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Phase 3 data from ANCHOR trial favor Lucentis
The late-breaking trial results were announced at Retina 2006 in Hawaii.
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WAILEA, Hawaii – Patients with wet age-related macular degeneration maintained visual acuity at 1 year better with injection of ranibizumab than with photodynamic therapy, according to interim results of a phase 3 trial.
The results of the trial, comparing Lucentis (ranibizumab, Novartis/Genentech) with Visudyne (verteporfin for injection, Novartis/QLT) photodynamic therapy in the treatment of wet AMD, showed that ranibizumab offers patients with AMD the best chance for visual improvement, a speaker here said.
Carmen A. Puliafito, MD, MBA, called the 1-year follow-up data from the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) trial “extraordinary.” Dr. Puliafito presented results of the late-breaking trial here at Retina 2006, held in conjunction with Hawaiian Eye 2006 on the island of Maui. The results were first announced 2 days earlier at the Macula 2006 meeting in New York.
In the first year of the 2-year ANCHOR study, 36% of patients treated with 0.3 mg of Lucentis and 40% of patients treated with 0.5 mg of the drug showed improvement in visual acuity by 15 letters or more, said Dr. Puliafito, who was co-course director of Hawaiian Eye 2006.
On average, patients treated with 0.3 mg of Lucentis gained 8.5 letters, and those treated with 0.5 mg gained 11 letters at 1 year, he said. In contrast, patients treated only with Visudyne PDT lost an average of 9.5 letters after 1 year, according to information from Genentech.
“This is a high-powered, level-one prospective trial,” Dr. Puliafito said. “The strong evidence is that Lucentis gives your patients the best chance of improved vision.”
![Carmen A. Puliafito, MD, MBA [photo]](/images\OSN\200602b\puliafitoBG.jpg) Carmen A. Puliafito, MD, MBA, HawaiianEye 2006 co-programdirector, called the 1-year follow-up data from the ANCHOR trial “extraordinary.” |
Of 140 patients treated with Lucentis, 44 (31%) treated with 0.3 mg and 54 patients (39%) treated with 0.5 mg achieved a visual acuity of 20/40 or better after 1 year, compared with roughly 3% of those in the Visudyne group, he said.
Adverse events in the Lucentis group included conjunctival hemorrhage, increased IOP, eye pain, vitreous floaters, endophthalmitis and intraocular inflammation; the latter two events occurred in fewer than 1% of patients per group. Of systemic adverse effects, myocardial infarctions occurred at a higher rate in the group treated with 0.5% mg of Lucentis than in the other two study arms.
Dr. Puliafito said he is not concerned about non-ocular events that have been associated with Lucentis use.
“I think the amount of the drug that gets into the system is infinitesimal,” he said. “Certainly this is something that people are going to look at, but personally I don’t think this means anything. We need to have better information about the pharmacokinetic effects these agents have after intravitreal injection.”
More presentations from Retina 2006 are highlighted in the remainder of this article. Many of these items appeared first on OSNSuperSite.com as daily reports from the meeting.
Macugen as first-line treatment
Using Macugen (pegaptanib sodium, Pfizer/OSI) as a first-line treatment for age-related macular degeneration produced significantly better visual results than those reported in previous clinical trials, according to Polly Quiram, MD.
Dr. Quiram discussed the results of a retrospective study of patients who received as a first-line treatment. The study included the first 90 patients with fresh lesions who had not been previously treated, she said. Patients with lesions of all sizes and with all levels of visual acuity were included.
Average visual acuity at baseline was 20/80. After treatment with Macugen, visual acuity improved to about a mean 20/50, with some patients achieving 20/20 or 20/25.
“Our results were a surprise even to us,” Dr. Quiram said.
Of these previously untreated patients, 90% had stabilized or improved vision after Macugen treatment. Of that group, 20% experienced at least a three-line gain in VA and 70% had stabilized vision, she said.
Dr. Quiram contrasted these results to those of the VISION (VEGF Inhibition Study in Ocular Neovascularization) trial. In that trial, just 6% of patients demonstrated a three-line or more vision gain, and 30% had stabilized vision, she said.
Dr. Quiram said many of the patients treated as part of the VISION trial had undergone previous procedures and had poor visual function from the outset.
When Dr. Quiram began using Macugen as a first-line therapy, she noted that results were “substantially better” than she had expected based on results from the VISION trial.
“With our increased use of Macugen, we noticed a significant number of above-line gainers,” she said. “Our impression was that Macugen had better results than those recorded in the VISION trial; this was the impetus of our study.”
Follow-up in the retrospective study ranged from 3 to 11 months; the mean number of injections needed to reach a three-line or more gain was 3.5, she said.
Dr. Quiram said the study’s limitations include its small size and a selection bias away from predominantly classic lesions.
“The importance to us is that it has validated our current treatment of Macugen, using it as a first-line treatment for occult and minimally classic lesions. We hope that other centers similar to ours will retrospectively review their data so we can identify the more responsive subtypes and can better evaluate combination therapy.”
‘Stop the RNA’ and delay progress to AMD
A small interfering RNA compound has delayed the progression of age-related macular degeneration in early clinical testing, according to Peter K. Kaiser, MD.
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![Peter K. Kaiser, MD [photo]](/images\OSN\200602b\kaiser.jpg)
Speaking about the ophthalmic applications of short interfering RNA (siRNA), Dr. Kaiser said that RNA proteins are what cause conditions such as AMD.
“But can we stop the protein before it’s made?” he asked rhetorically. “If you stop the RNA, there is no process, and you can turn off certain RNA proteins.”
Dr. Kaiser described Sirna-027 from Sirna Therapeutics, a partially modified RNA that inhibits vascular endothelial growth factor. Sirna has described RNA interference as a natural selective process for turning off genes triggered by short interfering molecules that engage certain cellular proteins.
“If you inject it into the vitreous, it might break down unstable RNA,” Dr. Kaiser said.
In a phase 1 study, Dr. Kaiser said, all 23 patients have “experienced stabilization of visual acuity, and 23% experienced visual improvement of three or more lines of visual acuity within 8 weeks of Sirna-027 injection.”
He said no serious adverse events or dose-limiting toxicities were observed.
Dr. Kaiser said phase 2 studies of the drug are scheduled to begin in the first quarter of 2006. Sirna announced last year that it has partnered with Allergan to develop the compound for ophthalmic use.
PDT still a viable option
Photodynamic therapy is a viable treatment for AMD, and it may have better patient acceptance than multiple intravitreal injections, said Nancy M. Holekamp, MD.
“Patients are consumers. They don’t mind having a needle stuck in their eye, they just don’t like doing it every 6 weeks for a year,” she said. “Some of them may not drive, and they don’t want to have to come back so many times for [intravitreal] treatments.”
Dr. Holekamp said there is “still a role for PDT, given that so much attention is being paid to the anti-VEGF drugs.” She said patients “may wish to have the fewest number of treatments to achieve good results, assuming that safety, cost and vision outcomes are similar.”
Dr. Holekamp described results of an unpublished study that was presented at the 2003 Macula Society meeting. The goal of the study was to identify patients whose vision improved by up to two lines with a single PDT treatment. The retrospective study included 587 eyes with AMD or pathologic myopia. Myopic eyes and AMD eyes with occult choroidal neovascularization were more likely to have a good outcome after a single PDT treatment, Dr. Holekamp said.
In a separate presentation, Dr. Holekamp noted that PDT can also be effective for patients with CNV in non-age-related macular degeneration.
“PDT probably works better than anti-VEGF drugs for CNV in non-age-related macular degeneration,” she said.
Younger patients, patients with relatively good vision and patients with predominantly classic CNV can be candidates for PDT, she said.
She described results of the VIP (Verteporfin in Photodynamic Therapy) Study Report No. 3. Change in visual acuity at 2 years was “in favor of the treated eyes,” she said.
An improvement of greater than one line was seen in 40% of treated eyes vs. 13% of untreated eyes, she said. In addition, there was improvement of more than three lines in 12% of eyes.
“The change in visual acuity at 2 years was in favor of the PDT-treated group. This group was more likely to have improved visual acuity through 2 years,” Dr. Holekamp said.
AMD most likely more than one disease
AMD is a multi-factorial disease that will “keep us confused for a while” about the prospects for genetic treatment, according to Eugene de Juan, MD.
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![Eugene de Juan, MD [photo]](/images\OSN\200602b\dejuan.jpg)
“Many diseases look the same but are very different. AMD is going that way. It is almost certainly not a single disease,” Dr. de Juan said.
Aside from known risk factors such as diet, smoking and systemic health, most estimates hold that roughly 50% of the causes of AMD have to do with genetics.
The first gene discovered to be associated with AMD, known as ABCA4, is also believed to cause Stargardt’s disease, along with retinitis pigmentosa and pattern dystrophy, Dr. de Juan said. This gene, however, is apparently not associated with vision loss in AMD.
Most researchers concur that the most important genetic finding regarding AMD has been the identification of complement factor H, which appears to cause AMD in 35% of people who test positive for the gene, he said.
Yet complement factor H is not associated with geographic atrophy, according to Dr. de Juan, meaning that “geographic atrophy is either a different disease, or maybe it’s not related to choroidal neovascularization,” he said.
The finding of proteins associated with AMD, including synaptopodin, a platelet-derived growth factor, supports the notion that there are “interacting genes,” Dr. de Juan said, “which may explain much of the variability of expression.”
“[Understanding AMD] is not going to be simple. It’s going to be complex and multifactorial,” he said.
Andrew P. Schachat, MD, who moderated the session at which Dr. de Juan spoke, added that the variability of genetic findings signals the need for the biotechnology industry to attempt to identify multiple drug targets to treat AMD genetically.
Early screening for AMD possible with new perimeter
A new diagnostic device may offer an earlier, more reliable way to detect new CNV and to diagnose intermediate AMD before a patient’s vision is severely impaired, said Dr. Schachat in a separate presentation.
He said the new device from Carl Zeiss Meditec is called the PreView PHP (for preferential hyperacuity perimeter).
Without a technology to detect wet AMD early in its course, Dr. Schachat said, physicians will not be able to draw the maximum benefit from emerging therapies for the disease.
“At the time of diagnosis, 40% [of AMD patients] are already legally blind, and 80% have subfoveal lesions. It would be nice to detect wet AMD earlier,” he said.
Dr. Schachat reviewed the findings of a study released last year that evaluated the sensitivity and specificity of the PreView PHP in 122 patients. The sensitivity of the device was 82%, and specificity was 88%. These results were comparable to those of retina specialists, who also evaluated each patient in the trial, he said.
The test takes 5 to 10 minutes per eye to complete. It displays on a screen a total of 500 data points, which are tested three to five times each.
“Whenever patients see a blip in the line, they press a button, and the machine keeps track of when you seen the blips,” Dr. Schachat said.
He said the perimeter could be particularly useful in a primary eye care setting to identify people at risk and refer them to a retinal specialist earlier than would otherwise be possible. He said investigators predicted that with the use of PHP, eight out of 10 patients with intermediate AMD or CNV will be diagnosed earlier than they are today.
The PreView PHP is available in Europe and the United States.
Two retinal devices launched
Two devices for imaging or treating retinal disease were introduced during Hawaiian Eye 2006. Steven D. Schwartz, MD, described his experience with the two new devices in a presentation at the meeting.
OptiMedica launched the PASCAL (Pattern Scan Laser) Photocoagulator for treatment of retinal and choroidal disorders.
Dr. Schwartz said he has been using a prototype of the laser for the past month and is pleased with the results.
“Every early indication is that the outcome is much better with this laser, in terms of safety, accuracy, precision and comfort,” Dr. Schwartz told Ocular Surgery News in an interview following his presentation.
The semi-automated PASCAL 532-nm laser employs short pulse durations of typically 20 ms, according to information from OptiMedica. It is designed for panretinal, focal and macular grid photocoagulation.
Optos launched a device for performing dynamic ultrawide-field angiography fluorescein angiography, the Optos P200MA, also at the meeting. The system allows the surgeon to view the entire posterior segment, according to the manufacturer.
Dr. Schwartz said it “has changed the way we image vascular disease.”
He added that the software is user-friendly and that the resolution is better than any other imaging device he has used.
25-gauge system advantages
Vitreoretinal surgery with 25-gauge instruments gives surgeons “numerous advantages” over larger-gauge systems, Dr. de Juan said.
He said 25-gauge instrumentation should be used “in the majority of vitrectomy cases because of improved patient outcomes, greater safety and shorter operating times.”
Since 25-gauge technology was introduced in 2000, he said, “all major vitreous surgical instruments have embraced this technology,” including those from Bausch & Lomb, Alcon, Synergetics and DORC Ophthalmics. He said most of these companies are also working to improve their systems.
Dr. de Juan said, however, that the risk of endophthalmitis after TSV-25 surgery remains “unclear.”
“Because of reduced conjunctiva washing and shortened surgical times, the surgery becomes similar to cataract in terms of infection risk,” he said.
Although the risk is small, “increased care is needed for surgical prophylaxis,” Dr. de Juan said.
New hydrogels for sustained-release drug delivery
Thermoreversible hydrogels, though not yet available for ocular use, present great promise for sustained-release drug delivery, according to William F. Mieler, MD.
Dr. Mieler said the aqueous-based delivery systems consist of a drug dissolved in a solution of temperature-sensitive polymer. For diseases such as age-related macular degeneration, a sustained-release drug delivery system could enable physicians to reduce the number of injections needed, he said.
“At room temperature, the constituted product exists as a solution. After injection and upon exposure to body temperature, the product gels,” Dr. Mieler said.
He said three companies are currently working on such hydrogels: MacroMed, RxKinetics and Pike. None has formulated an ocular application to date.
Another company, QLT Inc., has created Atrigel, a compound that acts similarly to a gel, solidifying at body temperature. Atrigel has been used subcutaneously in humans for delivery of a handful of drugs, and it is currently in early animal studies for ocular applications, he said.
Dr. Mieler said it is a matter of time before these compounds are adapted for ophthalmic use.
“While this talk is quite theoretical, we have the team in place to take this all the way,” he said.
Image: Archer ME, OSN |
![Donald J. D’Amico, MD [photo]](/images\OSN\200602b\damico.jpg)
Keratoprosthesis helpful in ‘hopeless’ eyes
Vitreous surgery combined with keratoprosthesis surgery “salvages very useful vision in an increasing number of hopeless eyes,” according to Donald J. D’Amico, MD.
Dr. D’Amico described the use of vitreous surgery in combination with implantation of a permanent keratoprosthesis, or K-pro. He said K-pro surgery can be used in patients whose eyes might otherwise be considered “hopeless,” including patients with trauma, chemical burns, repeated graft failure and chronic uveitis.
Dr. D’Amico said his management plan for these patients includes intraocular endoscopy to see if the retina is operable. If it is, he performs implantation of the K-pro and waits 3 weeks until the eye heals. Then he performs vitreous surgery using the K-pro for visualization.
He said that in a series of 17 patients, mean visual acuity was 20/400 before surgery and 20/200 postoperatively.
Dr. D’Amico warned surgeons that “vitreoretinal complications are frequent and occur due to previous disease.” He said more refinement of the surgical instruments and techniques is still needed.