New Alzheimer's Drug Signals A Coming Increase In Research

Sidebar: For Further Information A mere two drugs currently are available for people who suffer from Alzheimer's disease, and the second, Aricept, was approved only recently. Observers call Aricept a clear improvement over the first medication, Cognex, and are optimistic that it will spur more research into Alzheimer's treatments, opening up more job opportunities for scientists studying the catastrophic brain disease. But they caution against high hopes, as there still is no way to stop its progression. NEW & IMPROVED: Aricept, only the second FDA-approved Alzheimer's drug, has fewer side effects than its predecessor. Aricept was developed by the Eisai Co. of Japan and is being sold in the United States by Pfizer Inc. of New York under a joint agreement. Its approval from the Food and Drug Administration came in late November. Both Aricept and Cognex--which is made by Parke-Davis, a division of Morris Plains, N.J.-based Warner Lambert Co.--work by inhibiting a brain enzyme called acetylcholinesterase (AChE). AChE breaks down acetylcholine, a chemical messenger that helps brain cells to communicate with each other. Acetylcholine has been found to be absent in people with Alzheimer's, and by curbing its breakdown, Aricept and Cognex help many of these patients to retain memories for longer periods. While Cognex must be administered four times daily and can have serious side effects, including liver toxicity, Aricept must be taken just once a day and has far fewer side effects. "In my opinion, our product is the first product that's practical for most patients," says Lawrence Friedhoff, executive vice president for research and development at Eisai America Inc., Eisai's Teaneck, N.J.-based U.S. affiliate. "The other one showed that this approach could work, but it wasn't really practical for an elderly patient population, often with other illnesses and other medications." Many researchers in the field call Aricept good news not only for Alzheimer's patients, but also for job hunters who would like to take their shot at developing treatments for the disease. 'MULTIPRONGED': John Trojanowski sees potential similarities in the way AD and AIDS treatments are being developed. Aricept's action on the body is similar to Cognex's, but with the benefit of reduced toxicity, states John Q. Trojanowski, a professor of pathology and laboratory medicine at the University of Pennsylvania School of Medicine and director of Penn's Alzheimer's Disease Center. He speculates that mixing treatments, an approach that has had some recent success in AIDS patients, may be an approach used someday on people with Alzheimer's. "It is a part of a stepwise process in moving toward better and better therapies," Trojanowski says. "One can imagine, looking at the AIDS field, how things may unfold in Alzheimer's disease." Because it simply eases symptoms and does nothing to stop the advancement of the disease, Aricept is not revolutionary, just useful, according to researchers and industry advocates. "It clearly is a bit of a step forward over what was previously available, and it appears to have clinically meaningful benefits, but the benefits remain modest," states Steven H. Ferris, executive director of the Silberstein Aging and Dementia Research Center at New York University Medical Center, where he is also a professor of psychiatry. "There continues to be great need for better treatments, particularly treatments that might have a more primary effect on the course of the disease or possibly delay the disease." FUTURE ANALYSIS: Marguerite Kay hopes that her findings will speed the development of a blood test for Alzheimer’s. "If we are to delay or prevent the tragedy of [Alzheimer's], we need more job opportunities for researchers," comments Marguerite M.B. Kay, Regents Professor of Microbiology and Immunology and Medicine at the University of Arizona College of Medicine and a geriatrician and researcher at Tucson's Veterans Affairs Medical Center. "Solving the enigma will require bright, dedicated researchers. I expect that more job opportunities will be available when companies realize that there is no `quick fix' for this devastating disease." RADICAL CHANGE: A "completely different paradigm" of AD drugs is needed, according to Daniel P. Perry. Daniel P. Perry, executive director of the Alliance for Aging Research, a private, nonprofit foundation in Washington, D.C., calls for a "completely different paradigm" of Alzheimer's drugs to be developed, ones that would attack the disease itself instead of simply treating its symptoms. He envisions the use of estrogen, anti-inflammatory medications, and gene-based therapies. But regardless of what researchers eventually develop, most observers agree that the introduction of Aricept could incite greater competition among the pharmaceutical and biotechnology companies studying Alzheimer's treatments. "One of the elements of the argument we were making in `93 [when Cognex was being debated] was `get the first drug out there and you will stimulate competition from others,'" Perry says. "`You will encourage investment. You will draw more research efforts into getting the next generation of the drug, and the next beyond that.' And that is what I think we're beginning to see with the Eisai drug." Ferris predicts that until more breakthroughs are made, the race will be on to create better types of acetylcholine enhancers. "Cognex never gained wide acceptance in the field because of concerns about side effects. So [Aricept] is the first of several more drugs of this type that are likely to become available. There will be considerable competition between companies that will be marketing somewhat similar drugs, at least superficially similar drugs." GOLDEN YEARS: As people live longer, competition to develop age-related treatments will stiffen, predicts Nunzio Pomara. While Aricept knockoffs may soon hit the market, others believe that the way of the future is not copycat drugs, but legitimate improvements. "There are enough companies that are going to increase their research and development of drugs for Alzheimer's disease, because none of these [current] drugs are really effective," observes Nunzio Pomara, director of the division of geriatric psychiatry at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, N.Y., and a research associate professor of psychiatry at New York University's School of Medicine. "They're not cures. There's going to be efforts to find more effective agents. The fact that these drugs are being approved is encouraging, because we can have a paradigm to which the new drugs can be compared." Eisai America's Friedhoff believes that the introduction of Aricept will increase competition to find more treatments. "There's already a great deal of competition. There are many products in development. If the product is commercially successful . . . obviously that will encourage other people to try the same approach, or approaches they might feel would be even better. It depends on the reception by the Alzheimer's disease community. But if we are successful, you would expect it to stimulate further competition. That's pretty much a rule in our industry and other industries." He adds that commercial success for Aricept would encourage Eisai to reinvest money in Alzheimer's research. Pomara believes that Aricept "will have a positive effect [on research], given that dementia illness will become more prevalent as more of us reach the age at which we're at a greater risk." "The market for drugs such as [Aricept] is going to be increasing worldwide," he forecasts. "To the extent that companies conduct this type of research, which I think it's in their interest to continue, I think there will be a need for all sorts of clinicians and other ancillary personnel, to develop the studies and bring them to clinical trials." In the short run, Aricept itself will mean up to thousands of new jobs as Eisai increases its presence in the U.S., according to Samuel D. Isaly, a partner at Mehta and Isaly, an international health-care investment firm based in New York. Perhaps more important, he notes: "Alzheimer's is a progressive disease, and Aricept is not the ultimate answer." Isaly speculates that a hypothetical recent graduate who wants to tackle Alzheimer's should get lots of chances in Aricept's wake. "The existence of sort of the first product of consequence doesn't really change [things]," he says. "It's an unmet need, and [Aricept] doesn't meet it fully. There's going to be plenty of work to do, as Mr. New Graduate will find, over the next decade. It's not just years or months." OPTIMISTIC: Sheryl Williams points to progress in researching AD’s "biological underpinnings." Other Alzheimer's drugs similar to Cognex and Aricept are being tested, and should arrive on the market in the next couple of years. It's much harder to predict when treatments that have an impact on the progression of the disease will be developed, notes Sheryl Williams, vice president of medical and scientific affairs for the Chicago-based Alzheimer's Association. However, she is confident that such treatments eventually will be available: "We have enough information to actually start looking at slowing the progress of the disease by looking at the biological underpinnings. That is progress." 'DOWN THE ROAD': Leonard Berg estimates that drugs treating the causes of AD won’t be available for several years. The bad news is that the next big advances are "still down the road," according to Leonard Berg, a professor of neurology and director of the Alzheimer's Disease Research Center at Washington University in St. Louis. "The really exciting stuff is going to come from different kinds of research based on what we learn from genetic causes and various sources of genetic damage to nerve cells in the brain," says Berg, a former chairman of the Alzheimer's Association's scientific advisory board and a current member of its board of directors. He notes that trials of estrogen, nonsteroidal anti-inflammatory drugs, and agents that protect against oxidative damage are under way. "Even these can only be expected to be of some limited value in slowing down the progression of the disease. That's significant, but the treatments that are directed toward the fundamental problems in the brain-what is it that starts it off in the first place?- I think those trials are three to five years off. Bringing something to market won't happen until three or four years after that." All of this points to the need for more people doing more science, experts observe. "It's through further research that we'll have drugs that get more at the basic physiology," Ferris says simply. Researchers can take heart that not only do observers predict an increase in the competition, but also the competition is taking place on several fronts. "At least three different types of [Alzheimer's] drugs are currently in trials," states Kay. "They are different because they have different mechanisms of action than the acetylcholinesterase inhibitors. The drugs currently in trials are based on scientific investigations into differences in protein processing and immune response." Alliance for Aging Research 2021 K St., N.W. Suite 305 Washington, D.C. 20006 (202) 293-2856 Fax: (202) 785-8574 E-mail: agecom@aol.com Alzheimer’s Association 919 N. Michigan Ave. Suite 1000 Chicago, Ill. 60611-1676 (800) 272-3900 Fax: (312) 335-1110 World Wide Web: http://www.alz.org Eisai America Inc. Glen Pointe Center East 300 Frank W. Burr Blvd. Teaneck, N.J. 07666 (888) ARICEPT Fax: (201)-287-9744 Parke-Davis/Warner Lambert Co. 201 Tabor Rd. Morris Plains, N.J. 07950 (201) 540-2000 Fax: (201) 540-3320 World Wide Web: http://www.warner-lambert.com Pfizer Inc. 235 E. 42nd St. New York, N.Y. 10017 (212) 573-2323 Fax: (212) 808-8799 World Wide Web: World Wide Web: http://www.pfizer.com She concludes: "There is tremendous competition to find a drug or drugs that will alleviate the symptoms of [Alzheimer's]. This competition is driven by humanitarian as well as financial reasons." Kay herself may have nudged the competition along with her recent findings on band 3, a transporter protein found throughout the body that may provide a marker for AD (M.M.B. Kay, Gerontology, 43:44-66, 1996). She is hopeful that the work may eventually lead to a blood test for Alzheimer's. In addition to enabling physicians to make a firm diagnosis of the disease, "I was hoping the development of a blood test would really enable therapies to be brought to market much faster, and would allow us to see whether they are intervening at a biochemical level." Meanwhile, the search for advances continues. Earlier this month, researchers at the Weizmann Institute of Science in Rehovot, Israel, reported how a substance derived from a moss used in Chinese folk medicine blocks AChE (M.L. Raves et al., Nature Structural Biology, 4:57-63, 1997). The team consisted of Weizmann graduate student Mia L. Raves; Israel Silman, the Bernstein-Mason Chairman of Neurochemistry at the Israeli institute; and Joel Sussman and Michal Harel of its structural biology department, along with Alan Kozikowski, a medicinal chemist at Georgetown University, and Yuan Ping- Pang, a chemist at the Mayo Clinic in Jacksonville, Fla. They speculate that such a discovery may someday lead to new Alzheimer's drugs that, while acting much as Aricept and Cognex do, would be structurally different and able to be given in much smaller doses, thus reducing potential toxicity. "A little bit of success, even if it is a modest step forward, would certainly whet the appetite of pharmaceutical companies to push more," muses Penn pathologist Trojanowski, referring to Aricept. "We are beginning to see incremental successes that I would say auger well for the likelihood that there will be multinodal, multipronged therapies coming online, maybe even in `97- certainly very shortly-for Alzheimer's disease. This has to be seen as encouraging, even though it's not the dream compound."

New Alzheimer's Drug Signals A Coming Increase In Research

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