October 26, 2004.
By Larry Haimovitch,
Medical Device Daily.
NEW ORLEANS - The annual meeting of the American Academy of Ophthalmology (AAO; San Francisco), the largest gathering of eye physicians in the world, took place here this weekend at the Morial Convention Center.
The AAO meeting typically covers a broad rage of topics of interest to the ophthalmic community, including cataract and refractive surgery, glaucoma diagnosis and management and major retinal disorders such as diabetic retinopathy and age-related macular degeneration (AMD).
AMD is a chronic and progressive disease of the macula, or central part of the retina, and is the leading cause of severe vision loss and blindness in patients over the age of 50 in the developed world. According to an article in the April issue of Archives of Ophthalmology, the Eye Diseases Prevalence Research Group estimates that about 1.8 million Americans have AMD. Moreover, owing to the rapidly aging population, the number of persons having AMD will increase by 50% to nearly 3 million by 2020.
Prior to 2000, there was only one AMD treatment option - thermal laser photocoagulation, which is fraught with numerous disadvantages and therefore is not widely used. In April 2000, the FDA approval of the pharmaceutical agent Visudyne, developed by QLT (Vancouver, British Columbia) and marketed worldwide by Novartis Ophthalmics (Basel, Switzerland), sparked a surge in interest in AMD. This heightened interest has continued in the past four years.
Visudyne is the first new pharmaceutical agent designed for AMD therapy and also is the first drug using photodynamic therapy, which uses light-activated drugs, called photosensitizers, to treat diseases that exhibit rapid tissue proliferation, e.g., the growth of tumors or abnormal blood vessels.
Visudyne is expected to register worldwide sales in 2004 of about $430 million. This is testimony more to the desperate need for new treatment options rather than the efficacy of this drug, which typically does not improve the course of the disease, but rather prevents severe vision loss from progressing in about half the patients.
The promise of other agents with greater efficacy reaching the market soon has fueled tremendous interest in both the retinal and financial communities. A week before the AAO meeting, Alcon Laboratories (Fort Worth, Texas), reported disappointing clinical results for its flagship AMD agent Retaane, as initial analysis of the one-year data of Retaane, compared to Visudyne, showed that it did not meet its primary "non-inferiority" endpoint. Specifically, the percentage of patients who maintained vision, as defined by less than three lines of visual acuity, was 45% for Retaane, vs. 49% for Visudyne.
At an analysts' meeting held here last Friday, Alcon's management team reiterated statements made in its press release that in analyzing the data, there were two controllable factors - drug reflux and treatment timing - that contributed to the poor results. Thus, the company indicated that these issues could be readily overcome and said it plans to submit a New Drug Application (NDA) before year-end.
Gerry Cagle, PhD, senior vice president, research and development, told the analysts that "we have looked very carefully at that data, have met with the FDA and have decided to move forward with an NDA filing." There was considerable skepticism by most of the analysts attending the meeting, with some noting that the results of the company's earlier Retaane trial had not been robust, due to a high patient dropout rate.
Several retinal specialists interviewed by Medical Device Daily after the Alcon meeting indicated that failing to meet its primary endpoint could mean a rejection by the FDA, in spite of Alcon's ability to rationalize the clearly disappointing results.
The ongoing challenge in effectively treating AMD is to attack the disease earlier in its progression. To that end, Alcon is in the midst of a clinical study called the Risk Reduction Trial, which aims to assess the efficacy of treating patients with advanced dry (earlier stage) AMD who appear to be at risk of progressing to wet AMD. This trial uses a novel transscleral drug delivery device that implants a tablet behind the eye, enabling even longer-term delivery of Retaane.
Enrollment for this trial began early this year and patient follow-up will occur over a period of four years. A total of some 2,500 patients ultimately will be enrolled at 100 sites worldwide. The FDA has given a "fast track" designation to this trial, because it represents a significant unmet medical need for a serious condition.
According to Jason Slakter, MD, clinical professor of medicine at New York University School of Medicine (New York), who discussed Retaane at the Alcon analysts' gathering, "more than ever, we need to reduce the risk of getting full-blown AMD by treating it earlier." Slakter, well known in the retinal world, also reminded the analysts that "AMD is a very nasty disease that thus far has not benefited [from] any magic bullets."
There was considerable interest at the AAO in two other compounds - Macugen, being developed by Eyetech Pharmaceuticals (New York), and Lucentis, being developed by Genentech (South San Francisco, California).
Both work by inhibiting the effect of ocular vascular endothelial growth factor (VEGF), which the retinal community believes may thwart the development of choroidal neovascularization (CNV), or the formation of new blood vessels. Left untreated, CNV can cause bleeding and scarring in the macula, destroying central vision.
Just prior to the AAO meeting, Eyetech, which has partnered with the pharmaceutical giant Pfizer (New York) to market Macugen worldwide, reported that the treatment effect of Macugen extends for two years. This treatment benefit, which required an additional eight to nine injections in year two, was also seen for patients who received Macugen for two years compared to those only receiving one year of therapy.
Macugen was positively reviewed on Aug. 27 by the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee and final approval is expected within the next few months. Market analysts have very high expectations for Macugen, with several recent investment banks projecting peak global sales in excess of $1 billion.
While Macugen clearly has the best near-term prospects, based on its likely near-term FDA approval and solid clinical results, Genentech's agent may be the most promising drug for wet AMD therapy. Importantly, although Lucentis also is a VEGF inhibitor, it binds to all four forms of VEGF, whereas Macugen binds to just one. Some retinal specialists believe that this is a very important distinction and will make a marked difference in clinical outcomes.
Genentech is in the midst of four key Phase III AMD trials and has completed patient enrollment in three of them.
The first, called MARINA, compared two different doses of Lucentis to a placebo treatment and completed enrollment of about 700 patients at year-end 2003. The second trial, called FOCUS, completed its 170-patient enrollment in early 2004 and compared Lucentis and a sham injection to Visudyne and a sham injection. The third trial, called ANCHOR, compares Lucentis and a sham Visudyne treatment to Visudyne and and a sham injection and completed enrollment of more than 400 patients within the last few weeks. Finally, the PIER trial, currently enrolling up to about 180 patients, will compare two different doses of Lucentis to a sham injection.
Although Genentech has not released any pivotal Phase III data as of yet, the positive buzz in the retinal community, based on the Phase I/II data and anecdotal reports, is enormous. For example, Philip Rosenfield, MD, from the Bascom Palmer Eye Institute of the University of Miami School of Medicine (Miami), speaking at a Genentech-sponsored evening seminar, noted that there was a "dramatic" improvement in visual acuity (VA) patients treated with Lucentis in the Phase I/II trial. Moreover, this gain in VA was corroborated by optical coherence tomography imaging, a relatively new non-contact, non-invasive imaging technique used to obtain high-resolution, cross-sectional images of the retina. It is increasingly being relied on to assess the benefits of AMD drug therapy and may someday supplant the current gold standard, fluorescein angiography.
Rosenfield, one of the best-known retinal specialists in the U.S., said that he is "spectacularly impressed with the Lucentis results" and believes that enough patients have been treated with a known mechanism of action that the Phase III results should be equally impressive.
Peter Kaiser, MD, of the Cleveland Clinic Foundation (Cleveland), speaking at a Sunday morning symposium, expressed similar sentiments, telling MDD: "I think that Lucentis is the real deal and if I were a betting man, that is where I'd put my money."
Given that the Phase III trials are still in the follow-up period, final FDA approval for Lucentis could take up to two years. However, it appears at this juncture that it will be the winner in this high-stakes market opportunity.
© 2004 Thomson BioWorld.
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