Summary of Research and Developments in Macular Degeneration, 2010-2011

by Dan Roberts
June 19, 2011
Introduction
Since 2006, I have done my best to condense the high points of the previous year’s macular degeneration research into a single report that is concise and understandable for the layperson. I do so, because I understand first hand how important it is to be aware of everything being done on our behalf by the scientific community. Fear of the unknown is often the worst part of this disease. Information, therefore, is an effective weapon that we should all have access to.
Developments in the field of low vision treatment are occurring at an exponential rate. So fast that vision restoration and cures could conceivably become realities in some of our lifetimes. Through the years, we have seen impressive achievements in the areas of surgery, nutrition, and pharmacology. This past year, pharmacology has taken the lead, so most of this summary will discuss the drugs that are now under development and in clinical trials.
PHARMACOLOGY
Results From the Comparison of AMD Treatments Trial (CATT)
The most interesting development this past year was the findings from the Comparison of AMD Treatments Trial (CATT), sponsored by the National Eye Institute. This trial was designed to study the relative safety and efficacy of Genentech’s Lucentis, the approved treatment for wet AMD, and off-label Avastin, a similar, but less expensive drug originally developed by the same company for treatment of colon cancer. At the end of the first year of the two-year trial, the two compounds have been found to be extremely similar in their improvement of mean visual acuity and in the occurrence of adverse events.
These are top line results, with more detail to come later. Meanwhile, the subjects will continue under observation as the trial proceeds through its second year. Five related trials are also underway in the UK and Europe, all of which deserve watching for potential new findings.
In addition to the general findings, the results also revealed surprisingly little difference in the efficacy of scheduled injections and the efficacy of injections delivered on an as-needed basis for both drugs.
The general consensus of opinion among doctors using Avastin is that they will continue using the drug off-label. At the same time, they will ensure that patients are fully aware of adverse events (SAE) that have been determined at this time to be neither significant nor insignificant to the end results. No discussions have yet been held with the Centers for Medicare and Medicaid Services (CMS) regarding changes in policy for reimbursement for Avastin as a treatment for wet AMD.
Another report will be published following conclusion of the trials next year. Meanwhile, it is important that patients discuss their treatment with their doctors for a full understand of the current findings.
Fenretinide
ReVision Therapeutics’ Phase 2 trials have been completed with a surprising outcome. In addition to expected positive results, researchers have found that the drug fenretinide, taken orally once a day, also reduces by 2.2-fold the rate of conversion to neovascularization (hemorrhaging) in patients with geographic atrophy (end stage dry AMD). This means that fenretinide, in addition to slowing the progression of dry AMD, could also become a pre-treatment for wet AMD, a condition that is responsible for 85-90% of AMD related vision loss.
As a result of these findings, the scientists hope to move forward to a larger phase 3 clinical trial to evaluate this therapeutic effect in a larger patient population.
Lucentis “Super Dose”
Genentech’s HARBOR trial has revealed that a higher dose of Lucentis (ranibizumab) for treatment of wet AMD has been found to be more effective in fifty “incomplete responders” over 24 months. “Incomplete responders” are individuals who have shown no appreciable response to the normal treatment. Intravitreal injection with 2.0 mg, however, rather than the current 0.5 mg, led to a significant decrease in retinal thickness (swelling) after the first 3 months, plus a 4-letter gain after 8 weeks. This improvement was maintained up to one year with no serious adverse events.
AL-8309
Alcon Pharmaceuticals Company is developing a topical drug, AL-8309, which, when given one to two times daily has been shown to block the inflammatory response in rodent retinas exposed to blue light. Since inflammation is thought to be a contributor to development of AMD, and since AL-8309 inhibits the complement system that initiates inflammation, the drug is showing promise as a potentially effective treatment for dry AMD.
VEGF Trap-Eye
Regeneron Pharmaceuticals, Inc. and Bayer Health Care, have entered phase 3 trials comparing the anti-angiogenic drug, VEGF Trap-Eye, with Lucentis for treatment of wet AMD, central retinal vein occlusion (CRVO), and diabetic macular edema (DME). The drug is expected to improve patients’ visual acuity over time without the need for monthly intravitreal injections.
In the Phase 3 GALILEO study, patients with CRVO received six monthly injections of either VEGF Trap-Eye at a dose of 2mg or sham injections. At the primary endpoint patients gained 15 letters of vision from baseline. At a secondary endpoint they gained, on average, 18 letters of vision. These early findings showed that VEGF Trap-Eye has the potential to provide patients and physicians a new treatment option for central retinal vein occlusion.
Regeneron is now seeking marketing approval for treatment of CRVO in the United States. Bayer HealthCare is planning to submit regulatory applications in Europe in 2012.
Lucentis
The current treatment protocol is recognized by the company as a burden on patients. Researchers are, therefore, working on ways to improve the delivery method. One possibility is reduction of frequency of injections.
Practitioners are finding that not all patients are responding as expected with Lucentis. About 10% of patients have actually lost 2-3 lines of acuity after treatment. To address this issue, the new DAWN study will identify ahead of time, by means of a blood test, how well a patient will respond to the drug. Treatment could then be adjusted for best benefit. Genentech scientists are also looking at potential genetic causes for those patients who are not responsive to Lucentis.
As a side note, Novartis Pharmaceuticals Corporation is initiating a 5-year patient management study (LUMINOUS) to gain further understanding of long-term effectiveness of Lucentis, treatment patterns, long term safety, and health-related quality of life issues. The study was launched in 34 countries in March 2011.
NT-501
Another drug, NT-501, developed by Neurotech, is a treatment designed to protect, and in some cases rescue, dying photoreceptors in the retina in order to preserve vision. This treatment relies on a growth factor produced by the human body called neurotrophic factor (CNTF). Human cells engineered to produce CNTF are implanted in the eye in a tiny specially designed capsule which protects these cells from the patient’s immune system and continually releases a small amount of the growth factor. Neurotech has announced that this so-called encapsulated cell technology (ECT) has completed Phase 3 trials with good results.
There have been no serious ill effects associated with the treatment or with having the capsule implanted. NT-501 is also being tested as a treatment for other retinal degenerative disorders including retinitis pigmentosa.
New Treatment Possible for Dry AMD
A new study published in the February 2011 journal Nature reports that dysfunction of an enzyme called DICER1 may be a cause of geographic atrophy (dry AMD). Researchers at the University of Kentucky found that levels of the enzyme are higher in healthy retinas than in eyes affected by AMD. They demonstrated that low DICER1 levels lead to buildup of a toxic genetic material called alu, This, in turn, causes geographic atrophy (dry AMD).
Two treatments may potentially halt the progression of the disease: one which boosts levels of the enzyme, and the other which breaks down the toxic Alu RNA. To test the hypothesis, the University of Kentucky is planning to start human trials by the end of 2011.
SURGERY
Human Retinal Cells Developed From Non-embryonic Stem Cells
On March 24, 2011, Georgetown University Medical Center reported in the journal “Stem Cells” that their researchers have, for the first time, produced retinal cells from human induced pluripotent stem (hiPS) cells, rather than embryonic stem cells. hiPS cells are derived from the patient’s own body, thus bypassing the moral issue of using human embryos.
This is an important step in the research, but several viability and safety issues still need attention before hiPS cells can be introduced into humans.
Microplasmin for vitreal adhesion
A single intravitreal injection of a new drug called microplasmin has been shown in Thrombogenics’ Phase 3 trials to relieve adhesion of the vitreous (the gel that fills the inside of the eye) to the inside of the retina. This reduces risk of damage from the tugging of the vitreous on the retina, which can lead to such conditions as diabetic vitreous hemorrhage and macular hole. It accomplishes this by inducing a gentle post vitreous detachment (PVD), and that can help eliminate the need for surgery to remove the vitreous from the eye.
Implantable Miniature Telescope Approved
VisionCare Ophthalmic Technologies, Inc. announced on July 6 that the FDA approved the company’s Implantable Miniature Telescope to improve vision in patients with end-stage AMD.
The telescope implant is designed to improve visual acuity. The magnification provided by the implant reduces the impact of the blind spot caused by end-stage AMD.
VisionCare will conduct a post-approval study to monitor patient outcomes under commercial conditions. A second smaller study will follow clinical trial patients for an additional two years.
VisionCare is submitting an application to the Centers of Medicare and Medicaid Services for a new code to establish Medicare beneficiary access to this implantation procedure. For more information about the telescope implant and related treatment program, see www.centrasight.com.
Radiation Therapy Continues To Show Promise
In October, NeoVista made public the company’s one-year results from the preliminary study MERITAGE-I. The study was designed to examine their radiation procedure (epimacular brachytherapy) for patients undergoing chronic therapy with anti-VEGF agents for wet AMD. Study results showed that a single radiation treatment stabilized visual acuity in 79% of this patient population, while decreasing the number of anti-VEGF injections required. Most importantly, 47% of patients enrolled in the study experienced some improvement in their visual acuity, while 10% of patients gained 15 or more letters of visual acuity at 12 months.
The study results also pointed to a favorable trend with respect to a reduced number of anti-VEGF injections following delivery of radiation versus the period of time leading up to the intervention. In addition, 25% of patients remained injection-free at 12 months following the procedure.
NUTRITION
AREDS2
The National Eye Institute’s second Age-Related Eye Disease Study (AREDS2) is continuing. The original AREDS formula was approved in 1998. This time, subjects are being given a slightly altered formula containing the original vitamin dosages minus beta-carotene, a lower dosage of zinc, and addition of lutein, zeaxanthin and omega-3. The purpose is to see if the revised formula will help even more to slow the progression of AMD to the advanced stages. The new study began in June 2008, and results are expected in the year 2013. Meanwhile, many nutriceutical companies have gone ahead and updated their products to reflect the more current research. It is advisable to discuss with all of your professional care providers any additions or changes in your diet or supplementation.
TECHNOLOGY
iPad2
The most common complaint about low vision technology is the high price of assistive devices. With government assistance available only to veterans, many people simply cannot afford to purchase the products that can make their lives so much easier. With this year’s introduction of Apple’s new iPad 2, however, that has almost become a non-issue.
For less than half the cost of most electronic magnifiers, visually impaired people can now own virtually every low vision gadget all wrapped up in a device no larger than a thin book. The iPad2 can read to you in 21 languages, magnify images and text, tell you what color your shirt is, guide you across town, magnify the face of your grandchild, call a friend, shop online, manage your finances, identify currency, help you type a letter, read Braille, tell the date and time, and so much more. And it can all be done using tactile buttons or touch screen controls. Apple also offers a year of personal training on the iPad2 for $99.
This has set the standard, and we can now expect more advances at even lower prices to come our way. And if that doesn’t brighten your day, read on:
Driving Blind
The National Federation of the Blind announced on January 29, 2011 that, for the first time, a blind individual has driven a street vehicle in public without the assistance of a sighted person.
The car was equipped with laser range-finding sensors that conveyed information to a computer inside the vehicle, allowing it to create and constantly update a three-dimensional map of the road environment. The computer sent directions to vibrating gloves on the driver’s hands, indicating which way to steer, and to a vibrating strip on which he was seated, indicating when to speed up, slow down, or stop.
Also this past year, Google revealed it’s own version of what they call an autonomous vehicle. The company has been working in secret on vehicles that can drive themselves.
According to the New York Times, seven Google test cars have driven 1,000 miles without human intervention and more than 140,000 miles with only occasional human control. One even drove itself down Lombard Street in San Francisco, one of the steepest and curviest streets in the nation. The only accident, engineers said, was when one Google car was rear-ended while stopped at a traffic light.
They say this technology may be available to the public in eight years. If that happens, one of the thorniest problems of low vision, transportation, will no longer be an issue.
AMD Numbers Continue to Fall
“The number of Americans with macular degeneration fell 30 percent in about two decades,” according to a study published in the January issue of the Archives of Ophthalmology, “reducing the threat from the leading cause of [visual impairment] among the elderly.”
The study authors explained that “Reductions in smoking and blood pressure, key risks for the condition, and increased use of antioxidant vitamins that keep the disease at bay may account for the decline”. The study also revealed that the rate of advanced AMD among all the participants was 0.8 percent, and that AMD affects approximately 6.5% of adults ages 40 and over, compared with the previous estimate of 9.4%.
Data was obtained from 7,081 people, aged 40 and older, who took part in the 2005 to 2008 National Health and Nutrition Examination Survey.
Other research has been confirming this trend. In 2007, a study found a lower 5-year incidence of early AMD in patients born or examined more recently, compared to similarly aged persons born or examined in an earlier period. 2,968 participants with early AMD and 3,588 participants with late stage AMD were examined at 5-year intervals between 1988 and 2005 as part of the Beaver Dam Eye Study.
Then, in 2010, a study reported to the Association for Research in Vision and Ophthalmology showed a 68% lower incidence of macular degeneration in the Baby Boom population. That research suggested that improvements in environment, behaviors, and other such modifiable factors may have contributed to the results. The “birth cohort” effect remained even after adjusting for AMD risk factors such as obesity, heavy drinking, and sunlight exposure.
The results of this research further emphasize the importance of environmental and lifestyle factors to retinal health.
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This wraps up my summary for this year. I hope you will share this information with your family, friends, and doctors. You are in a position to help others understand, and by doing so, you will be serving a valuable purpose. Thank you for your help!

Encapsulated Cell Technology (ECT)–A New Drug Delivery System

by Dan Roberts
Updated March 30, 2015
A means of delivering drugs into the retina on a time release basis is being developed and proven safe and effective. It is achieved by a method called Encapsulated Cell Technology (ECT), being tested by Neurotech SA with support from the National Eye Institute (NEI), Bethesda, Maryland.
A drug called ciliary neurotrophic factor (CNTF) is produced and released by a device called Renexus (formerly NT-501) into the vitreous of the patient’s eyes. CNTF is produced by genetically modified cells contained in the ECT. The ECT acts, therefore, like a miniature factory for production and distribution of the drug. The device may prove to be a safer, more effective and more convenient drug delivery system than the injection procedure currently used for administration of the antiangiogenic and anti-inflammatory drugs in AMD patients.
Results from Phase 1 trials showed not only that the ECT device works and is safe, but that CNTF is a potentially effective drug treatment for slowing down all forms of hereditary retinal diseases by its trophic action on nerve cells. Trophic factors are molecules that can protect nerve cells from degeneration. When treated with CNTF, subjects showed an improvement in acuity of one line compared to no improvement in the partner eye.
In March 2009, Neurotech announced that NT-501 stabilized best corrected visual acuity (BCVA) at 12-months, with 96.3% (p=0.078) of treated-patients losing fewer than three lines of vision, or 15 letters, versus 75% of the patients in the sham-treatment group. These results from the Phase 2 trials were reported to the Association for Research in Vision and Ophthalmology (ARVO) meeting on May 6, 2009 in Ft. Lauderdale.
In May 2011, results from Phase 3 presented to the annual ARVO meeting showed continued promise, with CNTV leading to stabilization of vision in subjects starting with good visual acuity of at least 20/63, and lessening of the progression of lesion size in geographic atrophy.
Neurotech announced on March 30, 2015 that the FDA approved a Phase 2 clinical study of the cell therapy. The study will enroll 150 patients. The safety and efficacy of one NT-503 ECT implant will be compared to Eylea injections every 8 weeks in patients who have been treated with at least 3 anti-VEGF injections and still have active disease.  Patients will be followed for 2 years with a 12-month interim assessment.

Summary of Research and Developments in Macular Degeneration: 2006-2007

by Dan Roberts
This is a summary of all major research and developments pertinent to macular degeneration that occurred between mid-May 2006 and mid-May 2007. It is organized by month of occurence under the subsets “Pharmacology,” “Surgery,” “Nutrition” and/or “Miscellaneous.” The final section, “The Future,” summarizes work in progress that may lead to promising developments in the coming year.
An audio/visual presentation of this summary is available on the International MD Support Group website. In most cases, full articles are available from the MD Support Library. Copies are permitted as long as proper credit is given.
May 2006
Pharmacology
Triple therapy found to be effective for wet AMD
Triple therapy with a combination of intravitreal Kenalog, photodynamic therapy (PDT), and intravitreal Macugen (pegaptanib sodium) has been found to be safe and effective for treatment of wet AMD. Improvements in visual acuity and in macular thickness in sixteen patients were reported at the ARVO meetings by JM Colina-Luquez MD, ophthalmologist, New England Retina Associates, Hamden, Connecticut
7.9% of those who had had prior therapy had an improvement in visual acuity of 3 lines or more, compared to 33% of those with newly diagnosed disease. This is an improvement in acuity from 20/200 to 20/50.
Macugen may present risk of increased IOP
Optometrist Allison Toler, OD (East Florida Eye Institute, Stuart, Florida) and ophthalmologist Ronald Frenkel, MD, Bascom Palmer Eye Institute, University of Miami, Miami, Florida) reported to the ARVO meeting that treatment with pegaptanib sodium (Macugen) may run the risk of significantly increased intraocular pressure (IOP). In a study of eight patients, mean pre-injection IOP was 12.9 mm Hg and mean post-injection IOP was 39.4 mm Hg. The IOP returned to normal in most cases within 30 minutes of the injection, and eventuially all patients showed normal IOP levels.
The researchers then compared Macugen injection to Avastin (bevacizumab) injection. The spikes in IOP were similar, but IOP decreased faster in patients who underwent Avastin treatment. As a result of these findings, physicians were cautioned to closely monitor IOP levels in glaucoma patients who are also being treated with Macugen.
Intravitreal injections affect the fellow eye
S.D. Martin et al (Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Kentucky Lions Eye Center, Louisville, KY) reported to the ARVO meeting that intravitreal injections of anti-VEGF drugs (i.e. Kenalog, Macugen and Avastin) also have an effect in the fellow eye. This is possibly the result of systemic absorption. Conclusions were drawn from analysis of pre- and post-injection ocular coherence tomography (OCT) graphs of 29 patients over a six-week period. Intravitreal use of these drugs, therefore, should be done with caution, since such absorption might also affect other systemic functions of the body. The researchers suggested that lower dosages of Macugen may be wise.
Surgery
No association between cataracts and macular degeneration
Susan Bressler, MD (Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland) reported to ARVO that analyses of data from the Age Related Eye Disease Study (AREDS) has shown “no clear evidence of an association between cataract surgery and neovascular age-related macular degeneration,” and that “most patients undergoing cataract surgery can probably be reassured that surgery will not markedly increase their risk for progression to neovascular age-related macular degeneration.” The conclusion was drawn from checking outcomes after 1,704 cataract surgeries and 543 neovascular ARMD events after baseline among 8,152 eyes with a median follow-up of nine years.
Nutrition
New Lutein and Zeaxanthin Findings
The Melbourne Collaborative Cohort Study presented evidence to ARVO that neither lutein nor zeaxanthin are protective against the progression of AMD.
The same study of over 41,000 subjects showed an association between high intake of unsaturated fats and development of AMD, and that olive oil intake may be beneficial.
At the same meeting, a second multicenter study of 300 subjects showed that daily supplementation with 18 mg lutein and 2.4 mg zeaxanthin over six months resulted in a slight increase in macular
pigment density.
Miscellaneous
Blue light risk
Research from the University of Chicago has confirmed that the blue light wavelength peaking at 440 nm causes retinal damage through photochemical change and apoptotic cell death. The study authors repeated the recommendation stressed by MD Support at the 2005 ARVO meeting that blue blocking lenses be worn to protect the retina from direct exposure to strong blue light (i.e. sunlight, either natural or artificial).
June 2006
Pharmacology
VEGF Trap
Regeneron Pharmaceuticals announced positive results at the sixth week of its Phase I dose-escalation study of intravitreal anti-angiogenic drug VEGF Trap. 21 patients received a single injection of one of six doses, from 0.05mg to 4mg, and were monitored for 12 weeks.
July 2006
Pharmacology
Avastin Demonstrating Safety and Efficacy
In a paper presented at the 2006 meeting of the Association for Research in Vision and Ophthalmology researchers suggested that off-label Avastin has demonstrated safety and efficacy after over 5,000 injections. In July 2006, Lebanese researchers published positive results from a small study of 17 patients. Thirteen eyes (76%) showed total resolution of subretinal fluid, and the median acuity improved from 20/200 to 20/50. No systemic or ocular side effects were reported, but further controlled studies are needed.
Lucentis Approved for Wet AMD
On June 30, the Food and Drug Administration (FDA) approved Lucentis (ranibizumab injection) for the treatment of patients with wet age-related macular degeneration (AMD). Lucentis is the first treatment which, when dosed monthly, can maintain the vision of more than 90 percent of patients with this type of AMD.
“This approval is of great importance for the 155,000 Americans who are diagnosed each year with AMD, a common cause of severe and irreversible vision loss in older adults,” said Dr. Andrew von Eschenbach, Acting Commissioner of Food and Drugs. “At a time when our elderly population is rapidly increasing, this product preserves quality of life for those affected by this disease, helping them to regain the ability to participate in everyday activities such as reading and driving.”
The per vial price of Lucentis is $1950. The average patient will receive between 5 and 7 treatments in the first year of therapy ($9,750 and $13,650 a year), which is covered by Medicare and secondary insurance. Most patients will have a co-pay of $50 or less per treatment. For patients who are uninsured, Genentech has established financial assistance through its Access to Care Foundation. Eligible patients who cannot afford their co-pays may be able to receive co-pay assistance through one of the independent public charities to which Genentech provides funding. For more information, call 1-866-LUCENTIS (1-866-582-3684).
Research
Godfather gene discovered
News has come out of Sydney, Australia about a so-called “Godfather Gene” called C-jun that, if switched off, may be another way of stopping inflammation and neovascularization. Researchers based at the Centre for Vascular Research, University of NSW, have developed a drug that may be able to act as that switch.
The drug, called Dz13, targets the gene and destroys it, thus cutting off the blood supply that not only harms the retina, but also promotes cancerous tumors and inflammation. Scientists are, therefore, hoping that Dz13 will prove to be effective against several diseases, including wet macular degeneration, cancer, heart disease and arthritis.
Human trials were to begin in early 2007, so it may be several years before definite conclusions can be drawn.
August 2006
Pharmacology
New eyedrop treatment being tested for wet AMD
On August 22, 2006, Athenagen, Inc. announced that it had begun human testing of its topical (eye drop) therapy for wet AMD. Phase I trials of ATG003, a formulation of mecamylamine, are expected to generate data by the end of the year, and the company plans to move directly into a larger safety and efficacy study in early 2007.
Research
Stem-cell procedure promising
University of Washington scientists reported on August 14, 2006 that they have successfully used stem cells to treat diseased tissue in mouse retinas.
Tom Reh, UW professor of biological structure and leader of the research, said that if such research continues to be successful, the first human tests of the technique could begin in about two years.
The UW team used a mix of “growth factors,” natural proteins that encourage cell growth to coax the embryonic cells into becoming retinal cells. When the scientists mixed the new cells with damaged mouse retina, the cells replaced key cells essential to vision. Reh said his team now have begun injecting the new cells into the eyes of retina-damaged mice to see if there is actual vision improvement. “If things,” he said, “continue to look [good] over the next six months and other research moves ahead, we should be in a position to use this for eye diseases.”
Miscellaneous
Age-related Macular Degeneration Does Not Cause Blindness
A poll sponsored by MD Support shows that a strong majority of people affected by AMD do not think of themselves as blind, and they do not want the term to be used to describe their visual impairment.
The results of a recent MD Support opinion survey show that 93% of people with AMD are averse to the use of the word “blind” in connection with their condition. 91% of them do not consider themselves to be blind, 93% know they will not go blind from AMD and 93% think the word by itself should not be used in connection with AMD. These are convincing statistics that are now available for the first time to eye care professionals, patient advocacy organizations and public service agencies. Hopefully, the message is clear and will be heeded.
September 2006
Pharmacology
Research
Stem cell experiments slow vision loss in rats
On September 21, 2006, Raymond D. Lund, (University of Utah’s John A. Moran Eye Center in Salt Lake City) and Robert Lanza (Advanced Cell Technology Inc. in Worcester, Mass.) reported that cells grown from human embryonic stem cells slowed vision loss when injected into the eyes of rats with a disease similar to macular degeneration.
According to a recent press release (“Stem Cell Experiments Slow Vision Loss in Rats” by Rick Weiss, Washington Post, Thursday, September 21, 2006; Page A12) the researchers achieved the transformation in all 18 stem cell lines they worked with, proving that their approach can consistently produce the crucial pigment cells. Then they injected the cells, about 20,000 per eye, into the retinas of 14 rats with a genetic disease similar to macular degeneration. Eight control rats received eye injections without any cells.
Forty days after treatment, the team measured retinal electrical activity in response to flashes of light, and it found that the treated rats were twice as responsive as the untreated ones, which by then were going blind. A separate test — which tracks eye and head movements in response to a moving display, a measure of an animal’s ability to discern fine details — showed that the treated rats had twice the visual acuity of the untreated rats nearly three months after treatment.
Microscopic examination of the retinas at autopsy showed that the treated eyes had healthy photoreceptor layers five to seven cells thick, while the untreated eyes had an average thickness of just one cell. (Healthy rats have layers 10 to 12 cells thick.) None of the cells divided abnormally or grew into tumors, the team reported in the September issue of the journal Cloning and Stem Cells.
Miscellaneous
Medicare Starts Paying for Visual Rehabilitation Services
People who qualify for Medicare and whose eyesight has significantly declined due to macular degeneration, diabetes or certain other conditions can now get up to nine hours of vision rehabilitation through a new Medicare-sponsored demonstration project.
The five-year project is available in six areas of the United States: Atlanta, New York City, New Hampshire, Kansas, North Carolina and the state of Washington. It will allow the Centers for Medicare and Medicaid Services (CMS) to study the demand for – and effectiveness of – services aimed at helping visually impaired individuals make the most of their remaining vision.
After the project concludes, administrators will decide whether to extend reimbursement for those services to all Medicare recipients across the country, Greene said. “We think there’s a strong possibility that they’ll do that.”
In the six areas chosen, Medicare will pay for therapy services provided in clinics or at home by certified vision rehabilitation therapists, orientation and mobility specialists, low vision therapists and occupational therapists, but not the low vision aids themselves.
October 2006
Research
New Molecule Discovered
Case Western Reserve University and the Cleveland Clinic Cole Eye Institute have discovered a molecule that triggers neovascularization in the retina. Called Carboxyethylpyrroles (CEPs), it attaches to proteins in the retina, causing blood vessel growth that leads to sight loss in wet AMD. The next step is to identify the receptors that are activated by the CEPs and then develop drugs that can block the formation of the toxic molecule.
Miscellaneous
Leaders in the Low Vision Industry Reach Consensus on Important Patient Issues
MD Support took part in a roundtable discussion hosted by the National Association of Visually Handicapped in Washington, D.C. It proved to be informative and worthwhile, as the participants left with a better understanding of the concerns of patients and a consensus of opinions on potential improvements in care and management. Leaders from twelve advocacy, health and research organizations were present, in addition to representatives from Novartis Ophthalmics (sponsors) and the National Eye Institute. Three main topics were discussed in the day-long session:
1. Identifying and appreciating patient expectations and experiences with AMD diagnosis and treatment in order to help health care personnel provide individualized, efficient and holistic treatment.
2. The role of support services in helping AMD patients continue to perform daily tasks and maintain a positive attitude.
3. The language used to discuss the effects of AMD on vision and the effects of using terms such as “visually impaired,” “legally blind” and “blind.”
Unanimous consensus was reached on three principal issues:
1. Patients must be guided to information and emotional support immediately upon diagnosis. This would be best accomplished through support services at the clinic, direction to low vision counseling and/or guidance to reliable community and Internet resources.
2. Areas of concern that need to be addressed by support services are activities in daily living (including transportation), low vision evaluation, counseling, orientation and mobility, employment, and library resources.
3. To help lessen the often profound emotional response to a diagnosis of AMD, sensitivity is needed in the language used to describe the condition. In particular, the word “blind” should not be used without qualification to describe AMD to patients.
A Safer Way to Treat SAD(ness)
Research has shown that melatonin is a necessary antioxidant for physical and psychological health. The high point of the melatonin cycle, however, lasts 9-10 hours, and the average person does not have (or allow) that much time to sleep. Blue light exposure during the day may make a person less drowsy and depressed by suppressing melatonin levels in the blood, but the body still needs up to 10 hours of high melatonin levels for peak health.
Compounding the dilemma, blue light exposure appears to lead to macular degeneration in some people, due to interruption of the photoreceptor cells’ metabolic visual cycle (see www. mdsupport. org/library/hazard.html). This makes blue light therapy risky, especially for people with compromised retinas.
The obvious answer is to get more sleep; but for those who cannot do so, one option to potentially harmful blue light therapy has been proposed by Richard L. Hansler, Ph.D. (Director, Lighting Innovations Institute, John Carroll University. Executive Director, Light and Health Foundation). Dr. Hansler’s well-thought-out suggestion is to allow full completion of the melatonin cycle by avoiding blue light for 9-10 hours, beginning before sleep and continuing until morning. One easy way to accomplish this would be to simply wear your blue-blocking glasses for awhile before going to bed. Another is to switch to lamps that filter blue wavelengths.
November 2006
Pharmacology
New Anti-angiogenic Drugs Enter Trials
Two new drugs are now in trials to test their safety and efficacy in treatment of wet AMD. On October 31, MacuSight, Inc. announced the start of a Phase I study of sirolimus (rapamycin). On November 1, 2006, TargeGen announce the initiation of Phase I trials involving the prodrug, TG100801.
Sirolimus, which is injected into the eye, differs from other anti-angiogenic drugs in that it is a highly-potent, broad-acting compound that may be useful in treating a wide range of ocular diseases and conditions. TG100801 is administered as an eye drop, which makes it attractive to patients who are now having to undergo injections that are uncomfortable and carry certain risks.
Research
New Gene Discovery Provides Potential Marker for AMD
The protein Complement Factor H (CFH) has previously been found to play a role in the development of drusen leading to AMD. CFH has implicated inflammation as part of the AMD pathogenesis, and now, discovery of a new gene may complete the picture. Researchers have recently found that a single mutation in the gene HTRA1 on chromosome 10q26 is a major genetic risk factor for wet AMD.
Studies that genotyped 581 people with AMD and 309 without AMD have provided a strong predictor for individuals who have family histories of the disease. A blood test to identify the mutant HTRA1 gene can now identify those who are up to seven times more likely to develop AMD than those with a normal gene. Not only will this allow such individuals to take preventative steps to lower their risk, but identification of the gene as a drug target can bring about new treatments for AMD and other retinal diseases brought on by drusen formation.
Drusen Lasering Ineffective
Drusen are thought to be fatty waste products from the photoreceptor cells. They often appear on the macula (the center of the retina) in the early stages of macular degeneration, and they can cause gradual loss of central vision.
In 1999, ophthalmologists took an interest in using the laser to destroy drusen, based upon the theory that ridding the retina of these deposits may slow the development of MD, or even stop the progression from the “dry” form to the “wet” form. Two studies, however, have recently shown drusen lasering to be ineffective, and even potentially harmful, as a treatment for macular degeneration. The studies were called Complications of AMD Prevention Trial (CAPT) and Prophylactic Treatment of AMD (PTAMD).
In 2006, PTAMD researchers reported that laser treatment “to an eye with multiple large drusen in a patient whose fellow eye has already suffered a neovascular event places the treated eye at higher risk of developing choroidal neovascularization.” They concluded by advising against using prophylactic subthreshold diode laser treatment in these eyes.
Then, on November 1, 2006, the National Eye Institute announced that their CAPT studies have been small, and the results inconsistent. No difference in vision or in progression to advanced AMD between treated and untreated eyes were observed, so doctors are advised to reconsider drusen lasering as a treatment for AMD.
Miscellaneous
Exercise May Protect Against Wet AMD
A study at the University of Wisconsin has shown that regular exercise may help to prevent the wet form of age-related macular degeneration (AMD). As reported in the November 2006 issue of British Journal of Ophthalmology, the study monitored almost 4,000 people between the ages of 43 and 86 over a period of 15 years. Researchers discovered that those who engaged in regular physical activity at least three times a week were 70% less likely to develop neovascularization. One explanation put forth is that– like coronary disease–inflammation, high cholesterol and high blood pressure are suspected to contribute to the development of wet AMD, and exercise helps to reduce those three conditions. The study showed that exercise had no effect on the incidence of dry AMD.
December 2006
Pharmacology
Avastin still showing success
Three abstract sessions at the AAO meeting in December revealed that intravitreal treatment with bevacisumab (Avastin) for wet AMD and pathologic myopia is showing no systemic adverse events and that the off-label drug is showing success in inhibiting neovascularization and improving visual acuity. The general conclusion is that re-treatment is needed at 2-3 month intervals. The study titles were:
“Safety and effectiveness of intravitreal bevacizumab for subfoveal choroidal neovascularization in pathologic myopia” (Hernandez-Rojas, ML, et al, abstract #673).
“Intravitreal bevacizumab (Avastin) in the treatment of neovascular age-related macular degeneration” (Avery, RL, et al, abstract #673).
“Intravitreal bevacizumab (Avastin) for recurrent choroidal neovascularization” (Frederico Graue-Wiechers, et al, abstract #722).
Updates on anti-angiogenic drug studies
At the same meeting, reports were presented on recent research in the areas of antiangiogenic drug therapy for wet AMD, including Genentech’s MARINA and PIER studies of ranibizimab (Lucentis) and Alcon’s progress on the anecortave acetate (Retaane 15 mg) trials. Nothing particularly new was presented, but some interesting findings were discussed:
Elias Reichel, M.D. reported that in the MARINA trials, there was improvement at all visual acuity levels, but there was not a big difference if the patient’s baseline vision was either low or excellent. This “floor-to-ceiling” effect is not unusual with this kind of study, but it is useful information for patient communicating with patients about expectations.
Nancy Holekamp, M.D., discussed key anatomic endpoints in the MARINA trials, in particular, the total lesion area over time (no growth of the lesion area was noted in the treated patients), the mean area of leakage (the amount of decrease was statistically significant) and the mean foveal retinal thickness (treated eyes showed a significant thinning of the retina). The bottom line is that all anatomic outcomes from the trial favored Lucentis, and the treatment is so effective over a long period of time without any signs of toxicity, there is no indication that anything in lieu of Lucentis should be used to treat wet AMD.
Peter Kaiser, M.D., reported on subgroup analysis of Genentech’s PIER study. The primary endpoint was met, showing a difference of 16 letters visual acuity between the treated group and the sham group. Further, the dosing regimen was effective, but the visual acuity benefit was not as robust when injections went from monthly to quarterly. The persistence of monthly injections may depend upon who has dry lesions and who has wet lesions at the 5th month. The dry lesion group did better than the wet lesion group with quarterly dosing. This data is pointing toward better prediction of dosage outcomes for individual patients.
Jason Slakter, M.D., reported that Alcon’s anecortave acetate has shown weak anti-angiogenic activity, but the method of treatment (injection outside of the eyeball) gives it the chance to have an effect over a longer period of time. This, he said, justifies continuing the study in the face of the impressive Lucentis results.
Melissa Brown, M.D., M.N., M.B.A. (Center for Value-Based Medicine) addressed the question, “On what basis can doctors compare pharmacologic treatments for wet AMD?” She suggested value-based analysis, looking at both quality of life and cost, and starting with an examination of the evidence. In a comparison of several current interventions, she noted that Lucentis shows the highest percentage in quality of life, but highest in cost. Still, Lucentis–at approximately $50,000 per quality of life year–is within commonly accepted parameters in the field of medicine.
John Thompson, M.D., reported no significant difference in three dose levels of Acuity Pharmaceutical’s bevasiranib, an anti-VEGF small interfering RNA drug with the ability to turn off genes that cause wet AMD. Results indicate that treatment with direct VEGF inhibitors may be necessary initially before treatment with bevasirinab. Hopefully, a Phase III study will show effectiveness as long term treatment.
January 2007
Research
RHEO Therapy Back in Trials
It was recently announced here that OccuLogix’s multicenter MIRA-1 study failed to prove effectiveness of its RHEO System, a blood filtration device being used in Canada for treating dry AMD. Now the company has announced that it has obtained clearance from the FDA to commence a new phase III study called RHEO-AMD. If successful, the results are expected to support OccuLogix’s application to the FDA for approval to market its RHEO System in the United States.
Another source of stem cells
On January 7, 2007, researchers at the Institute for Regenerative Medicine at Wake Forest University School of Medicine discovered another potential source of embryonic stem cells in the amniotic fluid that protects babies in the womb. These cells appear to be almost as malleable as those in the embryo itself, and the advantage would be that harvesting them would not harm the embryo. Several more years of study are needed to assess their application in humans.
Lucentis Approved in Europe
Novartis AG announced on January 24, 2007 that Lucentis (ranibizumab) has received European Union approval for patients with wet age-related macular degeneration. According to a press release issued by the company, the EU commission decision applies to all 27 member states as well as Iceland and Norway. Lucentis will be launched in Europe beginning this year. It has already won approval in the United States, Switzerland and India.
February 2007
Pharmacology
Lucentis and Risk of Stroke
The media has recently reported on a letter sent by Genentech to retina specialists highlighting rates of stroke observed in their Phase IIIb SAILOR study of Lucentis.
Genentech has found in their planned 6-month interim analysis that 1.2 percent of patients treated with a high dose of Lucentis in a clinical trial suffered a stroke, compared with only 0.3 percent of those treated with a low dose. The difference was statistically significant.
MD Support encourages patients to not overreact to this news. The letter was simply a proactive attempt on behalf of Genentech to provide additional information to treating physicians. The observed rates of stroke in the SAILOR trials are within those observed in the MARINA and ANCHOR pivotal studies that lead to the FDA approval of Lucentis and that were reported in October in the New England Journal of Medicine. The FDA still stands with its approval based upon the trial results, which are clearly reported in the Lucentis package insert. (None of the Genentech studies, by the way, excluded patients with cardiovascular conditions.)
Avastin Benefits Patients With CNV From Myopic Degeneration
On February 15, 2007, Elias Reichel, M.D. reported to Hawaiian Eye/Retina 2007 that Avastin has shown good results in a small retrospective case series for treatment of choroidal neovascularization (CNV) from myopic degeneration. 15 eyes studied showed a mean improvement in acuity of 3 lines, central foveal thickness decreased an average of 93 µm (micrometers) and there were no complications.
CA4P for Myopic Degeneration Successfully Completes Phase II
Oxigene, Inc. has reported positive results from its safety and efficacy phase trials of CA4P in the treatment of myopic macular degeneration. Safety results were favorable and in line with expectations, with no drug related serious adverse events being reported.
The company also announced that it has completed a pre-IND meeting with the FDA regarding two topical ophthalmic formulations (eye drops and ocular mini-tabs) for CA4P in the treatment of age-related macular degeneration and intends to proceed with further development of topical formulations.
New anti-angiogenic eyedrops
On February 26, 2007, Othera Pharmaceuticals presented new preclinical data demonstrating the safety and effectiveness of OT-551, an antiangiogenic drug in eyedrop form. Results from the Phase I trials demonstrated that when the compound is added to either Lucentis or Avastin treatment there is a synergistic effect versus either treatment alone. Phase II trials are expected to begin in the second quarter of this year.
Another company, Athenagen, Inc., has announced successful completion of Phase I of a trial testing its topical (eye drop) drug ATG3 for wet AMD. On January 31, 2007, the company announced successful completion of Phase I, and that “the eye drop therapy showed excellent ocular tolerability. There were no study medication-related systemic side effects, consistent with the very low levels of the compound found in the blood following eye drop application.” Athenagen’s Phase II clinical trial is expected to begin in the first quarter of 2007.
Lucentis shown to be better than PDT
On February 15, 2007, Peter Kaiser, M.D. reported two-year results of the Phase 3 ANCHOR trial comparing Lucentis with photodynamic therapy (PDT) for wet AMD. The study showed that Lucentis helps maintain vision, with few adverse effects, significantly better than PDT. For details, see www.lucentis.com.
March 2007
Pharmacology
Positive Results From Combined Radiation/Avastin Treatment for Wet AMD
NeoVista, Inc. reports positive results from NVI-111 Study (concomitant radiation/Anti-VEGF) for the treatment of wet AMD. Using the Epi-Rad 90(TM) Ophthalmic System, manufactured by NeoVista, treatment involved intravitreal 24 Gy Strontium-90 beta radiation plus initial treatment with Avastin. At six months, 45% of the patients treated per protocol achieved >=3 lines of visual acuity gain. This compares favorably to the results obtained in Genentech’s MARINA Trial, which utilized 0.5 mg of Lucentis alone. In addition, all patients treated in this study achieved a mean change in visual acuity of 13.4 letters at 6 months, which compares favorably to the reported 6.5 letter gain at month six of the MARINA Trial.
NeoVista will soon begin its CABERNET trial incorporating the concomitant use of Lucentis and Epi-Rad 90 therapy. For more information, visit the company website at www.neovistainc.com.
DHA supplement trial
Retina South Africa E-News announced a Phase ll trial in the U.S. to test the effect of the fish oil supplement Docosahexaenoic Acid (DHA) on X-linked retinitis pigmentosa (RP). Some researchers believe that DHA supplementation may also slow the progress of the dominant form of RP and age related macular degeneration. Other research, however, has shown that oxidized forms of DHA are found in drusen. No patients should self-medicate without first consulting an eye care practitioner.
Zinc May Harm the Retina: New Finding
BBC News announced on March 18 that researchers at London’s Institute of Ophthalmology think the mineral zinc may play a role in the development of AMD. The study, published in Experimental Eye Research, found that drusen containing high levels of zinc may contribute to progression of the disease. When asked for her opinion on this new development, nutritionist Ellen Troyer, CEO of BioSyntrx, Inc., said:
“I’m carefully watching these studies. There is another study published in the Journal of Urology that links the ARED study participants to a much higher incidence of kidney problems. We [at BioSyntrx] repeatedly have said in every talk we give (as has every biochemist I know) that 80 mg of zinc is way too much for daily consumption, and that has been our position since the ARED study was published. This does not mean, however, that we should not supplement with reasonable amounts of zinc, because it is vital to good health. And it is beyond appalling that they continue to use zinc oxide when there are much safer forms of zinc.”
We will continue to stay in touch with Ms Troyer for updates. Meanwhile, anyone taking the AREDS formula containing high amounts of zinc may want to consider switching to a multi-supplement with less.
Miscellaneous
Visually Impaired, Not Blind
The word “blind” is becoming increasingly less associated with age-related macular degeneration (AMD). MD Support reports that the majority of press releases and media broadcasts are now using the more correct terms “low vision,” “vision loss” or “visual impairment.”
Dan Roberts, director of MD Support, spent five months tracking virtually every public article and news broadcast about macular degeneration appearing on the Internet. As of November 10, 2006, he had found that 58% were still using the word “blind” as a description of AMD. As of March 10, 2007, he reports that the ratio had dropped to 42%, and the trend is continuing downward.
April 2007
Nutrition
Beta-carotene May be Ineffective in Fighting Macular Degeneration
Vitamin A in the form of beta-carotene has been found to be ineffective in slowing the progression of maculopathies such as age-related macular degeneration (AMD). This conclusion was derived from a follow-up study derived from the Physicians’ Health Study 1, which found neither benefit nor harm from 12 years of supplementation with beta carotene on cancer or cardiovascular disease. The follow-up study found that beta-carotene also had no significant effect on development of AMD, advanced maculopathy or maculopathy with or without vision loss.
The landmark age-related eye disease study (AREDS) found that a high-dosage formula of antioxidants and zinc, which included beta-carotene, was effective in slowing the progression of AMD. Beta-carotene, however, was not studied separately. The supplement might still be indirectly effective when taken in combination with other antioxidants, but that has yet to be researched.
As always, MD Support recommends that patients consult with both their general physicians and eye care specialists before making any significant changes in dietary supplements.
May 2007
Pharmacology
Lucentis and Avastin comparable as first-line treatments
N.J. Sund, M.M. et al reported to the ARVO meeting that further evidence of the safety and efficacy of intravitreal Avastin and Lucentis as first line monotherapy in the treatment of neovascular AMD. In their study, both drugs showed comparable results as first line treatments in terms of visual acuity outcomes in the short term. (abstract title: Efficacy of Intravitreal Bevacizumab (AvastinTM) vs. Ranibizumab (LucentisTM) as First Line Monotherapy for the Treatment of Neovascular Age-Related Macular Degeneration?)
Surgery
Cataract surgery and AMD
R.C. Milton, et al reported to the ARVO meeting that their large clinic-based longitudinal cohort study showed no clear evidence of an association between cataract surgery and the geographic atrophy form of advanced AMD. Patients undergoing cataract surgery can probably be reassured that the surgery is unlikely to increase their risk.
(Abstract title: The Effect of Cataract Surgery on the Development of Geographic Atrophy)
Research
Blue light and macular degeneration
A.R. Wielgus, et al reported to the ARVO meeting that blue light exposure promotes the oxidation of A2E and iso-A2E in rodent eyes. A2E is a blue light absorbing retinal chromophore that increases with age. The researchers noted that, as A2E oxides are toxic to retinal tissue, this may partially explain blue light induced retinal injury. This study is another in a growing compendium of research pointing to a connection between blue light and macular degeneration. (abstract title: Blue Light Induces A2E Oxidation in Rat’s Eyes)
Ultraviolet radiation and macular degeneration
A.J. Harring, et al reported to the ARVO meeting that subjects who were exposed to higher levels of ultraviolet (UV) radiation for the majority of their lifetimes were less likely to develop neovascular (wet) AMD than subjects who were exposed to lower UV levels. These results should not be confused with studies that have shown a connection between UV exposure and the increased risk of corneal disease and retinal cell damage.
(Abstract title: UVR Exposure and Risk of Neovascular Age-Related Macular Degeneration)
Drusen reduction
T.I. Metelitsina, et al reported to the ARVO meeting that inreased blood circulation may result in the resolution of drusen. This conclusion was drawn from observing eyes that show more drusen reduction following laser treatment and noting that those eyes have larger increases in choroidal circulatory parameters. The 23 subjects were drawn from the Complication of Age-Related Macular Degeneration Prevention trial (CAPT). (Abstract title: Laser Induced Resolution of Drusen Is Associated With Increases in Choroidal Blood Flow)
Effects of cardiovascular disease and hypertension on AMD
U.Chakravarthy, et al reported to the ARVO meeting that cardiovascular disease is strongly implicated as an etiological factor in the development of choroidal neovascularisation in a proportion of older adults. The researchers emphasize the importance of control of blood pressure and cholesterol, avoidance of smoking and maintenance of a normal body weight. This is further evidence linking cardiovascular disease and high blood pressure with wet macular degeneration.
(Abstract title: Cardiovascular Disease and Hypertension Are Strong Risk Factors for Choroidal Neovascularisation)
Nutrition
Dietary antioxidants ineffective in preventing AMD
E.W. Chong, et al reported to the ARVO meeting that there is insufficient evidence from the published literature to support the role of dietary antioxidants, including the use of dietary antioxidant supplements, for the primary prevention of early AMD. This conclusion was based upon a systematic review and meta-analysis of 9 prospective cohort studies and 3 randomized clinical trials of dietary antioxidants and dietary antioxidant supplements.
Pooled results from prospective cohort studies suggested that vitamin A, vitamin C, zinc, lutein, zeaxanthin, beta-carotene, cryptoxanthin and lycopene have little or no effect in the primary prevention of early AMD, and Vitamin E had a modest protective association for early AMD. The three randomized clinical trials did not show antioxidant supplements to be protective in the primary prevention of early AMD.
This study shows that antioxidants and zinc will not prevent the onset of AMD. It does not dispute the original ARED study, which showed that antioxidants and zinc can moderately lower the risk of developing the wet form of the disease in patients with advanced AMD.
(Abstract title: Dietary Antioxidants and Primary Prevention of Age-Related Macular Degeneration:A Systematic Review and Meta-Analysis)
NSAIDs and progression to advanced AMD
H.Sen, et al reported to the ARVO meeting that there was no significant association between regular systemic use of anti-inflammatory drugs (aspirin or NSAIDs) and the likelihood of developing advanced AMD (defined as the development of either neovascular AMD or central geographic atrophy). This conclusion was drawn from data collected over a median of 11 years from the original AREDS group.
(Abstract title: Systemic NSAIDs and Age-Related Macular Degeneration: The Age-Related Eye Disease Study (AREDS)
Statins may not prevent CNV
C.A. McCannel1, et al reported to the ARVO meeting that there is no consensus in the literature on whether or not statins offer protection against progression to the advanced stage of AMD (defined as the development of either choroidal neovascularization (CNV) or central geographic atrophy (CGA) in patients with early AMD. Data gathered from subjects in the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) do not support the concept of a strong protective effect of statins against the development of CNV. CAPT statin users did have a lower risk of GA, but not to a statistically significant degree.
(Abstract title: Statin Use and the Incidence of Choroidal Neovascularization and Geographic Atrophy in the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT)
Phototrop continues to show effectiveness
J.Feher, et al reported to the ARVO meeting that “prospective case studies on the long term effects of Phototrop treatment (see www.mdsupport.org/library/phototrop.html) confirmed the previous clinical trial’s data on an initial improvement followed by stabilization of visual functions in early AMD. Surprisingly, fundus alterations may further improve after one year of treatment, as shown by three different objective methods. All of these findings give further support to the efficacy of the long term use of Phototrop in early AMD patients, as early AMD may continue to improve even after 12 months of use.”
(Abstract title: Long Term Improvement of Early AMD Treated With Phototrop: Prospective Case Studies)
Miscellaneous
Statins, smoking and wet AMD
A scientific abstract presentation at the 2005 AAO meeting, “Reduced Risk of Progression to Exudative ARMD with Statin Use” (Gregory R Nettune, MPH, et al) presented research finding that “the risk of exudative AMD was increased by smoking and reduced by use of statins. Further, the duration of statin use up to four years was associated with an increasing degree of protection.” The study also found that current smoking or smoking within the past 20 years led to a 6-fold increase in risk of conversion from dry to wet AMD. No difference was found in subjects who had not smoked in 20 years.
As reported at the 2006 ARVO meeting, research from Duke and Vanderbilt University Medical Centers (published in the online edition of the American Journal of Human Genetics, March 6, 2006) has discovered that a version of the LOC387715 gene significantly increases the risk of developing ARMD in tobacco smokers. This is an unusual instance wherein genetics and environment can combine to create a disease risk. The other example related to ARMD is the CFH gene and how its effects are related to the body’s immune system.
A more recent study (Johanna M Seddon, et al, “Association of CFH Y402H and LOC387715 A69S With Progression of Age-Related Macular Degeneration,” JAMA, April 2007) showed that common variants of CFH and LOC387115 increased the risk of progression to advanced AMD. The variants, called Single Nucleotide Polymorphisms (SNP), independently increased the risk of progression from early or intermediate stages to advanced stages of AMD by 2.6 times (CHF) and 4.1 times (LOC387715). The presence of both risk genotypes, when combined with smoking and body mass index of 25+, increased the AMD progression risk 19-fold.
Low vision devices and reading speed
N.Nguyen, et al reported to the ARVO meeting that their study confirms the importance and efficiency of visual rehabilitation with low vision aids. The researchers evaluated magnification requirement and reading ability before and after administration of appropriate low-vision aids to 484 patients with different stages of AMD.
Mean reading speed [words per minute] was 20±33 before and 72±35 after administration of low vision aids. With appropriate low-vision aid, patients increased their reading speed an average of 53±19 wpm. Patients with a lower magnification requirement (less than 10X) showed a higher increase of reading speed (59±31 wpm) than patients with high magnification requirement (40±18 wpm).
The researchers concluded that “all patients benefited greatly from the rehabilitation measures in optimizing reading ability and therefore qualify of life. In face of the increasing number of elderly patients with AMD, rehabilitation should start as early as possible.”
(Abstract title: Reading Ability Before and After Administration of Low-Vision Aids in Patients With Age-Related Macular Degeneration)
The Future
Encapsulated cell technology
Phase 2 of the encapsulated cell technology (ECT) trial to deliver growth factors to the retina is ongoing. Phase 1 trials (see www.mdsupport.org/library/summary2006.html) showed an unexpected improvement in vision. This 2 year trial is being funded by the National Eye Institute in hopes that slow delivery of the growth factors will preserve photoreceptor function and serve as a drug delivery system for other conditions, as well. For more information, see www.mdsupport.org/library/ect.html.
AREDS 2
A second age-related eye disease study (AREDS 2) is looking at changes to the original formula. Potential changes include lowering the amount of zinc, eliminating beta-carotene, and including the carotenoids lutein, zeaxanthin, and DHA/Omega 3 (fish oil). The study, which will collect data from about 4000 subjects over the next five years, is being sponsored by the National Eye Institute.
AREDS2 is now recruiting participants with bilateral large drusen or advanced in one eye. All participants will be followed annually with a minimum follow-up of 5 years. For more information, see http://www.areds2.org.
Implantable miniature telescope
VisionCare’s Phase clinical trials of the IMT have been successfully completed, and a 2-year follow-up has revealed no serious safety issues. The company now looks forward to completing the regulatory review process on the way to marketing the IMT for public use by the end of this year.
New Drug In Trials for Dry AMD
Fenretinide (ST-602), a drug that has been used to treat certain cancers, rheumatoid arthritis, acne, and psoriasis, has been found to also slow the production and accumulation of a toxin that leads to vision loss in macular degeneration patients. The toxin, called A2E, is a byproduct of vitamin A, the formation of which encourages production of waste deposits called lipofuscin. These deposits accumulate in the retinal pigment epithelium (RPE), interfering with the RPE’s ability to nourish the photoreceptors.
Early research showed that A2E accumulation was decreased by 60% in mouse models after 28 days of treatment with fenretinide. Sirion Therapeutics, Inc. is now running FDA-approved multi-center studies using up to 225 AMD patients as subjects. If the drug proves effective with dry AMD patients, it may then be used off-label for treatment of Stargardt’s disease, a juvenile form of MD.

Summary of Research and Developments in Macular Degeneration: 2005-2006

by Dan Roberts
This is a compilation of significant research in the field of macular degeneration during the period May 2005 through May 2006, beginning with new findings as presented at the 2006 meeting of the Association for Research in Vision and Ophthalmology (ARVO).
Triple therapy found to be effective for wet AMD

Triple therapy with a combination of intravitreal Kenalog, photodynamic therapy (PDT), and intravitreal Macugen (pegaptanib sodium) has been found to be safe and effective for treatment of wet AMD. Improvements in visual acuity and in macular thickness in sixteen patients were reported at the ARVO meetings by JM Colina-Luquez MD, ophthalmologist, New England Retina Associates, Hamden, Connecticut
7.9% of those who had had prior therapy had an improvement in visual acuity of 3 lines or more, compared to 33% of those with newly diagnosed disease. This is an improvement in acuity from 20/200 to 20/50.
(Poster presentation: Prospective and Preliminary Study Evaluating Triple Therapy of Intravitreal Triamcinolone, Photodynamic Therapy and Pegaptanib Sodium for Choroidal Neovascularization)
Macugen may present risk of increased IOP

Optometrist Allison Toler, OD (East Florida Eye Institute, Stuart, Florida) and ophthalmologist Ronald Frenkel, MD, Bascom Palmer Eye Institute, University of Miami, Miami, Florida) reported to the ARVO meeting that treatment with pegaptanib sodium (Macugen) may run the risk of significantly increased intraocular pressure (IOP). In a study of eight patients, mean pre-injection IOP was 12.9 mm Hg and mean post-injection IOP was 39.4 mm Hg. The IOP returned to normal in most cases within 30 minutes of the injection, and eventuially all patients showed normal IOP levels.
The researchers then compared Macugen injection to Avastin (bevacizumab) injection. The spikes in IOP were similar, but IOP decreased faster in patients who underwent Avastin treatment. As a result of these findings, physicians were cautioned to closely monitor IOP levels in glaucoma patients who are also being treated with Macugen.
(Poster presentation: IOP Effects of Macugen in Glaucoma Patients]
Intravitreal injections affect the fellow eye

S.D. Martin et al (Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Kentucky Lions Eye Center, Louisville, KY) reported to the ARVO meeting that intravitreal injections of anti-VEGF drugs (i.e. Macugen and Avastin) also have an effect in the fellow eye. This is possibly the result of systemic absorption. Conclusions were drawn from analysis of pre- and post-injection ocular coherence tomography (OCT) graphs of 29 patients over a six-week period. Intravitreal use of these drugs, therefore, should be done with caution, since such absorption might also affect other systemic functions of the body. The researchers suggested that lower dosages of Macugen may be wise.
(Poster presentation: Intravitreally Injected Anti-VEGF Drugs Exert a Biological Effect in the Fellow Eye)
No association between cataracts and macular degeneration

Susan Bressler, MD (Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland) reported to ARVO that analyses of data from the Age Related Eye Disease Study (AREDS) has shown “no clear evidence of an association between cataract surgery and neovascular age-related macular degeneration,” and that “most patients undergoing cataract surgery can probably be reassured that surgery will not markedly increase their risk for progression to neovascular age-related macular degeneration.” The conclusion was drawn from checking outcomes after 1,704 cataract surgeries and 543 neovascular ARMD events after baseline among 8,152 eyes with a median follow-up of nine years.
(Poster presentation: The Effect of Cataract Surgery on the Development of Neovascular Age-Related Macular Degeneration)
New Lutein Findings
    The Melbourne Collaborative Cohort Study presented evidence to ARVO that neither lutein nor zeaxanthin are protective against the progression of AMD. This is contradictory to previous studies showing the opposite.
The same study of over 41,000 subjects showed an association between high intake of unsaturated fats and development of AMD, and that olive oil intake may be beneficial.
At the same meeting, a second multicenter study of 300 subjects showed that daily supplementation with 18 mg lutein and 2.4 mg zeaxanthin over six months resulted in a slight increase in macular pigment density.
Blue light risk
    Research from the University of Chicago has confirmed that the blue light wavelength peaking at 440 nm causes retinal damage through photochemical change and apoptotic cell death. The study authors repeated the recommendation stressed by MD Support at the 2005 ARVO meeting that blue blocking lenses be worn to protect the retina from direct exposure to strong blue light (i.e. sunlight, either natural or artificial).
(See “Artificial Lighting and the Blue Light Hazard” at www.mdsupport.org/library/hazard.html.)
Statins, smoking and wet AMD
    A scientific poster presentation at the 2005 AAO meeting, “Reduced Risk of Progression to Exudative ARMD with Statin Use” (Gregory R Nettune, MPH, et al) presented research finding that “the risk of exudative AMD was increased by smoking and reduced by use of statins. Further, the duration of statin use up to four years was associated with an increasing degree of protection.” The study also found that current smoking or smoking within the past 20 years led to a 6-fold increase in risk of conversion from dry to wet AMD. No difference was found in subjects who had not smoked in 20 years.
As reported at the 2006 ARVO meeting, research from Duke and Vanderbilt University Medical Centers (published in the online edition of the American Journal of Human Genetics, March 6, 2006) has discovered that a version of the LOC387715 gene significantly increases the risk of developing ARMD in tobacco smokers. This is an unusual instance wherein genetics and environment can combine to create a disease risk. The other example related to ARMD is the CFH gene and how its effects are related to the body’s immune system (see below). 

VEGF Trap 

Regeneron Pharmaceuticals reported to ARVO positive results after at the sixth week in its Phase I dose-escalation study of intravitreal anti-angiogenic drug VEGF Trap. 21 patients received a single injection of one of six doses, from 0.05mg to 4mg, and were monitored for 12 weeks.
Ocular coherence tomography (OCT) useful in determining need for Lucentis treatment
A study is being conducted at the Bascom Palmer Eye Institute (University of Miami) to evaluate the use of optical coherence tomography (OCT) for determining when patients needed an injection of Lucentis. The PrONTO Study (Prospective Optical Coherence Tomography Imaging of Patients with Neovascular Age-Related Macular Degeneration Treated with Intra-Ocular Lucentis) has shown good results at the end of its first year under principle investigator Philip Rosenfeld, MD. The results were reported to the 2006 meeting of ARVO.
“By using OCT in this uncontrolled study”, said Dr. Rosenfeld, “we were able to give fewer injections into the eye and observed vision improvement for most of our forty patients.” Intermittent injections were given every 3 to 4 months as determined using OCT. After 1 year, 17.5% of patients needed no further injections, and 20% needed only one additional injection. In spite of such individual differences, Dr.Rosenfeld said that the need for treatment was easily monitored using OCT.
__________________________________________________________
The following research was published throughout the past 12-month period on the MD Support site. For complete information, visit the library at www.mdsupport.org/library.html.
Gene replacement therapy successful in early trials
      Researchers at Johns Hopkins University Medical Center have used gene replacement therapy to halt (at least temporarily) retinal bleeding in patients with the wet form of age-related macular degeneration (AMD). This was done by single injections of a PEDF (pigment epithelial derived factor) gene into the eyes of patients during a phase I clinical trial just completed.
The methodology used in this research can also be applied to treating other types of gene-related retinal diseases, such as retinitis pigmentosa, Usher’s syndrome, and choroideremia.
New drugs are stopping retinal bleeding

Drugs called “anti-angiogenics” are stopping retinal bleeding in patients with wet AMD. The first to be approved was Macugen in February 2005. Another drug, Avastin, is being used off-label by doctors who consider it to be more effective than Macugen.
If all goes well in the trials, a third drug, Lucentis, will soon follow. This drug has shown very high success rates in trials. Doctors are saying that, if it is approved later this year, Lucentis will probably become their first choice. At least seven other drugs are also being tested, both alone and in combination with others. Due to this research, vision loss from wet AMD may soon become a thing of the past.
Drusen fragments may lead to wet AMD

Drusen are cellular waste deposits in the retina that are associated with development of macular degeneration. In research sponsored by the National Eye Institute, fragments of two known components of drusen (named C3a and C5a) have been identified that may be the cause of dry age-related macular degeneration (AMD) progressing to the wet form. As a result of this new finding, the fragments can serve as markers for predicting which patients are at high risk for progression to the wet stage. The next step is to develop a substance that can block C3a and C5a, essentially halting the progression from dry to wet. That is not to say that drusen are the only cause of CNV, but this is research worth following.
Two genes shown to lead to AMD

In 2005, the first suspect protein was discovered by three separate research centers. Called Complement Factor H (CFH), it may be a cause of AMD in as many as 50% of cases. CFH helps to control the body’s immune response and inflammation. In a later study, the question arose as to why 29% of the subjects who had a variation in Factor H did not develop AMD. This led to discovery of a second gene, Factor B, which explains the analomy. While Factor H stops the immune response, Factor B activates it. The two opposites can, therefore, balance one another and prevent AMD from developing in some cases.
The two genes are now connected to development of AMD in three out of four people who have the disease. The next step is to learn how to control the body’s immune response that sets off inflammation. Once the viral or bacterial cause has been identified, that knowledge in combination with the newly-discovered genetic markers will make it possible to develop effective therapies for the prevention of the disease.
Other genes that have been recently found to be associated with AMD are ABCR4, FBLN5, FBLN6, LOC387715 and MTTL1. More than 50 genes have been linked to AMD so far.
Clinical Trial for Wet AMD

Genentech is enrolling patients in its Phase IIIb clinical study of Lucentis for patients with all subtypes of new or recurrent active subfoveal wet AMD. Called SAILOR (Safety Assessment of Intravitreal Lucentis for AMD), the one-year study will evaluate the safety of two different doses (0.3 mg and 0.5 mg) of Lucentis administered once a month for three months and thereafter as needed based on criteria-based re-treatment options. The study is being conducted at over 70 sites in the United States and will enroll approximately 5,000 patients. To inquire about participation, call 1-888-662-6728.
Encapsulated Cell Technology (ECT)–A New Drug Delivery System

    A means of delivering drugs into the retina on a time release basis has been developed and proven safe and effective. The NT-501 uses encapsulated cell technology (ECT) to manufacture and secrete a drug called ciliary neurotrophic factor (CNTF) into the vitreous of the eye. CNTF is produced by genetically modified cells contained in the ECT, which is implanted inside the eyeball. The device acts, therefore, like a miniature factory for production and distribution of the drug. The device may prove to be safer, more effective and more convenient than injection.
Results from Phase I showed not only that the ECT device works and is safe, but that CNTF is a potentially effective drug treatment for slowing down all forms of hereditary retinal diseases such as macular degeneration and retinitis pigmentosa.
New gene thought to increase AMD risk in smokers

Research from Duke and Vanderbilt University Medical Centers has discovered that a version of the LOC387715 gene significantly increases the risk of developing ARMD in tobacco smokers. This is an unusual instance wherein genetics and environment can combine to create a disease risk.
Stem Cells Promise Cure
    Stem cell transplantation is showing promise as a potential cure for retinal disease. Here is a summary of an article that appeared April 19th in Science Magazine regarding this exciting research:

Stem Cells Promise Cure For Vision Loss

Dr Rajender Prasad Centre for Opthalmic Sciences at AIIMS has been studying the effect of stem cells in patients who suffer from degenerative vision disorders. The study is being conducted on fifty patients who are severely affected by age-related macular degeneration or retinitis pigmentosa.
According to Dr Atul Kumar, Professor of Opthalmology and head of the team undertaking the research, significant improvement has been noticed in vision of the patients after one month of injecting stem cells. There is further improvement after a gap of three months.
The researchers are using autologous (derived from patient’s own body) bone marrow derived stem cells and injecting them into a loose tissue near the cornea. Follow-ups are then done after one, three, six and 12 months.
[end article summary]
This study is still in early phase I of clinical trials. Dr. Atul Kumar has had success over the past several years with corneal regeneration using stem cells, and now he is testing his theory that retinal regeneration might also occur. So far the results are promising. He is testing only dry AMD patients age 50+ and retinitis pigmentosa patients age 18+, with best corrected acuity of 20/400 in both cases.
OccuLogix Reports Positive MIRA-1 Analysis Results

New analysis of data from the MIRA-1 trials shows significant vision improvement in dry AMD patients treated with the RHEO procedure, a blood filtration treatment currently available in Canada, but not yet approved in the United States.
On March 9, OccuLogix, Inc. announced that eyes treated with the RHEO procedure showed that 50% of patients with vision worse than 20/40 improved after treatment to 20/40 or better and would be able to qualify for a drivers license. This compares to 20% of patients in the placebo group.
“Prior to the development of the RHEO procedure,” said Dr. Lawrence Yannuzzi (Columbia University and Manhattan Eye, Ear and Throat Hospital), “there hasn’t been a potential treatment for Dry AMD beyond vitamin therapy. These results, while not yet conclusive, are very encouraging and may offer patients living with Dry AMD hope for the future.”
OccuLogix plans on meeting with the FDA soon to discuss the study results. Further study will likely be required before approval for marketing in the United States. We will continue to provide further updates as they become available. For more information about the study or the RHEO procedure, see: www.occulogix.com and www.rheo.com.
Eye Drops May Treat Wet AMD

On April 5, 2006, TargeGen, Inc. (San Diego) announced that a “prodrug” called TG100801 may be effective as an eye drop treatment for wet macular degeneration. TG100801 converts to the active drug TG100572 as it penetrates the eye. TG100572 was shown to stop neovascularization and to decrease inflammation, both of which are characteristics of wet macular degeneration. TargeGen plans to initiate human clinical trials with TG100801 prior to the end of 2006.
Dr. Shiyin Yee of TargeGen presented the preclinical data last month at The 6th International Symposium on Ocular Pharmacology and Therapeutics in Berlin, Germany. Collaborating laboratories are Johns Hopkins University School of Medicine.
Fenretinide may slow vision loss from Stargardt disease

Fenretinide, a drug that has been used to treat certain cancers, rheumatoid arthritis, acne, and psoriasis, has been found to also slow the production and accumulation of a toxin that leads to vision loss in Stargardt’s patients. The toxin, called A2E, is a byproduct of vitamin A, the formation of which encourages production of waste deposits called lipofuscin. These deposits accumulate in the retinal pigment epithelium (RPE), interfering with the RPE’s ability to nourish the photoreceptors.
The efficacy study was conducted by Sytera and collaborators at The Jules Stein Eye Institute. Researchers found that A2E accumulation was decreased by 60% in mouse models after 28 days of treatment with fenretinide.
Since accumulation of lipofuscin is also a condition of eyes affected by age-related macular degeneration (AMD), Sytera is planning clinical trials using AMD patients as subjects. This will provide a larger population for the study than the relatively small number of Stargardt’s patients available. If the drug proves effective with dry AMD patients, it may then be used off-label for treatment of Stargardt’s disease.
Implantable miniature telescope helps improve visual acuity

On October 19, 2005, Isaac Lipshitz, M.D. announced positive results from VisionCare’s Phase I/III clinical trials of the IMT. After one year, subjects showed a mean improvement of over 3 lines in both distance and near visual acuity. 90% exceeded the primary endpoint of the trial with a 2-line improvement. Significant improvement in quality of life and daily living activities was also measured. A 2-year follow-up has revealed no serious safety issues, and the company now looks forward to completing the regulatory review process on the way to marketing the IMT for public use.
Bacterial infection linked to AMD
Further evidence has shown that the bacterium Chlamydia pneumoniae may lead to a higher risk of age-related macular degeneration. The evidence was presented in a study published in the November issue of the journal Graefe’s Archive for Clinical and Experimental Ophthalmology (Massachusetts Eye and Ear Infirmary, Dr. Murat Kalayoglu, lead author). That study found C. pneumoniae in the diseased eye tissue of five of nine people with wet AMD but not in the eyes of 20 people without AMD.
The researchers found that “C. pneumoniae is capable of modifying the function of important cell types involved in regulating normal eye function,” and that “C. pneumoniae infection led to increased production of vascular endothelial growth factor (VEGF), the key protein involved in wet AMD.” This, they hypothesized, could partially explain the increased VEGF levels in many AMD patients, and that C. pneumoniae may be acting as an accelerant of inflammation in AMD patients who have variations in their complement factor H (CFH) gene.
Lucentis maintained or improved vision in approximately 95% of patients in phase III study
On January 14, 2006, Genentech, Inc. announced positive one-year results from its second pivotal Phase III study of the investigational drug Lucentis (ranibizumab) in patients with wet age-related macular degeneration (AMD). Data from the ANCHOR study comparing Lucentis to verteporfin (Visudyne¨) photodynamic therapy (PDT) showed a difference in mean change in visual acuity of 18 letters for patients treated with 0.3 mg of Lucentis and 21 letters for patients treated with 0.5 mg of Lucentis from study entry compared to those treated with PDT at 12 months.
AdPEDF protein halts development of ocular blood vessels

In January 2006, Researchers at Johns Hopkins University Medical Center announced that they were able to halt (at least temporarily) choroidal neovascularization (CNV) with single injections of the PEDF gene into the eyeballs of patients during a phase I clinical trial.
AdPEDF is a protein produced naturally in the eye to promote survival of retinal and other nerve cells. It also regulates the growth of ocular blood vessels, as in patients with wet MD. The PEDF (pigment epithelium-derived factor) gene produces the AdPEDF protein. By injecting the PEDF gene into the eye, the researchers are able to elevate the level of AdPEDF, thereby halting the development of blood vessels.
Macugen update
    David Guyer, M.D., (Eyetech Pharmaceuticals, now OSI) reported that after 40,000 treatments to date, Macugen has shown no safety problems. He stressed that it is very important that doctors treat as early as possible and follow the treatment regimen exactly as outlined in the protocol. Data has shown that starting the injections too late into the progression of the disease and/or stopping the treatment early (before four injections) may prevent improvement.
Recent studies with negative or insignificant results
The following studies did not reach their primary endpoints during the past year:

      • Submacular surgery
      •Transpupillary thermotherapy
      • Radiation therapy
      • Comparison of anecortave acetate (Retaane 15 mg) with verteporfin PDT in patients with predominantly classic subfoveal CNV.
    • Visudyne VIO for occult AMD

EVIZON with Visudyne
Genaera announced that its Phase II clinical trial of EVIZON (formerly squalamine lactate) to treat wet AMD met its goal of demonstrating safety when dosed with Visudyne for PDT. The 40mg EVIZON treatment, combined with the PDT, was well tolerated, with approximately 90% of subjects maintaining vision at 29 weeks.
AREDS II
A second age-related eye disease study (AREDS), now in planning stages, might include lowering the amount of zinc, eliminating beta-carotene, and including the carotenoids lutein, zeaxanthin, and DHA/Omega 3 (fish oil). These changes are based upon new findings since the late 90’s and recommendations from nutritionists. AREDS II will study 4000 subjects using various combinations of the above supplements.
Vitamin E found to be safe
    Vitamin E in doses less than or equal to 400IU (as found in most supplements) is of no concern, despite recent misleading reports that high doses could be fatal.
The above information was gathered from four sources at the annual meeting of the American Academy of Ophthalmology: 1) an instructional course titled “New and Investigational Therapies for ARMD, 2005,” 2) a seminar titled “ARMD: Evolving Treatment Options,” 3) a symposium on “Pharmacotherapy for Macular Diseases” and 4) private discussions between this writer and researchers. 

Summary of Research and Developments in Macular Degeneration: 2005-2006

by Dan Roberts
This is a compilation of significant research in the field of macular degeneration during the period May 2005 through May 2006, beginning with new findings as presented at the 2006 meeting of the Association for Research in Vision and Ophthalmology (ARVO).
Triple therapy found to be effective for wet AMD
Triple therapy with a combination of intravitreal Kenalog, photodynamic therapy (PDT), and intravitreal Macugen (pegaptanib sodium) has been found to be safe and effective for treatment of wet AMD. Improvements in visual acuity and in macular thickness in sixteen patients were reported at the ARVO meetings by JM Colina-Luquez MD, ophthalmologist, New England Retina Associates, Hamden, Connecticut
7.9% of those who had had prior therapy had an improvement in visual acuity of 3 lines or more, compared to 33% of those with newly diagnosed disease. This is an improvement in acuity from 20/200 to 20/50.
(Poster presentation: Prospective and Preliminary Study Evaluating Triple Therapy of Intravitreal Triamcinolone, Photodynamic Therapy and Pegaptanib Sodium for Choroidal Neovascularization)
Macugen may present risk of increased IOP
Optometrist Allison Toler, OD (East Florida Eye Institute, Stuart, Florida) and ophthalmologist Ronald Frenkel, MD, Bascom Palmer Eye Institute, University of Miami, Miami, Florida) reported to the ARVO meeting that treatment with pegaptanib sodium (Macugen) may run the risk of significantly increased intraocular pressure (IOP). In a study of eight patients, mean pre-injection IOP was 12.9 mm Hg and mean post-injection IOP was 39.4 mm Hg. The IOP returned to normal in most cases within 30 minutes of the injection, and eventuially all patients showed normal IOP levels.
The researchers then compared Macugen injection to Avastin (bevacizumab) injection. The spikes in IOP were similar, but IOP decreased faster in patients who underwent Avastin treatment. As a result of these findings, physicians were cautioned to closely monitor IOP levels in glaucoma patients who are also being treated with Macugen.
(Poster presentation: IOP Effects of Macugen in Glaucoma Patients]
Intravitreal injections affect the fellow eye
S.D. Martin et al (Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Kentucky Lions Eye Center, Louisville, KY) reported to the ARVO meeting that intravitreal injections of anti-VEGF drugs (i.e. Kenalog, Macugen and Avastin) also have an effect in the fellow eye. This is possibly the result of systemic absorption. Conclusions were drawn from analysis of pre- and post-injection ocular coherence tomography (OCT) graphs of 29 patients over a six-week period. Intravitreal use of these drugs, therefore, should be done with caution, since such absorption might also affect other systemic functions of the body. The researchers suggested that lower dosages of Macugen may be wise.
(Poster presentation: Intravitreally Injected Anti-VEGF Drugs Exert a Biological Effect in the Fellow Eye)
No association between cataracts and macular degeneration
Susan Bressler, MD (Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland) reported to ARVO that analyses of data from the Age Related Eye Disease Study (AREDS) has shown “no clear evidence of an association between cataract surgery and neovascular age-related macular degeneration,” and that “most patients undergoing cataract surgery can probably be reassured that surgery will not markedly increase their risk for progression to neovascular age-related macular degeneration.” The conclusion was drawn from checking outcomes after 1,704 cataract surgeries and 543 neovascular ARMD events after baseline among 8,152 eyes with a median follow-up of nine years.
(Poster presentation: The Effect of Cataract Surgery on the Development of Neovascular Age-Related Macular Degeneration)
New Lutein Findings
The Melbourne Collaborative Cohort Study presented evidence to ARVO that neither lutein nor zeaxanthin are protective against the progression of AMD. This is contradictory to previous studies showing the opposite.
The same study of over 41,000 subjects showed an association between high intake of unsaturated fats and development of AMD, and that olive oil intake may be beneficial.
At the same meeting, a second multicenter study of 300 subjects showed that daily supplementation with 18 mg lutein and 2.4 mg zeaxanthin over six months resulted in a slight increase in macular pigment density.
Blue light risk
Research from the University of Chicago has confirmed that the blue light wavelength peaking at 440 nm causes retinal damage through photochemical change and apoptotic cell death. The study authors repeated the recommendation stressed by MD Support at the 2005 ARVO meeting that blue blocking lenses be worn to protect the retina from direct exposure to strong blue light (i.e. sunlight, either natural or artificial).
(See “Artificial Lighting and the Blue Light Hazard” at www.mdsupport.org/library/hazard.html.)
Statins, smoking and wet AMD
A scientific poster presentation at the 2005 AAO meeting, “Reduced Risk of Progression to Exudative ARMD with Statin Use” (Gregory R Nettune, MPH, et al) presented research finding that “the risk of exudative AMD was increased by smoking and reduced by use of statins. Further, the duration of statin use up to four years was associated with an increasing degree of protection.” The study also found that current smoking or smoking within the past 20 years led to a 6-fold increase in risk of conversion from dry to wet AMD. No difference was found in subjects who had not smoked in 20 years.
As reported at the 2006 ARVO meeting, research from Duke and Vanderbilt University Medical Centers (published in the online edition of the American Journal of Human Genetics, March 6, 2006) has discovered that a version of the LOC387715 gene significantly increases the risk of developing ARMD in tobacco smokers. This is an unusual instance wherein genetics and environment can combine to create a disease risk. The other example related to ARMD is the CFH gene and how its effects are related to the body’s immune system (see below).
VEGF Trap
Regeneron Pharmaceuticals reported to ARVO positive results after at the sixth week in its Phase I dose-escalation study of intravitreal anti-angiogenic drug VEGF Trap. 21 patients received a single injection of one of six doses, from 0.05mg to 4mg, and were monitored for 12 weeks.
Ocular coherence tomography (OCT) useful in determining need for Lucentis treatment
A study is being conducted at the Bascom Palmer Eye Institute (University of Miami) to evaluate the use of optical coherence tomography (OCT) for determining when patients needed an injection of Lucentis. The PrONTO Study (Prospective Optical Coherence Tomography Imaging of Patients with Neovascular Age-Related Macular Degeneration Treated with Intra-Ocular Lucentis) has shown good results at the end of its first year under principle investigator Philip Rosenfeld, MD. The results were reported to the 2006 meeting of ARVO.
“By using OCT in this uncontrolled study”, said Dr. Rosenfeld, “we were able to give fewer injections into the eye and observed vision improvement for most of our forty patients.” Intermittent injections were given every 3 to 4 months as determined using OCT. After 1 year, 17.5% of patients needed no further injections, and 20% needed only one additional injection. In spite of such individual differences, Dr.Rosenfeld said that the need for treatment was easily monitored using OCT.
__________________________________________________________
The following research was published throughout the past 12-month period on the MD Support site. For complete information, visit the library at www.mdsupport.org/library.html.
Gene replacement therapy successful in early trials
Researchers at Johns Hopkins University Medical Center have used gene replacement therapy to halt (at least temporarily) retinal bleeding in patients with the wet form of age-related macular degeneration (AMD). This was done by single injections of a PEDF (pigment epithelial derived factor) gene into the eyes of patients during a phase I clinical trial just completed.
The methodology used in this research can also be applied to treating other types of gene-related retinal diseases, such as retinitis pigmentosa, Usher’s syndrome, and choroideremia.
New drugs are stopping retinal bleeding
Drugs called “anti-angiogenics” are stopping retinal bleeding in patients with wet AMD. The first to be approved was Macugen in February 2005. Another drug, Avastin, is being used off-label by doctors who consider it to be more effective than Macugen.
If all goes well in the trials, a third drug, Lucentis, will soon follow. This drug has shown very high success rates in trials. Doctors are saying that, if it is approved later this year, Lucentis will probably become their first choice. At least seven other drugs are also being tested, both alone and in combination with others. Due to this research, vision loss from wet AMD may soon become a thing of the past.
Drusen fragments may lead to wet AMD
Drusen are cellular waste deposits in the retina that are associated with development of macular degeneration. In research sponsored by the National Eye Institute, fragments of two known components of drusen (named C3a and C5a) have been identified that may be the cause of dry age-related macular degeneration (AMD) progressing to the wet form. As a result of this new finding, the fragments can serve as markers for predicting which patients are at high risk for progression to the wet stage. The next step is to develop a substance that can block C3a and C5a, essentially halting the progression from dry to wet. That is not to say that drusen are the only cause of CNV, but this is research worth following.
Two genes shown to lead to AMD
In 2005, the first suspect protein was discovered by three separate research centers. Called Complement Factor H (CFH), it may be a cause of AMD in as many as 50% of cases. CFH helps to control the body’s immune response and inflammation. In a later study, the question arose as to why 29% of the subjects who had a variation in Factor H did not develop AMD. This led to discovery of a second gene, Factor B, which explains the analomy. While Factor H stops the immune response, Factor B activates it. The two opposites can, therefore, balance one another and prevent AMD from developing in some cases.
The two genes are now connected to development of AMD in three out of four people who have the disease. The next step is to learn how to control the body’s immune response that sets off inflammation. Once the viral or bacterial cause has been identified, that knowledge in combination with the newly-discovered genetic markers will make it possible to develop effective therapies for the prevention of the disease.
Other genes that have been recently found to be associated with AMD are ABCR4, FBLN5, FBLN6, LOC387715 and MTTL1. More than 50 genes have been linked to AMD so far.
Clinical Trial for Wet AMD
Genentech is enrolling patients in its Phase IIIb clinical study of Lucentis for patients with all subtypes of new or recurrent active subfoveal wet AMD. Called SAILOR (Safety Assessment of Intravitreal Lucentis for AMD), the one-year study will evaluate the safety of two different doses (0.3 mg and 0.5 mg) of Lucentis administered once a month for three months and thereafter as needed based on criteria-based re-treatment options. The study is being conducted at over 70 sites in the United States and will enroll approximately 5,000 patients. To inquire about participation, call 1-888-662-6728.
Encapsulated Cell Technology (ECT)–A New Drug Delivery System
A means of delivering drugs into the retina on a time release basis has been developed and proven safe and effective. The NT-501 uses encapsulated cell technology (ECT) to manufacture and secrete a drug called ciliary neurotrophic factor (CNTF) into the vitreous of the eye. CNTF is produced by genetically modified cells contained in the ECT, which is implanted inside the eyeball. The device acts, therefore, like a miniature factory for production and distribution of the drug. The device may prove to be safer, more effective and more convenient than injection.
Results from Phase I showed not only that the ECT device works and is safe, but that CNTF is a potentially effective drug treatment for slowing down all forms of hereditary retinal diseases such as macular degeneration and retinitis pigmentosa.
New gene thought to increase AMD risk in smokers
Research from Duke and Vanderbilt University Medical Centers has discovered that a version of the LOC387715 gene significantly increases the risk of developing ARMD in tobacco smokers. This is an unusual instance wherein genetics and environment can combine to create a disease risk.
Stem Cells Promise Cure
Stem cell transplantation is showing promise as a potential cure for retinal disease. Here is a summary of an article that appeared April 19th in Science Magazine regarding this exciting research:
Stem Cells Promise Cure For Vision Loss
Dr Rajender Prasad Centre for Opthalmic Sciences at AIIMS has been studying the effect of stem cells in patients who suffer from degenerative vision disorders. The study is being conducted on fifty patients who are severely affected by age-related macular degeneration or retinitis pigmentosa.
According to Dr Atul Kumar, Professor of Opthalmology and head of the team undertaking the research, significant improvement has been noticed in vision of the patients after one month of injecting stem cells. There is further improvement after a gap of three months.
The researchers are using autologous (derived from patient’s own body) bone marrow derived stem cells and injecting them into a loose tissue near the cornea. Follow-ups are then done after one, three, six and 12 months.
[end article summary]
This study is still in early phase I of clinical trials. Dr. Atul Kumar has had success over the past several years with corneal regeneration using stem cells, and now he is testing his theory that retinal regeneration might also occur. So far the results are promising. He is testing only dry AMD patients age 50+ and retinitis pigmentosa patients age 18+, with best corrected acuity of 20/400 in both cases.
OccuLogix Reports Positive MIRA-1 Analysis Results
New analysis of data from the MIRA-1 trials shows significant vision improvement in dry AMD patients treated with the RHEO procedure, a blood filtration treatment currently available in Canada, but not yet approved in the United States.
On March 9, OccuLogix, Inc. announced that eyes treated with the RHEO procedure showed that 50% of patients with vision worse than 20/40 improved after treatment to 20/40 or better and would be able to qualify for a drivers license. This compares to 20% of patients in the placebo group.
“Prior to the development of the RHEO procedure,” said Dr. Lawrence Yannuzzi (Columbia University and Manhattan Eye, Ear and Throat Hospital), “there hasn’t been a potential treatment for Dry AMD beyond vitamin therapy. These results, while not yet conclusive, are very encouraging and may offer patients living with Dry AMD hope for the future.”
OccuLogix plans on meeting with the FDA soon to discuss the study results. Further study will likely be required before approval for marketing in the United States. We will continue to provide further updates as they become available. For more information about the study or the RHEO procedure, see: www.occulogix.com and www.rheo.com.
Eye Drops May Treat Wet AMD
On April 5, 2006, TargeGen, Inc. (San Diego) announced that a “prodrug” called TG100801 may be effective as an eye drop treatment for wet macular degeneration. TG100801 converts to the active drug TG100572 as it penetrates the eye. TG100572 was shown to stop neovascularization and to decrease inflammation, both of which are characteristics of wet macular degeneration. TargeGen plans to initiate human clinical trials with TG100801 prior to the end of 2006.
Dr. Shiyin Yee of TargeGen presented the preclinical data last month at The 6th International Symposium on Ocular Pharmacology and Therapeutics in Berlin, Germany. Collaborating laboratories are Johns Hopkins University School of Medicine.
Fenretinide may slow vision loss from Stargardt disease
Fenretinide, a drug that has been used to treat certain cancers, rheumatoid arthritis, acne, and psoriasis, has been found to also slow the production and accumulation of a toxin that leads to vision loss in Stargardt’s patients. The toxin, called A2E, is a byproduct of vitamin A, the formation of which encourages production of waste deposits called lipofuscin. These deposits accumulate in the retinal pigment epithelium (RPE), interfering with the RPE’s ability to nourish the photoreceptors.
The efficacy study was conducted by Sytera and collaborators at The Jules Stein Eye Institute. Researchers found that A2E accumulation was decreased by 60% in mouse models after 28 days of treatment with fenretinide.
Since accumulation of lipofuscin is also a condition of eyes affected by age-related macular degeneration (AMD), Sytera is planning clinical trials using AMD patients as subjects. This will provide a larger population for the study than the relatively small number of Stargardt’s patients available. If the drug proves effective with dry AMD patients, it may then be used off-label for treatment of Stargardt’s disease.
Implantable miniature telescope helps improve visual acuity
On October 19, 2005, Isaac Lipshitz, M.D. announced positive results from VisionCare’s Phase I/III clinical trials of the IMT. After one year, subjects showed a mean improvement of over 3 lines in both distance and near visual acuity. 90% exceeded the primary endpoint of the trial with a 2-line improvement. Significant improvement in quality of life and daily living activities was also measured. A 2-year follow-up has revealed no serious safety issues, and the company now looks forward to completing the regulatory review process on the way to marketing the IMT for public use.
Bacterial infection linked to AMD
Further evidence has shown that the bacterium Chlamydia pneumoniae may lead to a higher risk of age-related macular degeneration. The evidence was presented in a study published in the November issue of the journal Graefe’s Archive for Clinical and Experimental Ophthalmology (Massachusetts Eye and Ear Infirmary, Dr. Murat Kalayoglu, lead author). That study found C. pneumoniae in the diseased eye tissue of five of nine people with wet AMD but not in the eyes of 20 people without AMD.
The researchers found that “C. pneumoniae is capable of modifying the function of important cell types involved in regulating normal eye function,” and that “C. pneumoniae infection led to increased production of vascular endothelial growth factor (VEGF), the key protein involved in wet AMD.” This, they hypothesized, could partially explain the increased VEGF levels in many AMD patients, and that C. pneumoniae may be acting as an accelerant of inflammation in AMD patients who have variations in their complement factor H (CFH) gene.
Lucentis maintained or improved vision in approximately 95% of patients in phase III study
On January 14, 2006, Genentech, Inc. announced positive one-year results from its second pivotal Phase III study of the investigational drug Lucentis (ranibizumab) in patients with wet age-related macular degeneration (AMD). Data from the ANCHOR study comparing Lucentis to verteporfin (Visudyne¨) photodynamic therapy (PDT) showed a difference in mean change in visual acuity of 18 letters for patients treated with 0.3 mg of Lucentis and 21 letters for patients treated with 0.5 mg of Lucentis from study entry compared to those treated with PDT at 12 months.
AdPEDF protein halts development of ocular blood vessels
In January 2006, Researchers at Johns Hopkins University Medical Center announced that they were able to halt (at least temporarily) choroidal neovascularization (CNV) with single injections of the PEDF gene into the eyeballs of patients during a phase I clinical trial.
AdPEDF is a protein produced naturally in the eye to promote survival of retinal and other nerve cells. It also regulates the growth of ocular blood vessels, as in patients with wet MD. The PEDF (pigment epithelium-derived factor) gene produces the AdPEDF protein. By injecting the PEDF gene into the eye, the researchers are able to elevate the level of AdPEDF, thereby halting the development of blood vessels.
Macugen update
David Guyer, M.D., (Eyetech Pharmaceuticals, now OSI) reported that after 40,000 treatments to date, Macugen has shown no safety problems. He stressed that it is very important that doctors treat as early as possible and follow the treatment regimen exactly as outlined in the protocol. Data has shown that starting the injections too late into the progression of the disease and/or stopping the treatment early (before four injections) may prevent improvement.
Recent studies with negative or insignificant results
The following studies did not reach their primary endpoints during the past year:

  • Submacular surgery
  • Transpupillary thermotherapy
  • Radiation therapy (multiple negative studies)
  • Comparison of anecortave acetate (Retaane 15 mg) with verteporfin PDT in patients with predominantly classic subfoveal CNV.
  • Visudyne VIO for occult AMD

EVIZON with Visudyne
Genaera announced that its Phase II clinical trial of EVIZON (formerly squalamine lactate) to treat wet AMD met its goal of demonstrating safety when dosed with Visudyne for PDT. The 40mg EVIZON treatment, combined with the PDT, was well tolerated, with approximately 90% of subjects maintaining vision at 29 weeks. For more about EVIZON, see www.mdsupport.org/library/anti-angio.html.
AREDS II
A second age-related eye disease study (AREDS), now in planning stages, might include lowering the amount of zinc, eliminating beta-carotene, and including the carotenoids lutein, zeaxanthin, and DHA/Omega 3 (fish oil). These changes are based upon new findings since the late 90’s and recommendations from nutritionists. AREDS II will study 4000 subjects using various combinations of the above supplements.
Vitamin E found to be safe
Vitamin E in doses less than or equal to 400IU (as found in most supplements) is of no concern, despite recent misleading reports that high doses could be fatal.
The above information was gathered from four sources at the annual meeting of the American Academy of Ophthalmology: 1) an instructional course titled “New and Investigational Therapies for ARMD, 2005,” 2) a seminar titled “ARMD: Evolving Treatment Options,” 3) a symposium on “Pharmacotherapy for Macular Diseases” and 4) private discussions between this writer and researchers.