>> A much-touted cancer treatment could end up fighting something completely different: the dreaded macular degeneration
Selwyn Paskowitz was driving six years ago when suddenly out of his left eye he saw roadside lamp poles freakishly warp. Less than a year later Paskowitz could no longer make out people's faces, and dusky blotches like something out of a Mark Rothko painting marred his central vision. "It was annoying," says the 65-year-old retired naval officer, a bit stoically.
Paskowitz is one of nearly 9 million Americans suffering from age-related macular degeneration, or AMD, the leading cause of blindness in people over 50. Eight out of ten people with AMD have the milder, "dry" form of the disease, but that can develop into the more serious, "wet" form of AMD that accounts for 90% of the afflicted population's vision loss. AMD can distort and block central vision within days of its onset, or slowly darken the world over years. The television drama ER ran a purplish three-episode story with Bob Newhart playing a builder of architectural models who develops AMD, descends into depression and finally puts a gun to his head. While there is no cure, sufferers can still see well from the periphery and may be affected in only one eye.
The federal National Eye Institute in Bethesda, Md. estimates that every year 260,000 people will develop the disease, and the rate will increase as the population ages. [There are about 500,000 new wet AMD diagnoses each year, worldwide.] "It's an epidemic," says Frederick Ferris, an ophthalmologist at the institute.
Pharmaceutical companies have largely overlooked AMD, spending more time and effort treating cataracts and glaucoma, the latter of which affects 3 million Americans. Clinical trials for an AMD drug cost ten times more than a glaucoma trial because the latest imaging technology to examine the retina is expensive, as are the lengthy, complicated tests to diagnose AMD. [Another reason for the high expense to test AMD is that the FDA requires a minimum 12 months of patient follow-up.]
The only AMD treatment on the market now is Visudyne, a laser-activated drug from QLT Inc. and Novartis that stops blood vessels from leaking. Approved three years ago by the Food & Drug Administration, Visudyne treats only a particular type of macular degeneration that afflicts 25% of all wet-AMD patients. [Visudyne is approved only for the predominantly classic subtype of wet AMD in the U.S., but it approved more widely in certain countries.] Though it generates $350 million in annual sales, Visudyne hasn't lived up to its original hype, with most patients continuing to lose their vision. [That’s because Visudyne at best stops the leaking of the abnormal blood vessels, but it does not destroy them.]
But promising new treatments for macular degeneration are on their way, emerging, in an unlikely twist, from cancer research. Fighting both wet-form AMD and malignant tumors depends partly on squelching new blood-vessel growth, a process known as antiangiogenesis. In dry AMD vision is marred by yellow deposits called drusen. But in wet AMD rogue capillaries invade the retina, the thin film along the back of the eye that transmits images in the form of electrical signals to the brain. The spreading blood vessels leak their plasma under the macula, a quarter-inch-wide area that controls central vision. The macula swells and scars, robbing the eye's ability to see directly ahead; peripheral vision remains intact. "Macular degeneration is like cancer. You have very aggressive, abnormally growing vessels that are hard to turn off," says Carmen Puliafito, ophthalmology chairman at the University of Miami and an unpaid adviser on Macugen, an antiangiogenesis drug now in testing. [I find the analogy with cancer to be somewhat misleading because the blood vessels in AMD do not generally mutate and become refractory to treatment.]
Harvard Medical School's Judah Folkman pioneered the field of angiogenesis in the 1960s, but it wasn't until 1989 that Genentech researcher Napoleone Ferrara first isolated a protein crucial to angiogenesis called vascular endothelial growth factor, or VEGF. Genentech's first anti-VEGF drug, the colon-cancer fighter Avastin, has huge expectations and is anticipated to be approved in 2004.
Macular degeneration drugs from Eyetech Pharmaceuticals, Genentech and Genaera are all targeting VEGF. Genentech's Lucentis, now in final-stage trials, is a chemical fragment of Avastin. Ophthalmic giant Alcon Laboratories just completed a late-stage trial for its drug Retaane, a modified steroid that targets enzymes produced by stimulated blood vessels.
But the leading candidate right now appears [I would say appeare*d* --Dew] to be Macugen, from Eyetech, based in New York. In November the company released results from a 1,200-patient trial. The drug, which is delivered through an injection in the eye, improved vision in 6% of patients at the end of one year, defined as the ability to read more than three lines on an eye chart (22% were able to read at least one more line). More good news:70% had less than a three-line loss of vision, compared with 55% in the group that was given a sham injection. "The goal is to try to retain as much vision as possible," says Puliafito. Eyetech could file for approval early next year. If approved, Macugen could potentially treat all three types of wet-form macular degeneration [i.e. predominantly classic, minimally classic, and occult].
Founded in 2000 by ophthalmologists David Guyer, 43, and Anthony Adamis, 44, Eyetech has raised $143 million in venture money and in September filed for a public offering. Guyer, who is chief executive, and Adamis, chief scientist, declined to speak, citing the company's regulatory "quiet period."
Adamis had worked in Folkman's lab at Harvard in the early 1990s and, in 1994, published his discovery that patients with macular degeneration have high levels of VEGF protein in the affected eyes, causing blood vessels to proliferate. His work caught the attention of Nebojsa Janjic, a director of drug discovery at NeXstar Pharmaceuticals [now part of GILD –see below] a biotech firm in Boulder, Colo. Janjic had developed a cancer drug using an aptamer, or small string of synthetic RNA, that binds to one of the five known forms of VEGF protein and prevents it from docking to its receptor on the endothelial cell and sending out a signal for vessels to grow.
But the aptamer didn't hold up to scrutiny, failing to stop tumor growth in rats. Aptamers were also expensive to manufacture. After reading Adamis' paper, Janjic guessed that the eye might make a better candidate, since small amounts of the anti-VEGF drug could be delivered locally, causing blood vessels to shrivel up.
In 1996 Janjic met with Adamis, who, along with colleague David Guyer, helped NeXstar design clinical trials for what would become Macugen. In 1999 NeXstar enrolled the first patients, but then Gilead Sciences acquired the company. Gilead, focused on antivirals, decided to sell the drug. Guyer and Adamis were more than happy to buy it. In February 2000 they formed Eyetech, raised $35 million in venture capital and licensed Macugen, paying Gilead $7 million up front, with up to $25 million more in future milestone payments, plus royalties.
Although only a handful of patients were tested for three months, the initial results were very encouraging, with 25% of patients able to read an additional three lines on an eye chart. The results excited Pfizer enough that it agreed last year to pay up to $745 million to codevelop and market Macugen.
The drug may still fail to win approval, and some patients will squirm at the idea of getting poked in the eye with a needle every month or so. Patients run the risk of infection, which can lead to blindness and retinal detachment. In Macugen's trial 16 patients out of 890 injected developed such complications. (Genaera's goes in the arm, and Retaane uses a blunt tube that swerves around the eyeball). "I'm pretty sensitive when people start messing with my eyes," says Paskowitz. "The treatment has to be 100% effective." <<
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