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Systemic AMD treatment shows promise; prospective studies needed, expert says
Potential treatments for the retina edge closer to approval.
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CHICAGO – A systemic treatment for neovascular age-related macular degeneration is showing promising results, said Philip J. Rosenfeld, MD, PhD. He presented a summary of recent findings with the VEGF-blocking agent bevacizumab during Retina Subspecialty Day.
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Philip J. Rosenfeld |
The drug, which is approved for use in colorectal cancer, is attractively priced for this off-label ophthalmic application, but its safety profile in the eye is unknown, Dr. Rosenfeld said.
“Avastin (bevacizumab, Genentech) isn’t going to go away. The retrospective results are too promising and the pricing is too attractive,” Dr. Rosenfeld said. “It needs to be studied prospectively, and it needs to be compared to Lucentis.”
Lucentis (ranibizumab, Genentech) is also being studied in clinical trials for the treatment of wet AMD.
The cost of Avastin is particularly enticing, Dr. Rosenfeld said. A single dose of Macugen (pegaptanib, Pfizer/Eyetech) costs between $1,000 and $3,300, whereas a single dose of Avastin is about $5.50 per eye, he said.
Avastin is a full-length humanized monoclonal antibody directed at VEGF. It was the first anti-VEGF agent approved for the treatment of metastatic colorectal cancer in the United States.
Use of Avastin for AMD is off-label, Dr. Rosenfeld stressed. In cancer patients, Avastin with chemotherapy has been shown to prolong survival, he said.
“I’m sure that Avastin penetrates the human retina better than the monkey retina, but it probably does not penetrate as well as Lucentis,” he said. “What we need to find out is how much is enough. Avastin probably has twice the half-life in the vitreous cavity as Lucentis.”
Patients at the Bascom Palmer Eye Institute in Miami have been offered Avastin as a salvage treatment if their AMD has continued to decline despite other therapies, Dr. Rosenfeld said. Initial results show that a 1-mg dose of Avastin yields a “dramatic response” within 1 week, stabilizing the patient’s condition through 5 months of follow-up, he said.
The first 40 patients treated with the Avastin salvage therapy received an average of 1.8 injections over 3 months, Dr. Rosenfeld said. After 3 months, the patients had a slight improvement in visual acuity and an average decrease of retinal thickness on optical coherence tomography of more than 100 µm, he said.
The safety of systemic Avastin as it relates to the eye is unknown, Dr. Rosenfeld said.
“We feel confident that even after a high dosage, there are no bad effects, but we need to study systemic patients,” he said. “We know that Avastin was injected into a monkey eye in the 1990s without any serious problems.”
To minimize the risk of endophthalmitis, Dr. Rosenfeld said it is necessary to have a sterile solution of Avastin prepared by a credentialed pharmacy using sterile techniques.
“Systemic Avastin does have potential for an increase in hypertension and a doubling of thromboembolic events,” he said. “There have been no other adverse events of a high-dose systemic therapy.”
In this article, highlights of the Retina Subspecialty Day and the retina programs at the AAO meeting are recapped. These items originally appeared as daily coverage from the meeting on OSNSuperSite.com.
Miniature telescope at 1 year
Ninety percent of patients with exudative AMD who were implanted with a telescopic IOL showed at least a two-line improvement in visual acuity at 1-year follow-up in a multicenter study, said Paul Sternberg Jr., MD.
“Despite advances in the management of exudative AMD, there remains a large population of patients with end-stage disease in both eyes,” Dr. Sternberg said. The Implantable Miniature Telescope (IMT) from VisionCare Ophthalmic Technologies may help some of these patients achieve better vision, he said.
“The IMT is a visual prosthetic device, placed in lieu of a conventional IOL, with quartz micro-optics that render the patient’s central visual field over 55° of the central retina,” Dr. Sternberg explained. “Thus, it provides a relative reduction in the size of the patient’s scotoma induced by AMD.”
The IMT uses natural eye movement to allow distance and near vision, Dr. Sternberg said.
He reported results of a prospective, open-label study of the device that included 217 patients at 28 centers. Each patient was screened by a retinal specialist, and the implantation procedure was performed by an anterior segment surgeon. The patient then worked with vision rehabilitation specialists to integrate the modified vision into the patient’s daily life.
Candidates were required to have clinical evidence of AMD and a visual acuity of between 20/80 and 20/800 with intact peripheral vision, Dr. Sternberg said. The mean preoperative baseline visual acuity was 20/316, he said.
“At 1 year, 90% of the eyes implanted with the IMT achieved the primary endpoint of two or more lines of improvement, which is considerably higher than the target level of 50%,” Dr. Sternberg said.
The main safety concern was a 25% loss of endothelial cell density from baseline seen in the eyes that underwent surgery. This exceeded the target of 17% for the study, Dr. Sternberg said.
“The device appeared to be well-tolerated, although care must be taken to limit endothelial cell loss at the time of implantation,” he said. “The majority of the cell loss appeared at time of surgery, presumably while inserting the relatively large device. Fortunately, the endothelial cell density seemed to stabilize over time.”
The data from the trial have been submitted to the Food and Drug Administration for premarket approval of the lens. Approval is hoped for in the first half of 2006, Dr. Sternberg said.
“If approved, it will represent the first multispecialty medical model approach to improve visual function in patients with advanced AMD,” he said. “In fact, it may be an opportunity for us to refer some of those AMD patients, who were dropped on our doorstep a number of years ago, back to our anterior segment surgical colleagues.”
Diabetic edema drug treatments
Several medical therapeutic strategies for diabetic macular edema (DME) have shown promising early results in studies, said Alan Ruby, MD.
Dr. Ruby reviewed the results of studies of periocular, intravitreal and sustained-release drug delivery for DME.
Sub-Tenon’s injection of steroids is a low risk therapy for DME, Dr. Ruby said. In a study of 21 patients with diffuse DME, the mean visual acuity improved from 20/75 to 20/50, he said. At the 9-month follow-up point, none of the patients required reinjection.
Sub-Tenon’s Kenalog (triamcinolone acetate, Bristol-Myers Squibb) “does appear to be efficacious in reducing macular edema as assessed by optical coherence tomography,” Dr. Ruby said.
When injected intravitreally, Kenalog remains in the vitreous cavity for 3 to 6 months, and results are often achieved in 1 week, Dr. Ruby said. Intravitreal administration provides therapeutic levels of the drug rapidly, he said, but complications, while rare, can be serious.
Dr. Ruby also discussed two implants that provide sustained release of steroids.
Retisert (fluocinolone acetonide, Bausch & Lomb) may require patients to use IOP-lowering drugs and can cause cataracts, he said. The device, recently FDA approved, has a high cost and a high rate of complications, he said.
Posurdex (dexamethasone, Oculex/Allergan) a long-term implant, is an extended-release pellet made of a biodegradable polymer called PLGA. It is easy to insert in the office, and improvement of visual acuity was seen in 36% of patients in a recent study, he said.
For all of these therapies, Dr. Ruby said, further studies are warranted.
CNTF implant shows promise for retinal degeneration
An implant containing ciliary neurotrophic factor may be an effective future treatment for hereditary retinal degenerative disease, said Paul A. Sieving, MD, PhD.
Dr. Sieving presented the results of a phase 1 study of a ciliary neurotrophic factor (CNTF) implant in 10 patients for the treatment of retinitis pigmentosa.
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“As of today, the efficacy of neurotrophic therapies for treating humans have not yet been demonstrated, and it remains a problem in delivering large molecules into closed systems,” Dr. Sieving said to attendees at Retina Subspecialty Day.
CNTF has been demonstrated to be effective in preventing mutations across genotypes in a number of mouse, rat, cat and dog models, so there is hope that it could work in treating human retinitis pigmentosa, Dr. Sieving said.
In an open label, nonrandomized, single-center dose-escalation study, a 6-mm capsule containing CNTF was surgically implanted into the vitreous. The CNTF is slowly released by the implant, Dr. Sieving explained.
The capsule was implanted in one eye of each patient in the trial for 6 months, at which time the implant was removed from the vitreous and analyzed for CNTF output and integrity of the cells in the implant.
“There was no inflammation, no complications, and the patients’ visual acuity did not suffer,” Dr. Sieving said. “The subjects overall showed an upward trend in acuity, but the study was not designed or powered to test the significance of this possible outcome.”
The devices were found to contain viable CNTF cells, and the capsules had continued to secrete CNTF throughout the 6 months.
“With this study, the relative safety has been demonstrated in eyes that have advanced neurotrophic retinitis and macular degeneration,” Dr. Sieving said. Further studies will evaluate the ability of the treatment to slow neurodegeneration and prolong vision, he said.
Diabetic retinopathy research group seeks to expand
A nationwide collaborative group of physicians dedicated to research into the ocular complications of diabetes is seeking more members. One member urged physicians to join the Diabetic Retinopathy Clinical Research Network and share their expertise.
“The potential for benefits for patient care that might be achieved by all of you through this effort is vast,” said Lloyd P. Aiello, MD, PhD. He presented an update on the Diabetic Retinopathy Clinical Research Network and its achievements to date here at the American Academy of Ophthalmology meeting.
“The objective is the development of a cooperative network to facilitate multicenter clinical research on diabetic retinopathy, diabetic macular edema and associated conditions,” Dr. Aiello said.
The DRCR.net, a National Eye Institute-sponsored cooperative, was initiated in 2002. Neil Bressler, MD, has been selected as chairman-elect of the group for 2006, Dr. Aiello said.
DRCR.net initiatives include involvement of community and academic partners, collaboration with industry, and standardization of information to optimize trial and site efficiency, he said.
Currently the network includes 155 study sites in 43 states. More than 900 patients overall are enrolled in trials undertaken by the group.
In the past 3 years, seven trial protocols have been developed, one has been completed, four are currently under way and two are pending approvals by institutional review boards, Dr. Aiello said.
The DRCR.net trial protocols include a pilot study of laser photocoagulation for diabetic macular edema (DME), a randomized trial comparing intravitreal triamcinolone acetonide to laser photocoagulation for DME, an evaluation of vitrectomy for DME, a pilot study of peribulbar triamcinolone acetonide for DME, and an observational study of the development of DME following scatter laser photocoagulation. One protocol that has been completed is a study of temporal variation in optical coherence tomography measurements of retinal thickening in DME.
Retinitis pigmentosa therapy treatments promising
Genetic and other therapies for retinitis pigmentosa have shown promise in animal studies, but it may be several years before such treatments are available to clinicians, said John R. Heckenlively, MD.
Summarizing current research, Dr. Heckenlively said that there are 94 genes known to cause retinitis pigmentosa. He spoke on the subject during Retina Subspecialty Day.
“We can expect we’ll need a number of different treatments based on the gene involved and the mutation type,” Dr. Heckenlively said.
Numerous treatments are under investigation, the most promising of which is gene therapy, he said. He called stem cell therapy the retinal specialist’s “trump card.”
“Most current studies have not been successful, and the ethical and legal concerns are overstated,” he said. “Currently, stem cell therapy is looking more like a game of Texas hold ‘em than an organized scientific field. The problem is, we don’t have the knowledge to control or direct cells that are used in therapy.”
Pharmacologic interventions for retinitis pigmentosa are also likely to show benefit, Dr. Heckenlively said. In his lab, a clear therapeutic effect has been shown with pharmacologic agents, but he reiterated that gene therapy has been more promising to date.
He advised physicians show restraint when discussing potential treatments with patients, as the process of moving treatment protocols from the lab to human study is “clearly time-consuming and involved.”
Pfizer announces VISION Function study of Macugen
A new trial will assess functional vision in patients taking Macugen (pegaptanib, Pfizer/Eyetech) for treatment of AMD, according to the drug’s marketers.
The trial, called the VISION Function study (VEGF Inhibition Study in Ocular Neovascularization Function), will be conducted in 18 countries and will include more than 300 patients with choroidal neovascularization secondary to AMD. The trial will assess near vision, reading speed, contrast sensitivity and distance visual acuity of patients with neovascular AMD, according to a press release from Pfizer.
“The design of this study will provide us with visual function and quality-of-life information for patients using Macugen,” said Ronald Buggage, MD, Pfizer’s global ophthalmology medical director, in the release. “We are also interested in assessing the value of Macugen in treating AMD patients at an earlier stage in the development of their disease.”
Macugen is currently approved to be administered in a 0.3-mg dose once every 6 weeks by intravitreal injection. It is co-promoted in the United States by Pfizer and Eyetech; outside the United States, Pfizer has exclusive marketing rights.
Cataract surgery not likely a risk factor for AMD
Cataract extraction is probably not a significant risk factor for progression of AMD, said Frederick L. Ferris III, MD.
Dr. Ferris analyzed data from a subgroup of participants in the Age-Related Eye Disease Study (AREDS) to search for links between cataract extraction and AMD progression.
“The question of course is whether prior cataract surgery increases the risk of AMD,” he said.
Dr. Ferris and colleagues found no association between cataract surgery and AMD progression in the AREDS subset studied, he said. He described the group’s findings during the Retina Subspecialty Day.
There have been questions in the literature regarding the possibility that cataract surgery may cause AMD, or on the other hand that AMD-related vision loss may lead to cataract surgery in some patients, Dr. Ferris said.
“I think everyone has seen at least one patient who has come in and has had a cataract removed due to decreased vision, but the decreased vision is in fact from AMD,” he said.
Dr. Ferris said he used four statistical models to analyze the relationship between cataract surgery and AMD. They included ordinary logistic regression, the Cox proportional hazards model, repeated measures and a matched case-control approach. No significant association was found between cataract surgery and AMD among the AREDS population using any of those models.
“Overall, we think [cataract surgery] patients shouldn’t necessarily be worried that they will increase their risk for AMD,” he said.
Race may play a role in pars plana vitrectomy outcomes
In a comparison of white, black and Choctaw American Indian patients with proliferative diabetic retinopathy undergoing pars plana vitrectomy, no statistically significant difference was seen in visual outcomes, although a greater percentage of eyes of white patients showed improvement than the other groups, according to a poster presentation.
The poster by Hussein Wafapoor, MD, and colleagues, presented here at the American Academy of Ophthalmology meeting, evaluated racial differences in eyes undergoing pars plana vitrectomy for complications from proliferative diabetic retinopathy.
The researchers concluded that although the slight differences in improvement between the three groups were not statistically significant, higher rates of visual deterioration were seen in the black and Choctaw Indian groups compared with the white group.
The study also found that the rate of reoperation of eyes in the Choctaw Indian group was double that of the white and black groups.
The study authors noted in the poster that the racial differences seen in the study seen could have been influenced by the severity of disease at the time of presentation, which was greater in the group of black patients. They also noted that further studies should be performed to indicate whether or not genetic or socioeconomic factors, referral practices or health care access play a role in these differences.
Sirna-027 may offer useful treatment for AMD
Early results from a phase 1 trial of short interfering RNA for the treatment of neovascular AMD indicate the therapy is safe, well-tolerated and had no dose-limiting toxicity, according to a presentation here.
Edward J. Quinlan, MD, spoke about his results in 22 patients treated with Sirna-027 (Sirna Therapeutics) and followed for at least 8 weeks in a free paper session at the AAO meeting.
Dr. Quinlan’s remarks were described in a press release issued by Sirna during the meeting.
Single intravitreal injections of 100 µg, 200 µg, 400 µg, 800 µg or 1,200 µg were administered to patients in the trial, the release noted.
One hundred percent of patients showed visual acuity stabilization, and 23% had a “clinically significant improvement in visual acuity after 8 weeks from a single intravitreal injection,” according to the Sirna release. There was also a relevant decrease in central foveal thickness as measured by optical coherence tomography.
Sirna will continue to develop the drug through the completion of the phase 1 trial, which is expected by year’s end. Allergan will assume development of the drug beginning next year, the release said.
AREDS 2 seeks centers
With the NEI’s AREDS now complete, a proposed AREDS 2 is scheduled to begin in 2006, announced Emily Y. Chew, MD, one of the researchers in the original trial.
Image: Mullin DW, OSN |
Dr. Chew announced that the NEI anticipates the participation of 40 to 60 clinical and academic sites in the study, and the institute is accepting applications from study sites until November 23, 2005.
Observational data suggest that lutein and omega-3 fatty acids may reduce risk for AMD, Dr. Chew said, and the AREDS 2 will test that hypothesis clinically.
The objective of the study will be to evaluate treatment outcomes using lutein and zeaxanthin, omega-3 fatty acids as well as a combination of the treatments.
The design of the AREDS 2 will be similar to the original AREDS, with 25% of patients taking placebo, 25% taking a supplement containing lutein, 25% taking a supplement containing omega-3 fatty acids and 25% taking a combination of the two.
“We will look at moderate vision loss and progression to AMD as well as cataract surgery and progression along the AREDS AMD scale,” Dr. Chew said in a press release issued during the American Academy of Ophthalmology meeting.
The population will involve at-risk patients as well as patients with advanced AMD.
“AMD accounts for a very wide part of our patients with vision loss, and that is more than 50%,” Dr. Chew said. “We’ve already seen that the combination of antioxidants and zinc reduces the risk of vision loss and progression to AMD … we’re hoping this will give us further protection from AMD if possible.”
The application for study sites can be downloaded from www.areds2.org.
Subset analysis shows improved acuity with Vitrase after hemorrhage
Based on a pooled subset analysis of two phase 3 studies, a single injection of hyaluronidase resulted in an improvement of best corrected visual acuity in some eyes after vitreous hemorrhage, according to an Ista Pharmaceuticals press release.
Vitrase (ovine hyaluronidase, Ista Pharmaceuticals) has been studied in two randomized, double-masked, placebo-controlled phase 3 studies for clearing vitreous hemorrhage. The pooled subset study assessed the efficacy of a single intravitreal injection of Vitrase in patients with severely decreased visual acuity who did not have AMD.
Data were presented in a poster by Ronni M. Liebermann, MD, and colleagues at the AAO meeting.
Patients in the study received either 55 IU of Vitrase or saline injection, and an improvement of BCVA of at least three lines was evaluated for 1,070 patients using survival analysis, according to the press release.
At 3-month follow-up, there was a significantly higher proportion of BCVA improvement in patients who were treated with Vitrase (48.2%), compared to patients who received saline (37.3%).
The authors concluded that Vitrase was “effective in improving BCVA in patients who had vitreous hemorrhage that was not related to AMD,” the Ista press release said.