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).
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:
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.
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.
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.