Summary of Research and Developments in Macular Degeneration: 2008-2009

by Dan Roberts
June 11, 2009
Laser Rejuvenates the Retina

According to a study announced at the Euretina Congress in May 2008, a laser treatment that “cleans up” Bruch’s membrane may slow down the progression to AMD.
Bruch’s membrane is the tissue that separates the photoreceptor cells (our sight cells) from the nourishing blood vessel layer of the retina. It is through Bruch’s
membrane that the nourishment passes. As we age, however, the membrane can become clogged with debris, inhibiting the process and leading to cell malnutrition. Research at St. Thomas’s Hospital in London has resulted in development of a
therapeutic approach to the problem. The Retinal Rejuvenation Therapy (2RT, Ellex) uses a special green nanosecond pulse laser for “reconditioning” Bruch’s membrane and photo-regeneration. Improvement in visual function has been noted in
humans during preliminary studies. Now, under the guidance of
John Marshall, Ph.D., researchers are setting up a trial to treat the yet-unaffected second eyes of patients who have already lost vision in one eye due to neovascular problems.
The ultimate goal, said Dr. Marshall, is to treat patients in their 40s to keep their eyes young and prevent age-related degenerations of the retina. The treatment is noninvasive and seems to have no adverse effects on the photoreceptors or other parts of the eye.
Good Visual Outcome Following Cataract Surgery

A new study (Nature, Aug 2008) has found good visual outcome following cataract surgery in patients aged 90 and older. The study compared visual outcome of patients with macular degeneration, glaucoma and various other ocular conditions.
Overall visual acuity improvement was 68%, whereas unchanged and worsening rates were 16% each. Results showed that AMD patients showed less improvement than patients with glaucoma or with no visual problems.
The researchers concluded that approximately 70% of very elderly patients can achieve visual acuity improvement following cataract surgery, which rises to 82% in those without accompanying problems. Although patients with AMD show less improvement, 62.5% can still enjoy improvement in visual acuity.
Cataract Surgery Appears Safe

More recent studies, however, are disputing that finding, starting with a report in 2005 that patients who had cataract surgery did not have a higher risk of progressing to more advanced forms of macular degeneration when compared to those who did not have cataract surgery.
This was supported by research published in the February 2009 issue of the Journal of Ophthalmology. Led by Emily Chew, MD (also involved in the 2005 study), the team reported that, after reviewing 11 years of patient follow-up data from the large Age-Related Eye Disease Study (AREDS), “The frequency of neovascular age-related macular degeneration, geographic atrophy, and central geographic atrophy did not differ between patients who had cataract surgery and those who did not. . . [This] may provide some reassurance to patients with age-related macular degeneration who are considering cataract surgery.”
A large comprehensive cohort study reported by J.J. Wang to the 2009 ARVO meeting also confirmed previous studies in finding no significant increased incidence of AMD in eyes having undergone cataract surgery. Dr. Wang stressed, however, that here may be an increase in combination with other AMD risk factors.
New Drug May Reduce Number of Injections for Wet AMD
Regeneron Pharmaceuticals, Inc. and Bayer HealthCare AG Have announced that patients with wet AMD receiving VEGF Trap-Eye in a Phase 2 extension study on an “as needed” dosing schedule continued to show highly significant improvements in retinal thickness and vision gain at 52 weeks. During weeks 12 to 52, patients from all dose groups combined received, on average, only two additional injections. This supports Regeneron’s expectation that, with VEGF-Trap-Eye treatment, patients’ visual acuity will improve over time without the need for monthly intravitreal injections.
Zinthionein in Trials for Treatment of Dry AMD

Zinc has been shown to be an effective antioxidant, which is beneficial to the retina. In July 2008, researchers at Pipex Pharmaceuticals announced success with a complex that evidently results in a more potent antioxidant than zinc alone. This “zincmonocysteine” molecule was developed by combining L-cysteine and zinc in a ratio of 1:1.
Under the commercial name Zinthionein, it was then administered as a 25 mg oral capsule twice a day to 80 test subjects for a period of six months. According to the
phase 2 study results (David Newsome, primary investigator), these patients demonstrated a highly statistically significant improvement in visual acuity, contrast sensitivity and photorecovery time. Continued success in the trials could lead to a new and effective therapy for dry AMD.
More info: www.adeonapharma.com
New Dry AMD Gene Found

As reported in the Aug. 28 online edition of the New England Journal of Medicine, researchers have found a genetic link associated with dry AMD. That’s the good news. The bad news is that siRNA drug therapy may increase the risk for dry AMD in patients who have that genetic variant.
The research team found that the protein TLR3 helps fend off certain viral infections. However, it also increases the risk for dry AMD in subjects taking an experimental anti-VEGF drug called “small interference ribonucleic acid” (siRNA),
which activates TLR3. In fending off viral infections, TLR3 also attacks infected retinal cells, resulting in “a 60 percent spike in retinal cell death among mice and humans
genetically susceptible to developing dry AMD.”
Patients currently involved in the siRNA study (labeled Cand5) sponsored by Acuity Pharmaceuticals should contact their doctors for more information.
“Low Luminance Deficit” May Predict More Severe Vision Loss

It appears that, of people with advanced dry AMD (geographic atrophy) who have a corrected visual acuity of 20/50 or better, those who test more poorly in dim light may progress sooner to more severe vision loss.
A research team under the direction of MD Support advisor Janet Sunness, M.D. (Hoover Services for Low Vision and Blindness, Greater Baltimore Medical Center), found that visual dysfunction under low light can predict subsequent visual acuity loss in late-stage AMD patients.
Of subjects with a visual acuity of 20/50 or more, those who had the worst “low luminance deficit” at the beginning of the study showed a significantly greater loss of visual acuity at two years. 40% of this group showed a loss of three or more lines on the acuity test chart. Identification of this risk factor may provide an important means of predicting the rate of vision loss in patients with advanced dry AMD.
Brain Reorganizes to Adjust for Loss of Vision

A new study from Georgia Tech shows that when patients with macular degeneration focus on using another part of their retina to compensate for their loss of central vision, their brain seems to compensate by reorganizing its neural
connections. The study appears in the December edition of the journal Restorative Neurology and Neuroscience.
Eric Schumacher, assistant professor in Georgia Tech’s School of Psychology, said, “Our results show that the patient’s behavior may be critical to get the brain to reorganize in response to disease. It’s not enough to lose input to a brain region for that region to reorganize; the change in the patient’s behavior also matters.”
In this case, that change of behavior comes when patients with AMD make up for this loss by focusing with other parts of their visual field.
Schumacher and his research team found that when patients visually stimulated the preferred retinal locations, they increased brain activity in the same parts of the visual cortex that are normally activated when healthy patients focused on objects in their central visual field. They concluded that the brain had reorganized itself.
While there is evidence with other tasks that suggests that the brain can reorganize itself, this is the first study to directly show that this reorganization in patients with retinal disease is related to patient behavior. The research group is currently studying how long this reorganization takes
and whether it can be fostered through low-vision training in eccentric viewing.
The Latest on AREDS

Emily Chew, M.D., reported to the ARVO meeting that genotypes determine the extent of protection offered by the AREDS formula. In the ARED study, people with genotype TT showed the greatest protective effect, while those with genotype CC
showed the greatest risk of progression to advanced geographic atrophy.
Dr. Chew said that patients can probably discontinue the AREDS supplements once the advanced wet stage is reached. Patients with non-central geographic atrophy (dry MD) and no choroidal neovascularization (vessel growth and leakage) should continue.
Finally, Dr. Chew on the new AREDS2 study. This is a followup to the original “Age-Related Eye Disease Study” completed in 1998. That study resulted in most doctors recommending the AREDS formula to patients in the intermediate stage of
AMD, in order to slow progression to the advanced stage. The formula contains vitamin C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg; and zinc, 80 mg. The new formula now being tested is slightly altered, with less zinc, no beta-carotene, and the addition of lutein, zeaxanthin and omega-3 fatty acids DHA and EPA. The purpose is to see if the new formula will be even more effective. The AREDS2 cohort has been fully recruited, and first results are expected in 5 years.
PDT Still a Viable Treatment in Some Cases

Several years ago, photodynamic therapy (PDT) was the most effective treatment for wet AMD, but it has been mostly replaced by the new antiangiogenic drugs. This treatment involved injection of the light-activated drug Verteporfin (Visudyne) into a vein, followed by targeting the leaking blood vessel with a low power laser. This destroyed the vessel and stopped the leakage, but it also caused some residual
damage to surrounding cells after repeated procedures. Still, PDT is used in some cases where the vessel’s location is not close to the center of the macula and quick action is necessary.
Now, a new less damaging and more effective approach called “Targeted” Photodynamic Therapy (TPT) is being studied. According to Dr. R.A. Adelman in a report to the ARVO meeting, a protein called Factor VII is conjugated with Verteporfin.
Intravitreal injection of the compound in a rat model with choroidal neovascularization showed efficacy at 1/10th the usual dose of Verteporfin and 3x better visual function
after lasering. This proved to be more effective and safer for surrounding cells than standard PDT at a significantly lower dose.
The Latest on Lucentis

Lucentis, developed by Genentech Pharmaceuticals, is one of two FDA approved drugs used in treatment of wet AMD. The other is Macugen, which has been shown to be less effective. Avastin is also being used off-label with reported success, but it has
yet to be shown to be safe and efficacious in large studies.
Three followup studies of Lucentis, called HORIZON, EXCITE and SUSTAIN, were reported on at the ARVO meeting by Drs. M. Singer, C. Simader and F.G. Holz.
The HORIZON study, which ended in Sep 2008, followed Genentech’s Marina, Anchor and Focus trials, all of which were followup studies of Lucentis. The results showed that the rate of ocular and nonocular adverse events was low, repeated
injections were well tolerated after 4 years, and delay in initial treatment resulted in a higher loss of vision.
The EXCITE study compared quarterly treatment with monthly treatment using Lucentis. Best corrected visual acuity and retinal morphology were found to be better with a monthly regimen of injections.
The SUSTAIN study analyzed safety of monthly dosages of 0.3 and 0.5 mg. Lucentis was found to be safe and effective, no matter what the amount of dosage or the interval of time between treatments.
Since monthly treatment on an as-needed basis at 0.5 mg has been found to be most effective, more refined testing (eg. higher resolution OCT) will be needed in order to better judge if and when patients need to be retreated.
Bilateral Injections Appear Safe

Dr. KariAnne Galler reported to the ARVO meeting that there is no particular increase in risk for patients with bilateral macular degeneration treated with bilateral injections
of anti-VEGF drugs. Also, there is a strong patient preference for the ease and convenience of having bilateral rather than unilateral injections.
Obama Lifts Limits on Stem Cell Research

President Obama has lifted the Bush administration’s limits on human embryonic stem cell research. Mr. Obama announced the decision on March 9, saying he hoped Congress would follow with bipartisan legislation that would ease the existing restrictions even more.
The president acknowledged that studying stem cells extracted from human embryos is deeply divisive, but he said the majority of Americans “have come to a consensus that we should pursue this research; that the potential it offers is great,
and with proper guidelines and strict oversight the perils can be avoided.”
First Human Embryonic Stem Cell Study Approved By FDA

Geron, a biotech company, has announced that the federal government will allow the world’s first test in people of a therapy derived from human embryonic stem cells. Until now, federal financing for research on embryonic stem cells has been restricted, because creation of the cells entails the destruction of human embryos.
The intended reversal of this policy by the newly-elected administration may or may not have influenced this recent decision.
Geron will enroll paralyzed patients who can be treated within 2 weeks of their injury. The subjects will then be evaluated for at least one year, after which the company hopes to increase the dose and expand the number of participants.
This release of government funding is expected to set a precedent for more stem cell research in the low vision field. For more information about the research to this point, see “The First Seven Years: An Overview of Stem Cell Transplantation Research for Treatment of Retinal Disease” on this site.
Stem Cell Therapy Presents Challenges

A special interest group discussed the challenges of bringing stem cell therapy to the patients. The topics were addressed by P.J. Coffey (Institute of Ophthalmology, University College, London), H. Klassen (Univ. of California, Irvine), and M. Friedlander (Scripps Research Institute).
The topics of discussion were:

  • Ways of getting the cells to the site of action, either by surgical insertion or injection into the vitreous fluid.
  • The safety of the procedure
  • The length of time it will take for the procedure to have an effect
  • The question of whether the body will reject the implants
  • Sources of stem cells

To summarize:
Dr. Coffey stated that the goal of The London Project at Moorfields Hospital is to reconstruct the macula by repopulating the retinal pigment epithelium (RPE) to nourish the photoreceptors. This has been accomplished successfully by macular translocation and RPE transplantation. The problem, however, is that these procedures take several hours and at least two separate visits to the clinic. The solution, said Dr. Coffey, is to implant (by injection) a permanent artificial membrane of human embryonic cells. This has been shown to stop pig photoreceptors from dying, and there has been no immunological response (i.e. rejection) so far.
Dr. Klassen discussed culture and transplantation of retinal progenitor cells (RPC), which he says is a key developmental stage in the pathway to replicating rod photoreceptors, even for Müller and ciliary cells. RPCs have been obtained from
animals and encouraged (by adding a growth factor) to differentiate into photoreceptors. They have been well-tolerated in the treated retinas. He added that human RPCs have been successfully used in China to repair the optic nerve.
Dr. Friedlander discussed adult stem cell based therapies. Sources for such cells are the cornea, bone marrow, peripheral blood, spinal cord blood, skin, hair and dormant stem cells. He introduced a new strategy involving rebuilding retinal vessels instead of inhibiting neovascularization. He described how this “vasculotrophic rescue” can be done with bone marrow derived stem cells.
FDA Panel Recommends Approval of IMT

On March 27, 2009, the FDA’s ophthalmic device panel recommended approval of Vision Care Ophthalmic Technology’s implantable miniature telescope (IMT) for patients with advanced stage AMD. After 5 years of trials and a prior unsuccessful submission to the panel, the IMT has now met all requirements for safety and efficacy.
The FDA usually follows the recommendations of an advisory panel, but is not required to do so. The panel recommended approval of the device with conditions including post-approval surveillance and labeling suggestions. The panel decision
was reached by a vote of 8 to 0.
Allen W. Hill, CEO of VisionCare, said “We are pleased with the panel’s recommendation for approval and will work closely with FDA to address the approval conditions. We look forward to providing the ophthalmic community a new treatment option to improve vision and quality of life for patients with untreatable, end-stage agerelated macular degeneration.”
I spoke to the panel shortly before the vote. I told them that, until now, nothing has offered long-term vision restoration for people in the advanced stage of the disease.
That stage has traditionally been one of transition to nonvisual skills such as cane use and Braille. With the IMT, it may be possible for some of us to put that off indefinitely, and that gives us one more cannon to fire.
For more information on the research, visit VisionCare’s website at www.visioncareinc.net or call (408) 872-0526.
Seeing With Your Tongue

One of the most interesting developments reported at Vision 2008 in Montreal was new device called BrainPort, which (according to the abstract) enables perception of visual information using the tongue and camera imaging system as a paired substitute for the eye.
Visual information is collected from a head mounted image sensor and translated into electrical patterns displayed on the surface of the tongue. The system has tested favorably on subjects with no vision, and it is now being adapted to assist individuals with macular degeneration and related diseases.
The long term goal is to develop a fully portable, unobtrusive
device that will track with the userís gaze point, capture information centered in the area of vision loss, and display the information on the tongue. This device will “fill in”
the area of vision loss, will be compatible with other vision-assisting devices, will not be surgically invasive, and will be easily customizable and upgradeable. Developers are hoping to have the BrainPort commercially available within 2
years. Here is where you can read more about it:
vision.wicab.com/technology
DIET & NUTRITION
Statins May Hasten Onset of Wet AMD

What effect do cholesterol-lowering drugs have on the retina? A pilot study in 2006 found “that treatment with simvastatin increased blood-flow velocity in the retinal arteries and veins and decreased intraocular pressure. (Nagaoka T et al. Arch Ophthalmol 2006; 124:665-670.)
This study supports the thinking that increased blood flow is generally beneficial to the retina. Recent research, however, has shown that taking statins to lower cholesterol levels might hasten the onset of wet AMD in people who are already
affected by the dry form. The abstract for this study may be read on the Web at www.tinyurl.com/5ksj6a.
Considering the proven beneficial effects of drugs like simvastatin for people with circulatory problems and high cholesterol, it would be wise to keep this information in mind, but it would not be wise to stop taking them altogether without professional consultation. Until researchers have sorted out the facts, a patient’s decision should be based upon individual circumstances and discussed with professional care providers.
Vitamin C May Lower Statin Levels

A UC Berkeley study, led by Gladys Block, PhD, suggests that 1,000 mg of daily supplemental vitamin C can lower concentrations of C-reactive protein (CRP), the marker associated with systemic inflammation. (Free Radical Biology and Medicine, Jan. 1, 2009). It suggests that a daily dose of supplemental vitamin C can lower CRP levels in healthy, non-smoking adults in two months.
Gladys Block and her staff found that for people with elevated CRP levels, the amount of CRP reduction achieved by taking vitamin C in this particular study is comparable to that in many statin studies.
A multinational clinical trial led by researchers at Harvard Medical School (the Jupiter Trial), found that among people who had high levels of CRP at baseline, levels of CRP were 37 percent lower in the subjects who took statins compared to those who took the placebo.
In the UC Berkeley study on vitamin C, participants who started out with CRP levels greater than 2 milligrams per liter had 34 percent lower levels of CRP with vitamin C compared with a placebo after two months.
“This is clearly a line of research worth pursuing,” said Dr. Block. “It has recently been suggested by some researchers that people with elevated CRP should be put on statins as a preventive measure. For people who have elevated CRP but not elevated LDL cholesterol, our data suggest that vitamin C should be investigated as an alternative to statins, or as something to be used to delay the time when statin use
becomes necessary.”
The benefits to the consumer are that Vitamin C is considerably less costly, and it does not carry the risk of serious side-effects associated with statins.
Source: Ellen Troyer, MT, MA (Chief Research Officer, Biosyntrx .com
Excess Weight Contributes to Mortality

by Ellen Troyer, MT MA
Biosyntrx Chief Research Officer
Excess weight is an epidemic in the United States. There is strong scientific agreement that excess weight (BMI over 25) contributes to overall mortality. It also significantly increases the risk of serious degenerative diseases, including cataracts, macular degeneration, glaucoma, and diabetic retinopathy.
The National Center for Health Statistics estimates that 65% of the U.S. population is overweight, with 34% of the population being clinically obese. Scientists have also identified the significantly increased risks associated with excess weight for 20 other diseases or conditions. According to the U.S. Surgeon General report, excess weight and obesity are responsible for 300,000 deaths every year in the U.S.
Vitamins B-6, B-12 and Folic Acid May Protect Against AMD

Ellen Troyer, MT MA
Biosyntrx Chief Research Officer
A recent study suggests that a combination of vitamin B-6, vitamin B-12 and folic acid may protect women against age-related macular degeneration. Epidemiologists at Harvard Medical School and Women’s Hospital in Boston analyzed data collected as part of a large trial originally designed to test the effects of other vitamins on women with heart problems. All subjects were permitted to take multivitamins with B-6, B-12 and folate up to, but not exceeding, recommended
daily allowances (RDAs). Those getting the B-6, B-12 and folate supplements received much larger amounts.
After 7.3 years, researchers found 82 cases of age-related macular degeneration among women taking placebos and only 55 cases in the women receiving the high-potency B vitamin supplements. While an explanation for the apparent protection from macular degeneration remains unknown, it is known that folate, B-6 and B-12 can drive down blood concentrations of homocysteine, a methionine metabolism by-product compound
suspected of damaging blood vessels.
On the surface this study seems to be very positive, but it raises some concerns about the folic acid dosage. Excessive supplemental folic acid can mask or obscure fairly common vitamin B-12 deficiencies in older people. This can result in an increased risk of progressive, unrecognized neurological damage. Dosage of supplemental folic acid over 1 mg per day has also been associated with impaired gastrointestinal absorption of zinc in some cases.
It’s good to remember that more is not always better.
Too Much Red Meat?

Research* has revealed that a diet high in red meat may increase one’s risk of developing AMD, while consumption of chicken may lower the risk.
Researchers followed 6,734 persons aged 58-69 years, from 1990 through 2006. Final data showed that higher red meat intake was positively associated with early AMD. The odds ratio for consumption of red meat 10 or more times a week versus less than 5 times a week was 1.47. Conversely, consumption of chicken 3.5 or more times a week versus less than 1.5 times a week was inversely associated with late AMD. The team concluded that different meats may differently affect AMD risk and may be a target for lifestyle modification.
Inflammation is being identified as the main culprit in the development of AMD, and cholesterol is inflammation’s “partner in crime.” Fatty red meat is a major source of cholesterol, while lean red meat actually produces less than the body does by itself.
High quantities of red meat, therefore, may be an important risk factor, but it appears that we can sidestep the problem by consuming less, and only the leanest cuts.
*Red Meat and Chicken Consumption and Its Association With Age-related Macular Degeneration, Elaine W.-T. Chong, et al (American Journal of Epidemiology, November 25, 2008).
Occurrence of AMD Declining

A new study reports 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.
The study included 2,968 participants with early AMD and 3,588 participants with late stage AMD, all of whom were examined at 5-year intervals between 1988 and 2005 as part of the Beaver Dam Eye Study.
The investigators cannot yet explain the results. Improvements in health care and lifestyle over the previous 15 years do not explain the decline, but other factors might. These include other exposures earlier in life (e.g., infectious disease
outbreaks such as the flu pandemic of 1918), dietary restrictions specific to a period (e.g., the Great Depression), or other unmeasured factors.
Personally, I would like to think that greater health conciousness and awareness of the risk factors for AMD have made a positive contribution. We can play a part in maintaining that decline by continuing to educate ourselves and others about how we may fend off this disease, at least until these promising cures we hear about reach our hospitals and clinics.
Thank you for reading this summary. The fact that it has been lengthy is testament to the encouraging work being done in the field, and let’s continue to remain positive about the positive outcomes, whether for our benefit or for the benefit
of those who follow us.

Cataract Surgery and Retinal Degeneration

by Dan Roberts
Originally published and updated 2/2/09
A cataract causes clouding of the normally transparent lens of the eye. As the lens becomes more opaque, the rays of light are prevented from focusing on the retina, leading to symptoms such as blurriness, light sensitivity, glare, distortion, and fading of colors and vision. Cataracts are very common in older adults, and can develop in approximately 50% of people between the ages of 65-75. About 70% of people over the age of 75 have cataracts. Cataracts can only be removed surgically, which is successful in about 90-95% of all cases.
Most retinal surgeons say that there is minimal danger of complications from cataract surgery on patients with retinal degeneration. The retina is located in the interior of the back of the eye, and cataract surgery does not interfere with this area. The surgery, most doctors maintain, will not improve vision lost from retinal degeneration, but it will not make the retinal condition worse. A 2003 study, however, concluded that cataract surgery in older persons may, in fact, be associated with an increased risk for developing wet ARMD. (Cataract surgery and the 5-year incidence of late-stage age-related maculopathy: pooled findings from the Beaver Dam and Blue Mountains eye studies. Ophthalmology. 2003 Oct;110(10):1960-7.)
A more recent study, presented at the annual meeting of the American Academy of Ophthalmology in October 2005 (Controversy of Cataract Extraction and AMD Progression. Changing Concepts and Controversies. Ferris FL, Chew EY, Gensler G, Milton R, and the Age-Related Eye Disease Study Research Group.) showed that those patients who had cataract surgery did not have a higher risk of progressing to more advanced forms of macular degeneration, when compared to those who did not have cataract surgery.
This conclusion was supported by further research published in the February 2009 issue of the same journal. Led by Emily Chew, MD (also involved in the 2005 study), the team reported that, after reviewing 11 years of patient follow-up data from the large Age-Related Eye Disease Study (AREDS), “The frequency of neovascular age-related macular degeneration, geographic atrophy, and central geographic atrophy did not differ between patients who had cataract surgery and those who did not. . . [This] may provide some reassurance to patients with age-related macular degeneration who are considering cataract surgery.”
Cataract surgery has been known to cause retinal detachment in approximately 1.5% of patients. This risk, however, is lessened now with extracapsular surgery, in which the posterior capsule of the natural lens is left in place to support the plastic replacement lens that is implanted during the operation. Patients should contact their ophthalmologists immediately if they develop a “curtain” blocking the vision, flashes of light resembling lightning streaks, or new floating spots in the visual field. These symptoms can sometimes be indicative of a retinal detachment. People at increased risk of retinal detachment include those who are very myopic, or have conditions such as Stickler Syndrome or Wagner’s disease.
Even with serious retinal problems, cataract surgery may be beneficial if performed by an experienced and skilled doctor, and most professionals say that it can be undertaken with reasonable confidence. According to MD Support medical advisor Martin Mainster, M.D., “The risk of adverse events from cataract surgery is low, but I’ve always counseled patients with AMD to defer cataract surgery until their vision loss from cataract formation significantly reduces their quality of life (the same advice I give all my other patients). At that point, the benefit/risk ratio is sufficiently high to warrant the procedure.”

Contact Lenses

Supplemental information provided by Edward J. Huggett, O.D. (St. Luke’s Cataract and Laser Institute) and Lensshopper.com.
Should a person continue to wear contact lenses after cataract surgery? This is a question that will become more common as the younger generation advances in age.
An artificial corrective lens is usually implanted into the eye, ending the need for glasses or contacts. There are, however, some cases in which additional correction is necessary following surgery:

  • The patient’s vision changes over time.
  • Implanting a replacement lens may not be feasible, due to the patient’s condition.
  • Temporary correction is needed until the patient’s vision stabilizes.

With the advances in cataract surgery there are few people who will need contact lenses after surgery, and that will be increasingly true with the increasing use of focusable IOL’s (e.g. Crystalens). But if a person who has had cataract surgery needs further correction then contact lenses are no more of a safety issue than prior to surgery, as long as usual precautions are followed. This is true for single vision contacts or multifocal contacts.
For further information about cataract surgery, see Cataracts as a Complication of Retinal Surgery.

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.