One day last summer, Susan Bosko was trying in vain to wipe little black spots off her white kitchen table when she came to a chilling realization: The spots weren't on the table. She knew immediately that the distortion was caused by age-related macular degeneration (AMD), which had already destroyed her vision in one eye. The disease has since forced Bosko to give up driving, reading, and traveling with her husband. Simple tasks like navigating the steps of the subway near her home in Brooklyn are now "a struggle," says Bosko, 77, whose husband also suffers from AMD. "Our lives have been turned around," she says.
The darkness engulfing Bosko and her husband is all too common. AMD is the leading cause of blindness in people over age 50. The disease attacks the macula -- an area of the retina at the back of the eye that houses light-sensing cells. As these cells die off, central vision deteriorates. Doctors anticipate an epidemic of AMD as baby boomers reach their 60s. The National Eye Institute estimates that the number of Americans with moderate to severe AMD will more than double to 17 million by 2020. There's no cure. And the one treatment cleared by the Food & Drug Administration, from Swiss drugmaker Novartis (NVS ), is only approved for a subset of patients.
A growing number of biotech and pharmaceutical companies are focusing on this desperate group of patients. And on Aug. 27, an FDA advisory panel will review the first new treatment for AMD in four years. Developed by Eyetech Pharmaceuticals Inc. (EYET ) of New York, the drug, Macugen, could hit the market as soon as 2005. Swiss eye-care giant Alcon Inc. (ACL ) and biotech leader Genentech Inc. (DNA ) in South San Francisco are close behind with competing treatments. And several smaller biotechs are already working on the next generation of drugs.
TARGETING A CAUSE
None of the early treatments is a magic bullet. For that reason, it may be several years before sales of all AMD drugs combined exceed $1 billion, according to industry analysts. Nevertheless, eye doctors are encouraged that so many companies are targeting the illness -- and that they are bringing new insights into the degenerative process to bear. For the first time, "we're trying to treat the root cause of this disease," says Dr. Steve Schwartz, associate professor of ophthalmology at the University of California at Los Angeles, who has advised both Eyetech and Genentech.
The agent of destruction in AMD is the proliferation of abnormal blood vessels under the retina. These can leak, causing fluid to build up under the macula, which leads to the descent into blurriness and blindness. It's not surprising, therefore, that two of the drugs that are closest to reaching the market target a protein -- called VEGF, for vascular endothelial growth factor -- that promotes the growth of blood vessels.
Eyetech's Macugen attacks VEGF by means of a new type of therapeutic molecule called an aptamer. A short strand of nucleic acid, it binds to the specific subtype of VEGF that scientists believe is most directly responsible for abnormal blood vessel growth. Eyetech's delivery method, however, is less than ideal. Ophthalmologists must inject Macugen into patients' eyes once every six weeks. With local anesthesia, the procedure is painless. But the shots can cause infections, cataracts, or worse, retinal detachments and blindness. "It's not the drug that presents a high risk of side effects, but rather the mode of administration," admits Dr. Anthony P. Adamis, chief scientific officer for Eyetech.
Perhaps a bigger hurdle is the response rate among patients in Eyetech's clinical trials. In an initial, small trial published in May, 2003, a respectable 26% of patients regained some vision. But in a much larger trial reported later that year, Macugen restored sight in only 6% of patients.
On the other hand, the drug did slow vision loss to some extent: Only 30% of patients in the large trial lost the ability to read three or more lines on a standard eye chart over 13 months -- far less deterioration than patients in the control group had experienced. That response rate is about the same as the rate Novartis achieved in trials for its drug, Visudyne. Some experts believe the FDA's panel of advisers is likely to welcome Eyetech's drug because it offers a second viable treatment option.
HURDLES AND HEADWAY
As Eyetech races to muster the necessary data, another biotech giant is stalking the same prey. That rival is Genentech, the company that pioneered the first successful VEGF-blocking drug. Last year, Genentech proved that its weapon, Avastin, could slow or stop the rampant development of blood vessels that tumors require in order to grow. Launched in the spring, Avastin can extend life by as much as five months for some late-stage colon cancer patients. The drug pulled in $133 million in sales in the quarter ended in June, and now Genentech is testing a variation of it, called Lucentis, in AMD patients. But despite its experience with VEGF blockers, Genentech faces some of the same hurdles that Eyetech confronts. Lucentis is also administered via a needle, and so far, it requires even more frequent injections.
Alcon has a very different drug in late-stage clinical trials, called Retaane. It targets enzymes that weaken blood-vessel walls in the retina and allow abnormal vessels to grow. One big selling point right out of the gate: It only needs to be administered to patients every six months. What's more, the safety issues surrounding anti-VEGF drugs could give a boost to Retaane, which is squirted into the diseased area without puncturing the eye. "Avoiding the needle is a major plus," says Jason S. Slakter, a surgeon and director at the Manhattan Eye, Ear & Throat Hospital who has participated in trials for Alcon, Genentech, and Eyetech.
While Alcon and its rivals are preparing to duke it out, several biotechs are working on entirely new methods for attacking AMD. One promising approach is called RNA interference. Scientists pursuing RNAi hope to activate the "off" switch in the genes that produce either VEGF or the receptor protein that allows it to do its destructive work. The technique involves injecting small double strands of RNA -- the molecules that translate DNA into proteins. The snippets bind to the messenger RNA and break it down.
As a result, the proteins that Macugen and the other new drugs are designed to destroy would never get produced in the first place. "We're turning off the spigot instead of mopping up the floor," says John Maraganore, CEO of Alnylam Pharmaceuticals Inc. (ALNY ) in Cambridge, Mass., one of several biotechs developing RNAi treatments for AMD.
Maraganore and others hope such gene-based approaches will help patients with advanced AMD regain their sight -- and prevent those in the early stages of the disease from losing any vision at all. Naturally, that's also the goal for Eyetech, Genentech, and Alcon, although none of their near-term treatments appears to achieve these ambitious goals. The most potent weapons against AMD could prove to be combinations of two or more new drugs, including Visudyne. But such trials will have to wait until the FDA gives a green light to the new treatments.
Because drug "cocktails" have been such an effective strategy in diseases such as HIV/AIDS, drug industry analysts are eager to see the multidrug trials begin in earnest. "It's not a zero sum game," says Jay Markowitz, a biotech analyst for T. Rowe Price (TROW ). After so many years struggling in the darkness, AMD patients and the physicians who treat them will welcome every ray of light.
By Arlene Weintraub in Los Angeles