As reported by A. Laban-Baker, VP Communications, AMDAI
Topics covered:
Introduction
One thing was clear from the presentations at the 2009 American Academy of Ophthalmology meeting, researchers are leaving no stone unturned in their quest to find new and better treatments for the challenging condition.
From anti-VEGF treatments to genetics, to nutrition, more than 25,000 ophthalmologists from all around the world heard about the latest advances and promising treatment initiatives on the horizon.
It is an exciting time for patients, echoed many of the presenters. But AMD is a complex disease with many potential causal factors, including genetic predisposition and a host of environmental factors, which appear to contribute to its pathogenesis. This provides for both challenges for treatment as well as opportunities to target new biochemical pathways in the pathogenesis of the disease.
During the Retina Sub-specialty Days, more than 30 presentations were held by leading researchers from around the globe, focused on AMD. Below are highlights from these presentations.
Genetics and Personalized Medicine
According to Ivana Kim, MD, Harvard Medical School, approximately 15 genes have been associated with AMD to date and the genes with the strongest association are complement factor H, and ARMS 2. Complement factor H has been associated with increased risk of AMD progression, as well as larger choroidal neovascular lesion size.
“Can genotype predict response to treatment?” The answer appears to be yes said Dr. Kim. Studies have shown that the polymorphism CFH Y402H may predict treatment response. Specifically, patients in the AREDS study population with this specific polymorphism seemed to benefit less from nutritional supplementation. This same polymorphism predicts poorer response to photodynamic therapy, and different allelic expressions of CFH Y402H are associated with varying response to anti-VEGF therapy.
Eric Postel, MD, Duke Eye Center, reported that new targets for AMD therapy are being identified, guided by genetic research. He added that the current best practice for (wet) AMD relies on the suppression of neovascularization for a finite period and does not adequately address the underlying disease or its progression. Better therapies might not only prevent the progression of obvious disease that leads to neovascularization, but may also lead to effective prevention at earlier stages. If such preventive treatment could delay the onset of AMD by a decade or two, that in effect, said Dr. Postel, could be a cure for most patients.
Tsontcho Ianchulev, MD, University of California, San Francisco, reported on the ranibizumab DAWN genetic sub- study which included preliminary data pointing to evidence that treatment outcomes may be significantly influenced by underlying genetics. Further evaluation is needed to confirm results and will be conducted in the upcoming ranibizumab HARBOR study, which will examine different dose levels and regimens of ranibizuamb for neovascular AMD.
Janey Lee Wiggs, MD, Ph.D, Harvard Medical School, said that rapidly developing genomic technologies associated with good genotyping information, will make the possibility of personalized medicine a reality in the not-to-distant future.
Current Clinical Trials for Avastin vs. Lucentis
Daniel Martin, MD of Emory University, presented an update on the six trials throughout the world comparing Lucentis and Avastin.
CATT--More than 1130 patients (of a target of 1200) are enrolled in the multi-centered trial to assess the relative safety and efficacy of Lucentis and Avastin. CATT is being conducted in 44 clinical centers and is funded by the National Eye Institute. CATT is expected to be the first study to report results in early 2011 with the other studies following in later 2011 and 2012.
IVAN is a head-to-head comparison of Avastin and Lucentis. It began enrolling in April 2008 (600 patient goal). Sponsored by the NHS, it is being conducted at 17 sites across the UK.
VIBERA is being conducted at 4 sites in Germany. It began in 2008 (enrollment goal of 360 patients).
MANTA is underway in Austria since June 2008: 320 AMD participants.
LUCAS is a 12 site study in Norway and began enrolling an anticipated 450 patients in March.
GEFAL is a 600-patient, 20-site study. French investigators opened enrollment in fall 2009.
Cataract Surgery and Progression of Wet and Dry AMD
In the United States there are more than 1.5 million cataract surgeries performed each year, according to Susan Bressler, MD Wilmer Eye Institute, Johns Hopkins. Eight millions Americans aged 55 or older are estimated to have intermediate or advanced AMD or unilateral advanced AMD. Since both conditions are age-related, large numbers of people are expected to have both conditions simultaneously.
While cataract surgery can improve visual function and quality of life of patients with AMD, there have been a number of concerns about cataract surgery accelerating the development or progression of AMD.
At the Wilmer Eye Institute, Dr. Bressler and colleagues conducted fluorescein angiograms and photos prior to patients undergoing cataract surgery and again a week later and then at 3 and 12 months. Nine of 71 eyes developed CNV by month 12 but only 3 of 65 eyes did so after week one. Also only 2 of 61 eyes developed geographic atrophy by month 12, but there were no confirmed cases that developed after 1 week of surgery.
Dr. Bressler also said that evaluation of the AREDS study data concluded that there was no clinically important increase in risk that cataract surgeries accelerate development of AMD. Dr. Bressler offered the hypothesis that AMD may be pre-existing, but undetectable or undetected.
People with varying levels of AMD can clearly have vision and quality of life improvements with cataract surgery. Dr. Bressler said all patients with AMD should be counseled about the natural course of their disease and be given some reassurance that there is no greater risk that disease progression will occur with cataract surgery.
A Tiny Capsule to the “Rescue”
George Williams, MD of Beaumont Hospital in Michigan and a consultant for Neurotech reported on recent results of a Phase II clinical trial on the company’s intraocular implant that consists of human cells that have been genetically modified to secrete ciliary neurotrophic factor (CNTF). CNTF, a growth factor capable of rescuing dying photoreceptors and protecting them from apoptosis, or programmed cell death, is delivered directly to the back of the eye by means of an Encapsulated Cell Technology (ECT) device. This device, implanted in a short, outpatient procedure helps bypass the blood-retinal barrier—often a major obstacle in treating diseases of the retina.
The trial results indicated that the ECT device with CNTF slowed the loss of vision in subjects with dry age-related macular degeneration involving geographic atrophy. There were no associated serious adverse events reported and both the device and the procedure were well-tolerated. The company plans to initiate a Phase 1 clinical trial for wet AMD in the near future.
Dry AMD Pipeline Review
According to Phillip Rosenfeld, MD, PhD, Bascom Palmer Eye Institute, three strategies have emerged in major areas of therapeutic areas of investigation: preservation of photoreceptors and RPE (neuroprotection); prevention of oxidative damage; and suppression of inflammation.
While there are a number of Phase I and Phase II clinical trials ongoing in the area of preserving photoreceptors and RPE, the only Phase III trial taking place is testing a drug called Trimetazidine (Vastarel), an anti-ischemic agent with cytoprotective effects which is believed can improve choroidal circulation in patients with dry AMD. The primary goal of this study is to slow the conversion of dry AMD to wet AMD.
Oxidative stress is also important in dry AMD and is considered to be a driving force in disease progression. In addition to the AREDS II trial, (Phase III), a topical antioxidant (OT-551) created by Othera Pharmaceuticals is being evaluated as a treatment for dry AMD and is currently in Phase II (OMEGA). OT-551 has been shown to possess anti-inflammatory, anti-angiogenic properties, as well as antioxidant properties.
There are also more than ten pre-clinical, Phase I and II clinical trials in the area of research to suppress inflammation.
Dr. Rosenfeld said that dry AMD is a human disease without any animal correlates. The only clues will be gathered from human clinical trials. Hopefully, one of the abovementioned strategies will prove beneficial. We should know some of these results within the next several years. Visit www.clinicaltrials.gov for a list of clinical trials for dry AMD.
Recognition and Management of Anti-VEGF Non-responders
Gaurav Shah, MD, Washington School of Medicine, reported that in clinical practice, about 15 percent of patients do not respond to Anti-VEGF treatments. Unresponsive lesions may be related not to poor therapies but to poorly directed therapies. Mature vascular complexes may not be amenable to anti-VEGF therapy. Successful exudative AMD therapy requires successful leakage resolution. It is essential that high-speed angiography is done for both identification and treatment in both failed and persistent leakage. Multiple and innovative approaches must be employed. Dr. Shah discussed patients who may have better treatment response with photodynamic therapy (dual or triple), and thermal laser and he highlighted ongoing research on NeoVista’s Epi-Rad device and the Macusight study for sirolimus (rapamycin). Moving forward, therapies must be tailored for the individual.
VEGF Trap-Eye
The VEGF Trap is a fusion protein specifically designed to bind all forms of Vascular Endothelial Growth Factor-A (VEGF-A) and Placental Growth Factor (PLGF). Both VEGF-A and PLGF are proteins that are involved in the abnormal growth of new blood vessels. According to Jeffrey Heier MD of Tufts University and Harvard Medical School, VEGF Trap-Eye offers the theoretical potential for increased efficacy or decreased treatment duration or burden.
Data from the CLEAR-IT 2 extension study of a novel anti-VEGF agent suggest clinically significant improvements in vision were achieved with low dosing burden and a favorable safety profile.
Based on the positive results achieved, two pivotal studies are fully enrolled with 1200 patients: VIEW 1 and VIEW 2. VEGF Trap-Eye is being evaluated using 4 and 8 week dosing intervals in direct comparison with ranibizumab dosed every month.
Radiation for AMD
Radiation is gaining attention again as a potential treatment for wet AMD, according to Pravin Dugel, MD, managing partner Retina Consultants. Unlike anti-VEGF agents, radiation is thought to eliminate CNV vessels permanently, rather than simply just suppressing them.
Dr. Dugel shared interim results from NeoVista’s MERITAGE I study using epimacular brachytherapy. The study’s goal was to reduce the number of injections while maintaining visual acuity. Preliminary study results suggest that a single procedure with the therapy can further improve visual acuity in a majority of patients while decreasing the number of injections required. Most importantly, 63% of patients enrolled in the study experienced improvement in their visual acuity while 50% of patients gained 5 or more letters of visual acuity at 6 months. Any reported adverse events related to the vitrectomy necessary with this therapy. More information is forthcoming from two large Phase III studies: CABERNET and MERITAGE II.
The IRAY by Oraya Therapeutics is an office-based surgery that allows a physician to deliver low dose, low energy, x-ray radiation to the macula. This is performed in a ten to twenty minute office procedure (in conjunction with an initial anti-VEGF dose). A Phase I trial in Mexico City is evaluating its safety, efficacy and biological effect in patients with AMD.
According to Peter Kaiser, MD, Cole Eye Institute, safety was excellent. No patients had moderate vision loss, 74% gained vision and almost half of the patients had a significant visual gain. There was a dramatic reduction in the need for Anti-VEGF after the initial loading dose. Fifty-six percent of patients required no additional anti-VEGF injections. IRAY will be entering pivotal studies in Europe and the United States within the next year to 18 months.
Topical Therapy for Exudative AMD
If efficacious, eye drops could offer patients an easy to administer alternative to frequent intraocular injections. Patients are familiar with eye drops for use for dry eye, redness, infections, etc. Eye drops could also offer significant advantages with regards to cost, patient compliance and convenience.
Pazopanib by Glaxo Smith Kline (GSK) is currently under investigation for use by AMD patients. Pazopanib is a second-generation multi-targeted tyrosine kinase inhibitor against all VEGF receptors. In the case of VEGF, a kinase inhibitor can prevent blood vessels from growing and leaking even though VEGF is present and binding to the endothelial cells.
Ronald Danis, MD, University of Wisconsin, Madison, reported on a study by GSK of patients with AMD. Change in visual acuity was statistically significantly improved in the high dose group. The mean change from baseline was 4.3 letters at day 29. Plans are underway for a larger Phase IIb study to further investigate these observations.
Overview of Maintenance for Anti-VEGF Therapy and Combination Therapies for Wet AMD
Intraocular pan-VEGF blockade (ranibizuamb/Lucentis) is the current standard for managing neovascular AMD. In practice, there are very few fixed regimens that are utilized, said Carl Regillo, MD, of Thomas Jefferson University and Wills Eye Hospital. We really don’t know with existing data whether any non-monthly therapy stacks up or compares to the pivotal studies. There is a trend with existing data to indicate that better outcomes are achieved with more treatment and closer follow up. Dr. Regillo said he is anticipating that trials such CATT and others will shed light on fixed vs. traditional PRN dosing.
According to Dr. Peter Kaiser, because anti-VEGF therapy currently has no treatment endpoint, there is very good rationale for combining anti-VEGF with a number of different modalities to offer a finite treatment strategy and thereby reducing social and economic burden to patients and healthcare systems.
Good safety and efficacy data to combine verteporfin PDT and ranibizumab were observed in the FOCUS and PROTECT trials. A large set of clinical trials (SUMMIT) are now underway to validate and expand on these findings. Hopefully by combining these treatments, clinicians can improve visual results, decrease the number of injections and allow for a more individualized treatment regimen for patients.
Implantable Miniature Telescope
For patients with bilateral advanced disease with severe vision loss, the only treatment option is low vision evaluation and low vision aids. The implantable miniature telescope (IMT) is geared towards these patients.
With the IMT, the image is enlarged so that it is projected onto healthy areas of the retina enabling the majority of the image to be seen. Unlike an external telescope, scanning is done with the eye rather than head movement. The field of view is 20 to 24 degrees rather than the 8 degrees that is typical for an external telescope. Jeffery Heier, MD, of Tufts University School of Medicine and Harvard Medical School, recounted previous efficacy reports. Patients began with a baseline of 20/300 vision and after one year and two years, vision improved to roughly 20/140. This resulted in an improvement in quality of life. Dr. Heier said this means we are increasing the ability for patients to care for themselves, to perform daily living activities and have face to face conversations with others. The device now meets all of the FDA requirements for safety and efficacy. In March 2009 the FDA panel gave unanimous recommendation for approval. Full approval is pending.
Retinal Prosthetic Devices
Mark Humayan, MD, Doheny Eye Institute, discussed Second Sight’s ARGUS II, a retinal prosthesis to provide sight to patients blinded from retinal degenerations, such as retinitis pigmentosa and potentially end-stage AMD. The device consists of a tiny camera and transmitter mounted in eyeglasses which converts the image to an electronic signal. Patients learn to interpret the visual patterns and produce them into meaningful images. A long-term clinical trial is underway in the US and Europe. Other studies using different approaches are taking place around the world with limited numbers of patients, most of whom have retinitis pigmentosa. While progress in the field is interesting, potential commercialization of these devices is still a number of years away.
Nutrition and AMD
Why is nutrition important for AMD? The retina and retinal pigment epithelium are susceptible to oxidative stress and are in an area of high oxygen load and designed to be exposed to light. So, according to Paul Bernstein, MD, Ph.D., Moran Eye Center, University of Utah, it makes sense that anti-oxidant nutrients that can mitigate oxidative damage may be important.
It is established that all patients with moderate to advanced AMD begin to take the current recommended AREDS formula—zinc vitamins C, E, and beta carotene (smokers should avoid beta carotene due to increased lung cancer risk). Current research is underway to determine the “next generation” of supplementation in the AREDS II trial sponsored by the National Eye Institute. All subjects are offered an original or slightly modified AREDS-type formulation plus various combinations of high dose carotenoids and high dose omega-3 fatty acids. Enrollment is complete with more than 4,000 patients and results are expected in 2010.
Lutein and zeaxanthin are dietary factors related to beta-carotene that are specially concentrated in the macula. Recent studies indicate that daily supplement of lutein and zeaxanthin with at least 6 mgs. may be beneficial.
Omega-3 fatty acids are essential lipid components of the disk membranes of the photoreceptor outer segments. Recent studies have linked high consumption of omega-3 fatty acids and DHA- rich fish with a lower risk of AMD.
Emily Chew, MD, of the National Eye Institute, reported on findings of a study that suggested daily supplementation of folic acid and vitamins B6 and 12 may reduce the risk of developing early stages of AMD. At this time, Dr. Chew said that folic acid and/or B vitamins cannot be recommended for treatment until further studies have replicated these findings. For now we should stick with the AREDS formula and await AREDS II.
