BBI Contributing Editor

WAIKOLOA, Hawaii The annual Royal Hawaiian Eye Meeting, which took place here in late January, has become an excellent venue for ophthalmologists and industry to meet in a casual atmosphere, while hearing the most up-to-date clinical information. Record attendance of about 1,000 physicians from all over the U.S. evidenced its growing importance.

The treatment of age-related macular degeneration (AMD) has become a very important topic in the past few years, as new pharmaceuticals have become available. Given their availability and the bias toward medical management in retinal diseases, it is not surprising that drug strategies dominated the sessions.

The first FDA-approved drug, Visudyne, developed by QLT (Vancouver, British Columbia) and marketed worldwide by Novartis Ophthalmics (Basel, Switzerland), registered global sales of about $445 million in 2004, in spite of modest efficacy and reimbursement issues.

The late-December FDA approval of Macugen (see sidebar, page 24), developed by Eyetech Pharmaceuticals (New York) and to be marketed by Pfizer (New York), has set the stage for a heated marketing battle this year.

Two other pharmaceutical agents are likely to play a key role in the future management of AMD. Kenalog (or its generic equivalent, triamcinolone acetonide) is an injectable synthetic corticosteroid that has long been used to treat inflammation in certain disease states. It has been off patent for many years and is an extremely inexpensive drug, particularly relative to the high price tag of both Macugen and Visudyne. It is not expressly approved for ophthalmic use.

Since Visudyne's approval, some retinal physicians have been experimenting with combination therapy, with intravitreal Kenalog injected after Visudyne is infused intravenously. In a talk on "Combination Therapy with Visudyne: Current and Future Treatment Strategies," Philip Rosenfeld, MD, associate professor of ophthalmology at the Bascom Palmer Eye Institute of the University of Miami School of Medicine (Miami), noted that his use of Kenalog has significantly reduced the need for the standard three-month interval called for in re-treatment with Visudyne and importantly, also has lowered the risk of severe vision loss, which occurs in about 4% of patients post-Visudyne administration.

Kenalog is "especially good for Visudyne non-responders," Rosenfeld said to a packed room of retinal specialists. Citing an article in the August 2003 issue of Ophthalmology written by Richard Spaide, et al., on the successful use of combination therapy, Rosenfeld said that Kenalog safely works by reducing inflammation and collateral damage, as well as preventing the up-regulation of VEGF. Increased VEGF can lead to the formation of troublesome new blood vessels in the macula and cause vision loss.

"This combination approach has become first-line therapy at our institution," Rosenfeld said. A couple of larger, controlled, prospective clinical trials, known as VISIT and VisTA, are now under way to determine if this combination therapy is superior to PDT alone. His comments set the stage for heated debates on various case studies that were presented to the panel and the audience. Several times, panelists stated "I don't know" or "we'll have to wait and see," when it came to deciding which therapy was best for the patient. The imminent launch of Macugen in the U.S., which demonstrates excellent safety and better efficacy than Visudyne, finally offers retinal physicians meaningful choices to treat AMD, although their exact regimen has yet to be determined.

It is important to note that the wave of enthusiasm for another potentially important new AMD contender that was initially reported after last fall's American Academy of Ophthalmology (AAO; San Francisco) meeting has continued to build. Lucentis, an anti-VEGF compound developed by Genentech (South San Francisco, California) has completed enrollment of its two key Phase III pivotal trials and one-year follow-up data on the large MARINA trial is expected in the second quarter. FDA approval is not likely until late in 2006 or early 2007.

Every clinical investigator who has been interviewed by BBI in the past few months has been effusive in their enthusiasm. A typical comment, by Peter Kaiser, MD, of the Cleveland Clinic Foundation (Cleveland) at an evening symposium here, was that Lucentis has "great promise and looks like the best agent yet developed for AMD." He cautioned, however, that the ultimate fate of the drug would rest on safety and efficacy in its pivotal trials.

Controversy and uncertainty also marked presentations on device-based AMD therapies. Elias Reichel, MD, associate professor of ophthalmology at the New England Eye Center of Tufts University School of Medicine (Boston) and study chairman of the Transpupillary Thermotherapy for Choroidal Neovascularization (TTT4CNV) trial, provided a more detailed analysis on the results of this multi-center, randomized, prospective, double-masked 303-patient study. The initial, bare-boned results of this trial, which were disappointing and caused Iridex's (Moun- tain View, California) stock to plunge were presented at the AAO in late October. Since release of the results, a vigorous sub-group analysis has been under way in order to determine which patients will benefit from TTT, which was FDA-approved several years ago under a 510(k) designation as a "kinder, gentler" laser therapy for wet AMD.

While this analysis has not been completed, Reichel said that "there is definitely a sub-group of patients that will benefit from TTT therapy." Indeed, early analysis of the data is showing "dramatic" benefits (defined as a gain in three lines of vision) for about 10% of the population treated by TTT.

One of the key advantages of TTT is that it achieves clinical benefits in a very cost-effective way, requiring just one or two laser sessions. Its total cost is dwarfed by the high cost of medical management. Indeed, Allen Ho, MD, associate professor of ophthalmology at Thomas Jefferson University (Philadelphia), saluted TTT therapy during a panel discussion, saying, "this is a simple, low-cost and attractive therapy." Not surpringingly, TTT is more widely used outside the U.S., where cost considerations are of higher importance.

The final sub-group analysis of the TTT4CNV trial data was to be presented at The Macula Society (Cleveland) annual meeting late last month.

Perhaps the most controversial therapy for AMD is rheopheresis, which is being developed by Occulogix (Toronto), a recent new public company. Rheopheresis is an advanced form of plasma therapy called membrane differential filtration, which removes from the plasma excess amounts of certain macro-proteins and fatty components (such as cholesterol and fibrinogen) that have been implicated in plaque formation, clotting, and blood vessel inflammation.

Because the exact mechanism of action is still not completely understood, and there is limited clinical data thus far, rheopheresis has been a controversial technology. However, according to world-renown refractive and cataract surgeon Richard Lindstrom, MD, of the Minnesota Eye Consultants (Minneapolis), rheopheresis is worthy of serious consideration.

Lindstrom, a member of the board of Occulogix, presented the results of three clinical trials which demonstrated that rheopheresis is both safe and effective in improving vision. These three trials, while small and insignificant on their own, collectively demonstrate that rheopheresis may be valuable in treating patients with late-stage dry AMD, which is vastly underserved relative to the final stage of the disease, wet AMD.

The company recently said that it has completed enrollment of its pivotal MIRA-1 trial. According to a report written by Mike Lachman, a respected ophthalmic industry analyst with investment bankers ThinkEquity (San Francisco), it appears that the company will be prepared to file a premarket approval application with the FDA in about a year or so, leading to a final approval before the end of 2006.

Rheopheresis has come a long way in the past few years and is gaining credibility. Summarizing this new attitude, Ho suggested that "ophthalmologists should keep an open mind on this technology."