avastin and followed for at least 12 months. The mean number of injections was 2.7 (range, 1-6). Mean baseline visual acuity was 20/200, and the mean 12-month visual acuity was significantly improved at 20/80. Optical coherence tomography demonstrated that mean central macular thickness significantly improved from 499.9 um at baseline to 286.1 um at 12 months. The investigators conclude that Avastin treatment resulted in a significant improvement in visual acuity and decrease in macular thickness at 12 months.

WHAT IT MEANS TO YOU: Macular edema is a major cause of vision loss. In the past little could be done for these patients. Now it is clear that anti-VEGF therapy is able to decrease macular edema from a wide variety of causes, including diabetic retinopathy, uveitis, and following cataract surgery. Clinical trials are already underway to approve Lucentis for the treatment of diabetic macular edema.

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Foveal Sparing Geographic Atrophy

A study of patients with foveal sparing geographic atrophy (GA) employing a novel combination of spectral domain optical coherence tomography (SD-OCT) and confocal scanning laser ophthalmoscopy (cSLO) finds that thickening of the fovea may reflect a pre-apoptotic stage of retinal cells indicating imminent atrophy.

Geographic atrophy represents the end-stage of dry AMD. On clinical examination, the fovea itself may remain uninvolved by the atrophic process until late in the course of the disease, a phenomenon referred to as foveal sparing.

In this study, simultaneous SD-OCT and cSLO (fundus autofluorescence) were performed in 18 eyes with GA and foveal sparing using a combined instrument. Fundus autofluorescence imaging showed an inhomogeneously reduced signal at the residual foveal island. SD-OCT scans disclosed mitigation of the foveal pit in the absence of extracellular fluid accumulation and an increased mean central retinal thickness of 248 um compared with 225 um in control eyes. Subanalysis revealed marked appearance of swelling and widening of visible structures at the central outer nuclear layer.

In summary, this study reveals previously unknown distinct structural foveal alterations by using combined high-resolution cSLO and OCT imaging in patients with GA clinically sparing the foveal retina. Notably, the loss of the normal foveal configuration occurred despite relatively preserved central visual acuity and in the absence of any cystoid spaces. These findings may suggest an already pre-apoptotic stage of foveal neuronal cellular elements and the development of incipient atrophy before cell death. This may be important for therapeutic interventions aiming to slow the progression of atrophy.

WHAT IT MEANS TO YOU: This study demonstrates how new imaging techniques reveal previously unrecognized changes in the retina of AMD patients, and thereby expand our understanding of the disease process. The underlying basis for the foveal sparing pattern of geographic atrophy remains a mystery, but it remains hopeful that a means can be found to prevent the ultimate destruction of the fovea by the disease process. This study, however, finds evidence that the atrophic process begins long before it is clinically evident. This information may be helpful in the development of future therapies for GA.

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Targeted Photodynamic Therapy

A study on laboratory rats using a modified form of Visudyne (verteporfin) that binds to choroidal neovascular tissue but not normal vasculature finds that photodynamic therapy is much more effective using the modified drug than standard verteporfin, and only 10% of the usual dose is needed.

Factor VII (fVII)-verteporfin binds tightly to endothelial cells of CNV but not normal vasculature. Targeted photodynamic therapy (TPT) is performed using fVII-verteporfin compared with standard photodynamic therapy (PDT) using Visudyne.

In this study CNV lesions were induced in laboratory rats by laser photocoagulation. The rats were then injected intravenously with fVII-verteporfin or Visudyne and treated with a laser in the usual manner.

The rats treated with Visudyne PDT showed leakage in 75% of the CNV lesions on day 7 and 100% of lesions on day 14. The rats treated with TPT at a dose of 0.5 mg/m2 showed leakage in 33% and 36% of the CNV lesions on days 7 and 14, respectively. When the dose was increased to 1.0 mg/m2, leakage was detected in 25% and 23% of the CNV lesions on days 7 and 14, respectively.

The investigators conclude that the frequency of leakage of CNV lesions was significantly reduced using TPT compared with PDT. Furthermore, the dose with fVII-verteporfin was approximately 10% of the usual dose of Visudyne. TPT may improve the efficacy and safety of PDT for treating CNV.

WHAT IT MEANS TO YOU: This study represents a major advance in photodynamic therapy. By localizing the drug to the CNV tissue, and thereby decreasing the amount that must be used, it may be possible to overcome a major disadvantage of PDT - namely collateral damage. Safety-enhanced PDT protocols have been developed that decreased the dosage of verteporfin and the amount of laser energy used to minimize damage to healthy surrounding choroidal blood vessels. For example, the RADICAL clinical trial is studying quarter and half fluence PDT in combination with Lucentis and steroid injections. Although TPD may be expected to have an enhanced safety profile compared to PDT, it remains to be seen if it can produce superior vision outcomes.

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Rheopheresis For Dry AMD

Results of the dry AMD treatment with Rheopheresis trial (ART) find that Rheopheresis is a safe and effective therapeutic option for patients with dry AMD. Rheopheresis is a method of therapeutic apheresis. Forty-three eyes of 43 patients (22 treatment and 21 control group) were analyzed. There was a statistically significant mean difference of 0.95 ETDRS lines (p = 0.01) between the Rheopheresis and control groups at 7.5 months. Nine percent of eyes in the group treated with Rheopheresis gained 2 or more ETDRS lines, as compared with 0% of eyes with no treatment. None of the treated patients had a loss in visual acuity in their study eyes, as compared with 24% of patients without treatment. The investigators conclude that Rheopheresis is a safe and effective therapeutic option for high-risk patients with dry AMD and no therapeutic alternative. This study is in contrast to most previous studies that have failed to find evidence for the effectiveness of Rheopheresis for AMD. This study was published online in Graefes Archive of Clinical and Experimental Ophthalmology.

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Lucentis Improves Vision In Patients With CRVO

Based on 6-month results from a phase 3 safety and efficacy study, Lucentis injection improved vision among patients with macular edema due to central retinal vein occlusion (CRVO), Genentech announced in a press release. The randomized, double-masked, sham-controlled, 12-month CRUISE trial, which enrolled 392 patients with macular edema secondary to CRVO at 95 trial sites in the United States, consisted of a 6-month, sham-controlled treatment period, followed by 6 months of observation during which Lucentis was administered on an as-needed basis. This follows Genentech's announcement earlier in August that its phase 3 BRAVO study showed that Lucentis improved vision in patients with macular edema due to branch retinal vein occlusion (BRVO) out to 6 months. Genentech plans to present full results from its CRUISE and BRAVO studies at the Retina Congress in New York later this year.

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Outcomes Of Lucentis Therapy In Private Practice

A retrospective chart review published in the journal Eye of patients undergoing Lucentis (ranibizumab) therapy for neovascular AMD in four private practices finds that the visual acuity outcomes are comparable to those from randomized clinical trials. A total of 158 patients records were reviewed from four Australian retinal practices. The mean baseline VA 6/17. At 6 months, the mean VA improved to 6/13 and remained stable until month 12. The mean number of injections were 4 in the first 6 months and 9 at 12 months. VA results were comparable with those of the ANCHOR and MARINA trials, and were achieved with a lower number of injections (P<0.0001). The researchers conclude that VA results achieved in daily clinical practice using Lucentis for neovascular AMD are similar to large prospective randomized trials.

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Quality Of Life Improvements Following Lucentis Therapy

A prospective study of near visual acuity, reading speed, central visual field and related quality of life measures in patients with wet AMD treated with Lucentis finds significant improvements is all of the visual function and quality of life measures investigated. In this prospective study 30 patients with wet AMD underwent a full ophthalmological examination, near visual acuity, reading speed, central visual field and quality of life measures at baseline and at 3 months after Lucentis treatment. The investigators found that Lucentis therapy results in significant improvements in important visual qualities, such as near visual acuity, reading speed, central visual field and several activities influencing quality of life. The improvement was greater for near activities than for distance activities. The investigators conclude that the beneficial effects of Lucentis treatment are more extensive than those reported previously. This study was published in the August edition of the journal Acta Ophthalmologica.

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Macugen For Diabetic Macular Edema

A retrospective chart review finds that intravitreal Macugen (pegaptanib sodium) is effective in the treatment of patients with diabetic macular edema (DME). Sixty-three eyes of 48 patients with a minimum of 6 months of follow-up were included in this study. Intravitreal Macugen was found to produce significant improvements in mean visual acuity and reductions in mean central macular thickness (CMT) at 6 weeks. An average of 3 injections were delivered over a mean follow-up period of 6.7 months. The investigators conclude that intravitreal Macugen may produce a clinically meaningful and statistically significant benefit in the treatment of DME. This study was published in the August edition of the journal Acta Ophthalmologica.

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