Macugen showed efficacy by 6 weeks in treatment of AMD

Specialists and clinicians presented updates on therapies, imaging and surgery at Retina 2005.

WAIKOLOA, Hawaii — A recently approved treatment for age-related macular degeneration showed a statistically significant difference from sham treatment in just 6 weeks, and that difference was sustained throughout the length of a 1-year study, according to one investigator of the drug.

Macugen (pegaptanib sodium injection, Eyetech/Pfizer), the first therapy for age-related macular degeneration that is based on inhibiting vascular endothelial growth factor, was approved by the Food and Drug Administration in December and made available to ophthalmologists in January.

Steven D. Schwartz, MD, one of the investigators in the recently published VEGF Inhibition Study in Ocular Neovascularization (VISION), outlined the study results for attendees of Retina 2005, a meeting held in conjunction with Hawaii 2005, The Royal Hawaiian Eye Meeting.

"Macugen fills an unmet medical need for about 75% of our AMD patients who we have been desperate to treat," Dr. Schwartz said. He said some clinicians have been using off-label therapies in an effort to treat patients who do not meet the labeling criteria for Visudyne (verteporfin for injection, Novartis/QLT) photodynamic therapy. One advantage of Macugen, he noted, is that it has been shown to be effective in all subtypes of choroidal neovascular lesions in AMD.

In addition to the efficacy shown at 1 year follow-up, Dr. Schwartz said there was a clear advantage of pegaptanib sodium injection in a subset of patient followed for 2 years.

In presenting the results of the VISION trials, Dr. Schwartz explained that there were broad inclusion criteria to replicate the "real world" as much as possible.

Using multiple logistic regression to compare the patients receiving Macugen 0.3 mg to those receiving sham treatment, no factors except Macugen use had a significant influence on the response, Dr. Schwartz said. In the 0.3 mg treatment group, 8% of patients gained three lines or more of visual acuity, compared with 2% in the control group, Dr. Schwartz said.

Visudyne PDT was permitted in the trial in patients with predominantly classic lesions. Overall PDT use was low, Dr. Schwartz said, with 75% of the patients undergoing no PDT. The numbers were too small to allow statistical analysis, he said.

Gene therapy in pediatrics

Genetic therapies will be key to preventing or treating a number of pediatric retinal diseases in the future, according to Antonio Capone Jr., MD. He spoke about the implications of genetic therapies for hereditary pediatric eye disease at the meeting.

Dr. Capone used as his example congenital X-linked retinoschisis, a genetic disease that primarily affects males and displays a great deal of phenotypic variability.

Dr. Capone said he and his colleagues have identified four subtypes of the disease and have learned much about its genetic makeup — if not how the gene actually functions. They have learned that the affected gene is 224 amino acids long and has 125 potential mutations, he said.

"This [new information] dovetails with the information we are getting from advances in microbiology," Dr. Capone said. "There is a confluence with how we're changing our thinking about other diseases."

He said there are two possible approaches to genetic therapy of the disease: to replace the defective gene or to destroy its aberrant product.

To treat each mutation separately — what Dr. Capone called a "boutique approach" — would not be feasible because of the number of possible mutations and the potential cost. A more feasible approach would be to introduce a ribozyme into the retina that targets multiple mutations at once.

This would address all downstream abnormalities and fix a lot of disease with one single approach," he said. "It is an enticing, attractive approach, although we don't know the effect or duration."

Brachytherapy for melanoma

Brachytherapy was found to be a successful treatment in some patients with choroidal melanoma, according to a review of a subset of patients followed in the Collaborative Ocular Melanoma Study.

"Immediate, globe-conserving brachytherapy maintains excellent tumor control and survival in the subset of patients with tumor growth," H. Culver Boldt, MD, said at Retina 2005, held in conjunction with Hawaii 2005, The Royal Hawaiian Eye Meeting.

Dr. Boldt said 44 patients in the study with suspected small choroidal melanoma were treated with brachytherapy. Patients with documented growth or malignant transformation were evaluated for clinical features, length of observation, complications and survival rates with and without metastatic disease.

He said results showed that for patients undergoing iodine-125 brachytherapy, mean overall vision was 20/50, and it was 20/30 in patients with tumors more than 3 mm from the optic disc or fovea. Dr. Boldt said no tumor growth was noted in the eyes undergoing brachytherapy.

He added that patients should be followed closely with photography and echography. He said the results in this subset of patients indicate a need for a randomized, prospective comparative study.

Sustained-release triamcinolone

A large-crystal non-micronized triamcinolone preparation "may be worthwhile pursuing," according to an investigator of the formulation.

Donald R. Sanders, MD, PhD, said the beneficial effects of the usual dose of intravitreal triamcinolone (4 mg) tend to diminish after about 3 months. He said investigators have attempted to prolong the effectiveness of intravitreal triamcinolone, but increased dosages of the steroid tend to cause IOP to increase.

Dr. Sanders said that larger crystal sizes of triamcinolone have a decreased surface-area-to-volume relationship, resulting in a slower dissolution time in lab studies. Therefore, these larger crystal formulations may not cause IOP to increase, he suggested.

In animal studies, Dr. Sanders said, this new composition differs in shape and porosity from that of non-micronized triamcinolone. He said the studies also showed a "significant difference in the dissolution rate" between micronized and non-micronized samples of triamcinolone.

He added that the larger particle size can still be injected through a 22-gauge needle, which is the same size used for traditional triamcinolone preparations.

Evidence needed on efficacy

More clinical information is needed to determine whether a combination of photodynamic therapy plus anti-angiogenesis therapy offers a measurable benefit for treating patients with wet age-related macular degeneration, according to a retina specialist.

Philip J. Rosenfeld, MD, PhD, urged surgeons to think carefully about the risks and benefits of combining the two types of therapies for AMD. He said this is especially important now that Macugen (pegaptanib sodium injection, Eyetech, Pfizer), an anti-vascular endothelial growth factor (VEGF) drug, has been approved by U.S. regulatory authorities.

The photodynamic therapy drug Visudyne (verteporfin for injection, QLT, Novartis) was approved as a treatment for some types of AMD in 2000. Another PDT drug, Photrex (rostaporfin, Miravant Medical Technologies) has been recommended for approval for use in AMD by a U.S. regulatory advisory panel.

Dr. Rosenfeld said that, to justify combining PDT with Macugen, "the potential benefits must outweigh the risks" of vision decrease after PDT.

If leakage can be stopped using anti-VEGF therapy and the only indication for using PDT is leakage, then the benefit of adding PDT to the treatment protocol must be clearly demonstrated, he said.

Evidence that might help surgeons sort through these options is still lacking, he added.

In contrast, Dr. Rosenfeld said there is a body of evidence supporting a combination of PDT plus intravitreal triamcinolone acetate injection.

"The question becomes: Are the benefits of PDT plus Kenalog [triamcinolone acetonide, Bristol-Myers Squibb] worth the increased risk? Right now they are. But with Macugen, we still need to know," he said.

Geographic atrophy, AMD

In determining the proper treatment of retinal disease, it can be just as important to understand the similarities between AMD and geographic atrophy as to understand the differences that distinguish them, said Michael L. Klein, MD.

"We always hear people talk about whether they are one or two diseases," Dr. Klein said. "Geneticists are interested in dividing them into phenotypes and compartmentalizing them to make it easier to find the genes. But I think we have to agree that it is really probably one disease with the more general process of angiogenesis that comes in."

Geographic atrophy (GA), characterized as end-stage atrophic AMD, has unique clinical features, including sharply demarcated, depigmented, visible choroidal vessels. Its growth can vary, but studies have shown that the borders of GA expand by an average of 139 µm per year, Dr. Klein said.

It is difficult to see GA because it is typically obscured by the presence of CNV, he said. The precursors of GA lesions typically appear after the resolution of CNV.

In many cases, GA can evolve from a patch of confluent, large drusen, he said. This is followed by hyperpigmentation, and then by fading of the drusen, disappearance of hyperpigmentation and the development of hypopigmentation.

Understanding this process could come into play as recent studies regarding treatment of drusen with laser emerge, Dr. Klein said.

"The laser-to-drusen studies are preoccupied with trying to prevent neovascularization. It may turn out that there is a role in preventing GA also," he said. "If we can cause regression in drusen, we may be able to avoid GA. At least it's a theoretical possibility."

Imaging and diagnosis

OCT for diagnosing AMD

Optical coherence tomography is useful for establishing a baseline in the diagnosis of AMD and may be "all that is necessary," according to one clinician.

Dr. Rosenfeld said that "if OCT imaging is all you need to decide when to treat patients, and OCT monitoring is all you need to decide when to re-treat, and OCT monitoring is capable of maintaining the visual acuity benefits achieved with pharmacotherapy, then it stands to reason that OCT imaging is all you need."

Dr. Rosenfeld described a study in which he and colleagues followed 23 patients with AMD with subfoveal choroidal neovascularization who had previously been treated with Lucentis (ranibizumab, Genentech). After 18 months of follow-up, 16 of 23 patients required re-treatment, and seven patients showed no sign of recurrent leakage.

In 16 patients who were re-injected, OCT imaging detected the earliest manifestation of leakage in all 16 patients.

Dr. Rosenfeld said that OCT has been used as a basis for when to inject, withhold or re-inject. He also said that patients may prefer OCT over fluorescein angiography because OCT is fast and noninvasive compared with fluorescein angiography.

Spectral OCT

Spectral ultra-high-speed, ultra-high-resolution OCT is "another leap" in retinal imaging, according to one clinician.

"It works 100 times faster than ultra-high-resolution OCT," according to Jay S. Duker, MD.

Dr. Duker explained that this technology creates images with up to 2.1 µm of sensitivity and up to 16,000 axial scans per second.

"You can even enlarge the image without any loss of sensitivity," Dr. Duker said. Using more modest pixel densities, larger numbers of images can be acquired, he said.

Dr. Duker added that ultra-high-speed, ultra-high-resolution OCT can provide much more information on the morphology of intraretinal layers than conventional OCT images.

Another advantage, Dr. Duker said, is that the technology enables three-dimensional imaging, rendering and mapping of retinal microstructures.

Multifocal exams

Multifocal, objective assessments of retinal function may have advantages over current subjective perimetry tools in the diagnosis of glaucoma, said L. Jay Katz, MD.

There is an urgent need to detect glaucomatous structural damage earlier than currently possible, Dr. Katz said.

"We have all these problems with our standard visual fields in terms of test duplication being difficult, some patients not being too cooperative, and [our] not being able to interpret the data," he said. In addition, with subjective perimetry there is a learning curve, "so with repeat testing the patients do better and better," he said.

At present, the VERIS system (Electro-Diagnostic Inc.) and the AccuMap test (ObjectiVision) are the only two commercially available units for multifocal objective retinal testing.

The VERIS, a multifocal electroretinography test, takes about 20 minutes per patient.

The AccuMap, a multifocal visual evoked potential (VEP) test, uses checkerboard pattern stimulation with 58 test areas. It covers the central 26º, except in the nasal area where it extends to 32º to capture early nasal defects. The test takes about 30 minutes per patient, Dr. Katz said.

"Multifocal VEP is an objective method for recording visual fields, and we may start looking at it more and more in the future," Dr. Katz said. "There appears to be reasonable agreement in at least some of the studies between VEP with standard perimetry and [Heidelberg Retina Tomograph] testing. Patient acceptance seems to be very high. They thus far seem to prefer this testing over standard perimetry."

Dr. Katz cited the absence of a learning curve with the test as an additional positive for clinicians.

"There is a lot work that still needs to be done," Dr. Katz said. "There has to be a better way to analyze the data, we have to have larger clinical trials and really try to see how this fits into how we evaluate patients in the future."

Vitreoretinal surgery

Advantages of silicone oil

The use of silicone oil in macular hole surgery has fallen out of favor in the United States, but in select cases it can be a useful and effective option, said Carl C. Claes, MD, of Belgium.

"With silicone oil in the eye and a 30-gauge aspiration needle, you drain the [balanced salt solution] and the edges of the macular hole are pulled together," Dr. Claes said. "Without even touching the hole you can close it, although you might have to repeat the maneuver several times."

Dr. Claes said with silicone oil there is no need for patients to maintain special positions postoperatively, as is the case with gas tamponade. This is an important factor to consider when dealing with children, the elderly or the obese patient.

"Also, the patient can return to normal activity after surgery, it is more comfortable for monocular patients, and flying does not present a problem," he said.

Dr. Claes and colleagues have been able to streamline their approach to macular hole surgery with silicone oil. Originally, repairing a macular hole required first the performance of vitrectomy and the placement of a silicone oil tamponade, then removal of the silicone oil, followed by phacoemulsification. Now, he said, they do the vitrectomy, placement of the tamponade and phaco all in one step, followed by silicone oil removal after about 2 months.

He said the disadvantages of using silicone oil are the need for two surgeries and the high rate of cataract progression. He noted that he would use silicone oil only in larger or late-stage macular holes or in patients with high myopia. Otherwise he uses a gas tamponade.

He said while the oil is typically removed after 2 months, if the patient has a history of glaucoma, the oil should be removed sooner because of the chance of transient ocular hypertension.

He also noted that some patients have complained of floaters postoperatively due to oil emulsification in the eye.

"It's not possible to remove all emulsifications, but if you do an extensive vitrectomy you can remove about 90%," Dr. Claes said. He noted that regular needles are not adequate for draining the oil, so he uses a specially designed fine needle and ensures that the patient remains immobile.

Retinoblastoma survival rates

The survival rates for patients with retinoblastoma "continue to improve," and the eyes of these patients are saved more often now than in past years, according to one clinician.

Improvements in treatment of the hereditary malignancy have prolonged survival, said Dr. Boldt.

"Retinoblastoma is the most common primary intraocular malignancy of childhood; there is an increasing incidence of the disease," Dr. Boldt said.

Treatment involves globe-conserving therapy including a combined application of laser ablation and chemotherapy, which "achieves excellent local tumor control," he said.

In a retrospective study of 226 patients examined over a 45-month period, 95% of the patients survived and 85% retained their globe, he said.

Surgery for foveal detachment

Vitreous surgery may be advisable for the correction of foveal detachment in highly myopic eyes at high risk of developing a macular hole, according to a retina specialist.

"Macular holes in highly myopic eyes are usually associated with retinal detachment. They often have a poor surgical success rate and poor visual outcomes," said Shoji Kishi, MD.

Dr. Kishi said this approach is particularly relevant in Japan because of the high incidence of myopia there.

He and colleagues studied highly myopic patients with posterior staphyloma who had experienced a recent decrease in vision. OCT revealed foveal detachment and retinoschisis in these patients, he said.

The study included 11 eyes of nine patients with an average age of 57 years. Most of the patients were women. The average preoperative visual acuity was 0.17, and the average refractive error was -14.4 D. Seven of the 11 eyes had posterior vitreous detachments.

The surgeons performed core vitrectomy, removed the premacular membrane and then removed the internal limiting membrane. Intraoperative Kenalog (triamcinolone acetonide, Bristol-Myers Squibb) was used.

The surgeons demonstrated during surgery the presence of residual vitreous cortex in all cases. They hypothesized that removing the remaining cortex at an early stage could help prevent the development of a macular hole in high myopia.

By performing vitrectomy and removing all the residual cortex, Dr. Kishi said, they were able to successfully reattach the fovea in all eyes. Only one of the 11 eyes went on to develop a macular hole. Some eyes took longer than others for reattachment to occur, he said, but by around 6 months all patients experienced improvement in visual acuity. Postoperative VA was on average 0.48.

"After surgery, visual acuity was greatly improved. If (the patient) had good preoperative visual acuity, it remained good after surgery," Dr. Kishi said.

Intraocular foreign bodies

Most patients with an intraocular foreign body have a "generally good prognosis," according to Dr. Boldt.

He said most patients with intraocular foreign bodies are young, with an average age between 29 and 38 years. While the incidence of intraocular foreign bodies occurring in the workplace has recently decreased, the rates are still between 33% and 72% in reported case series, Dr. Boldt said. Conversely, the incidence of intraocular foreign bodies occurring in the home has recently increased, to between 30% and 42%.

"Most intraocular foreign bodies are caused by hammering, power tools and weapons," Dr. Boldt said.

He stressed the importance of documenting the examination of the patient. "History is crucial in tailoring the evaluation and management of these patients," he said.

He also stressed the importance of knowing what type of imaging to perform. "If your suspicion of intraocular foreign body is low, plain film imaging may be useful to document its absence. If your suspicion is high, do a CT or an MRI," Dr. Boldt said.

Although there are several instruments and techniques used to perform intraocular foreign body removal, he said vitrectomy is the most commonly used technique.