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Decoding Alzheimer's


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Francesco Bellini hasn't been sleeping lately. The charged-up chairman of Neurochem Inc. (NRMX) is just months away from finding out if a drug developed by his Quebec-based company can actually slow the course of Alzheimer's disease. A clinical trial of the drug, Alzhemed, will wrap up in January, with results expected in the spring. "The summation of all our work and research for the last 12 years will happen in the next six months," he says.

Those 12 years have been focused on overcoming one of the toughest challenges in medicine: keeping Alzheimer's disease from slowly, relentlessly destroying the brain, something no drug has yet done. The data on Alzhemed have been promising but scant. In a 2002 study it stabilized the disease in nine patients over six months, but the small sample left plenty of specialists skeptical. Not Bellini, a scientist-entrepreneur who discovered one of the first effective treatments for aids. He bought a third of Neurochem and took the helm the same year the earlier Alzhemed trial was completed. "I started to feel very good about the drug as soon as I saw what it did for humans," he says.

Neurochem quickly moved ahead with a costly late-stage trial, enrolling 1,052 patients with mild to moderate Alzheimer's. There is plenty of debate in the Alzheimer's world over what the results of that trial are likely to be, but a recent follow-up of patients from the previous study found that four were still stable after four years on Alzhemed. In addition, Bellini says every patient who has completed the trial asked to continue the drug—a sign, he says, that it is helping. "I was expecting maybe 30% would ask, but 100%, that's remarkable."

It's not hard to understand why patients would want to continue: They are desperate for hope. Alzheimer's is a frightening trend for an aging population. One in 10 people over the age of 65 develops the disease. Over age 85, the odds rise to one in two. The diagnosis is an agonizing death sentence, as it takes anywhere from 3 to 20 years for Alzheimer's to kill—and it always does. The Alzheimer's Assn. estimates there will be 9 million Americans with the disease by 2020 and 15 million by 2050. If there are no disease-modifying drugs by then, the cost of care will top $1 trillion.

Whether or not Alzhemed works as hoped, its very existence is just one reason the outlook for Alzheimer's drug discovery is turning, finally, more positive than negative. A century after the disease was first identified, scientists are closing in on medicines that can safely delay or reverse its onset. The burden of proof doesn't rest solely on Alzhemed, either. Flurizan, a drug developed by Myriad Genetics Inc. (MYGN), is also in a late-stage trial, with results expected next summer. A few years behind Alzhemed and Flurizan are promising treatments from Wyeth Pharmaceuticals (WYE) and Eli Lilly & Co. (LLY) that provoke an immune response against the disease. Nearly 60 other drugs designed to modify the disease are also in clinical trials, including one from AC Immune of Switzerland that caught the attention of biotech giant Genentech Inc. (DNA), best known for its cancer treatments. Genentech just announced plans to invest $300 million for the rights to AC Immune's drug. "It's a whole new era," says Dr. Serge Gauthier, director of Alzheimer's research at McGill University's Center for Studies in Aging. "At least some of these medications are likely to work, and once we have disease-modifying drugs, we have opened the door to prevention."

It's particularly striking that the science is advancing despite a long-standing dearth of investment in Alzheimer's research. There are currently 4.5 million Alzheimer's patients in the U.S., and the direct and indirect costs of caring for them total more than $100 billion a year, making Alzheimer's the third most expensive illness after heart disease and cancer. Yet the federal government budgeted only $645 million for Alzheimer's research for 2007, $7 million less than the prior year. In contrast, $2.6 billion was allocated for research into HIV/AIDS, which afflicts one million Americans.

The massive funding pumped into HIV research led to predictable results: AIDS was transformed from a death sentence into a manageable disease in just 10 years. Scientists say the same could happen with Alzheimer's if there were a similar national will. "Look, if we doubled our research output it would halve the amount of time it will take to find a cure," asserts Dr. Leon J. Thal, director of the Alzheimer's Disease Research Center at the University of California, San Diego.

Certainly any disease could benefit from more funding, but with Alzheimer's the need for effective treatments is especially urgent. It is the only major cause of death in the U.S. where the numbers are getting worse, not better. That's because Alzheimer's is a disease of success. As people live longer and benefit from new treatments for common killers such as heart disease and cancer, the odds they will succumb to Alzheimer's increase. Proving the point, Los Angeles County just reported that deaths there from heart disease dropped 29% between 1998 and 2003, and from lung cancer by 19%. But deaths from Alzheimer's soared 220%.

Given the trend lines, any drug that ameliorates the disease is certain to be an instant blockbuster. Investment advisers Cowen & Co. (COWN) calculate that if just a few of the medicines in clinical trials pan out, U.S. demand for Alzheimer's drugs could reach $10 billion to $15 billion annually, up from about $1.3 billion now.

The market will be even larger if these new drugs are used by millions of senior citizens with faulty memories, a condition called mild cognitive impairment (MCI) that significantly raises the odds of developing Alzheimer's. The hope of every drug developer out there is that a successful Alzheimer's treatment may be able to prevent the disease from occurring in these higher-risk patients. "The MCI market is huge—20 or 30 million people," says Neurochem's Bellini.

The changing outlook for Alzheimer's is particularly striking because, unlike heart disease and cancer, there has been no gradual evolution from good drugs to better. The Food & Drug Administration has approved only five medicines for the disease, led by Pfizer Inc.'s (PFE) Aricept. All relieve only some memory loss, for some months, in some patients. Until recently, neither large pharmaceutical companies nor venture capitalists showed much interest in funding research into more effective drugs, given the low success rate. With no proven treatment, or even a proven cause, Alzheimer's research seemed just too risky.

The U.S. government has no plans to put together the equivalent of a moon shot to cure the disease. But a critical mass of committed scientists, philanthropists, and maverick entrepreneurs has come together and put forth new scientific approaches and new funding sources to push the field forward. The result: For the first time, scientists are beginning to whisper the word "cure."

PAST AND PRESENT

Rudolph E. Tanzi, a boyish-looking 47, ended up in Alzheimer's research in the early 1980s after he realized he probably wasn't going to make it as a rock star. Having recently graduated from the University of Rochester, he quit his band to work on the genetic causes of brain diseases at Massachusetts General Hospital. He earned a PhD from Harvard University, and in 1987 his team discovered a gene that plays a key role in the start of Alzheimer's, solving a central mystery of the disease.

Today, Tanzi is director of the Genetics & Aging Research Unit at Mass General's Institute for Neurodegenerative Disease, working with some 200 other researchers, several hundred mice, and his wife, Dora Kovacs, who studies the role of inflammation in Alzheimer's. Tanzi has started two companies to develop drugs based on his findings, written dozens of scientific papers, and still found time to pen a layman's history of Alzheimer's research, Decoding Darkness, published in 2000. "I can't imagine a more incredible puzzle to solve," he says.

The solution has been a long time coming. Alzheimer's was first identified at a medical meeting in Germany in 1906 by a Bavarian neurologist, Dr. Alois Alzheimer. He described a patient, Auguste D., whom he started treating for madness when she was 51. She died five years later, and when Dr. Alzheimer autopsied her brain he discovered it was riddled with sticky clumps and fibrous tangles. For the first time, dementia was classified as a distinct disease rather than a form of insanity, and there the science remained for 78 years.

It wasn't until 1984 that scientists figured out that those clumps are made of a protein found throughout the body called amyloid. The discovery gave birth to the amyloid hypothesis, which holds that the accumulation of amyloid plaque in the brain slowly destroys brain cells. This is still very much a theory. Some experts contend that the excess amyloid may instead turn out to be a by-product of some earlier disease process that already took hold of the brain. "Many in the field find the evidence behind the amyloid hypothesis compelling, but we can't exclude the possibility that other targets play an important role," says Dr. Richard A. Hodes, director of the National Institute of Aging (NIA). "It's critical that we not put all of our efforts in that domain."

Nevertheless, drugs targeting amyloid are much further along than any other approach because the amyloid process has been at least partially decoded. The gene discovered by Tanzi 20 years ago starts the process, creating a large protein called APP. Found in almost every cell of the body, APP sticks halfway out of the cell wall. Two scissor-like enzymes cut away a fragment of this molecule, which then floats away to facilitate communications between other cells. But for unknown reasons, these fragments sometimes go awry and become toxic.

In the brain, normal amyloid fragments are 38 to 40 molecules long. But in the mid-1990s scientists discovered that the wayward snips consist of 42 molecules. Those extra two molecules cause the amyloid fragment to fold in on itself until it looks like a bobby pin. As more and more bobby pins are formed, they become entwined, creating clumps called plaque.

The vast majority of Alzheimer's drugs in development target A-beta 42, as this overgrown fragment is known. There is wide variation in their methods, however. Some seek to reduce its production, while others try to keep it from accumulating into plaque. Tanzi and an Australian colleague, Ashley Ian Bush, came up with a "chelating" agent that washes A-beta 42 out of the brain before it can clump together.

Their drug is based on Bush's discovery that traces of zinc, copper, and iron prod amyloid to form into plaque. The two found a compound that removed those metals from the brain and caused amyloid levels to drop in mice. They then teamed up with a pioneering Alzheimer's scientist, Colin Masters, in 1997 to form Prana Biotechnology Ltd. (PRAN) in Victoria, Australia.

Coming up with the money for a drug startup is never easy, and Alzheimer's is on the bottom of venture capitalists' to-do lists. But Bush had a deep-pocketed friend in Australia who was looking for a new adventure. Geoffrey Kempler, 50, CEO of Prana, made his millions by securing the Australian rights to the Aveda (EL) line of beauty products. Fueled by a combination of "naiveté and enthusiasm," as he puts it, he spent a few million dollars getting Prana off the ground before its initial public offering in 2000.

Prana's metal-removing drug was tested in 36 patients in 2003, and it successfully lowered amyloid levels. But in April, 2005, problems with the drug's purity forced Prana to stop the program. The share price sank from $4 to $1 within days.

As it happened, Prana was working on a successor treatment designed to be safer than the first. Although still in shock over the blow to the market value, "we actually put our foot on the accelerator," says Kempler. The second drug successfully completed an initial safety study in 2005, and in December Prana started a larger trial with 80 patients in Sweden. If all goes well, the drug could reach the market in five years, says Kempler. The stock price, meanwhile, has risen to around $3 a share.

Tanzi is not counting on Prana alone. Alz-heimer's is such a complex disease that most experts anticipate giving patients a cocktail of drugs, much as they treat AIDS. Tanzi says he is willing to license his discoveries to any company seeking to develop an ingredient of that cocktail. Toward that end, in 2000 he co-founded TorreyPines Therapeutics Inc. (TPTX) in La Jolla, Calif., to work out a compound that lops off the amyloid fragment at the 38th molecule instead of the 42nd, rendering it harmless.

This year, Tanzi started work on his biggest project yet: identifying all the genes involved in Alzheimer's. He predicts he will have a genetic blueprint in hand within two years and a genetic test within five. Tanzi doesn't have to scrape around for cash this time, either. The Cure Alzheimer's Fund, founded by three Boston area families, pledged $3 million to his lab for this genetic detective work, stepping in where the NIA and venture capitalists refuse to tread.

PHARMA PARTNERS

In 2000, Wyeth CEO Robert Essner bucked a pharma industry trend and made Alzheimer's a research priority. It wasn't his idea. Essner, who came out of the marketing side of the business, was talked into a partnership with Elan Corp. (ELN) by Wyeth scientists enthralled with the Irish company's vaccine for treating Alzheimer's, which they thought was the most promising treatment out there.

The scientists warned Essner it would take three years and $100 million just to get the treatment into human clinical trials. They also conceded that they couldn't even hazard a guess at the likelihood of success, the odds were so low. Essner took the leap anyway: "Our scientists were so passionate that if I had turned them down, I would have had a mutiny."

Five years on, Essner figures Wyeth has spent more than twice that estimated $100 million. He has also made the concept behind the vaccine—that the immune system can be primed to fight off amyloid—the centerpiece of Wyeth's Alzheimer's program.

In the spring of 2002, Elan and Wyeth scientists were immersed in clinical trials of the vaccine. But in March they were forced to halt the trials when 15 of 300 patients developed encephalitis, a dangerous swelling in the brain. A deep gloom spread through the Alzheimer's research community. The Elan-Wyeth drug was the first to "cure" the disease in mice, but the risk of encephalitis forced doctors to halt human tests.

The researchers didn't give up. When they examined the blood of several patients in the trial, they saw that the vaccine had produced antibodies against the amyloid, as it was meant to do. In the fall of 2003, the companies announced that the autopsied brains of four vaccine recipients who had died of other causes had no amyloid plaque. A few months later, Swiss doctors reported that 19 of 28 patients treated with the vaccine had produced antibodies against amyloid, and 12 of those 19 either improved or stabilized their performance on memory tests—the first proof of principle that clearing amyloid could alter the disease in people.

The vaccine, a safer version of which is now in early-stage trials, calls for a patient to be injected with a tiny piece of the A-beta 42 protein found in deadly plaque. The injected fragment prompts the body to produce antibodies, which seek out and destroy more of the offending A-beta molecules. But tampering with the immune system can stir up unfortunate side effects, such as encephalitis. It's safer to send in some handpicked soldiers instead, otherwise known as monoclonal antibodies. The Wyeth/Elan partnership created such a lab-built antibody to target the same molecule used in the vaccine experiments, A-beta 42.

When injected into a patient, the antibody locates and destroys amyloid fragments without activating the immune system. Data released last spring from the first human trial of the drug, called AAB-001, showed that patients performed significantly better on memory tests, and there was reduced plaque in autopsied brains. Results from an ongoing Phase 2 trial are expected in early 2007. If positive, the company is likely to move into final testing quickly, putting the drug on track for FDA review by 2010. Meanwhile, Wyeth's strategy has attracted the sincerest form of flattery: Eli Lilly, Pfizer, and now Genentech are all developing amyloid antibodies.

There are also dozens of startup companies with intriguing anti-amyloid drugs. "We've got 30 to 50 drugs in Phase 2 and eight or nine in Phase 3," says William Thies, the Alzheimer's Assn.'s vice-president for medical relations. "They've passed an awful lot of hurdles. I believe some will work, and we will keep developing better and better medicines."

SOLDIER WITH FORTUNE

Leonard Lauder, the 73-year-old chairman of Estee Lauder Cos. (EL), is an elegant man with an elegant office. He works in a robin's-egg-blue room high up on Fifth Avenue with a to-die-for view of Central Park. Around his desk are artworks by Richard Serra, Agnes Martin, and Claes Oldenburg, and his large coffee table is covered with fashion magazines and lavish art books. All this beauty represents his "day job," as he puts it. In off hours, he is determined to find a cure for Alzheimer's. His reason is simple: "Name me one person who sooner or later doesn't worry about getting it."

Lauder is not content to use his fortune, estimated at $2.9 billion, to bolster long-standing Alzheimer's charities. In 1998 he and his younger brother, Ronald, founded the Institute for the Study of Aging solely to turn promising Alzheimer's research into commercial drugs. To date, the institute and an affiliated public charity have funded 167 projects, spending $25.5 million. "We figured that if we put enough money into it and backed enough ideas, we had a pretty good shot at coming up with a cure," says Lauder.

With the meager public funds available for Alzheimer's research, a scientist with a good idea must scramble for money. The Lauders' foundation aims to ease the burden. The two brothers knew how frustratingly slow the hunt has been for an Alzheimer's drug, and thought a venture philanthropy that focused on drug discovery rather than basic research might be able to close the gap between the two. They hired Dr. Howard Fillit, a renowned geriatrician who had treated their mother at Mount Sinai Medical Center in New York (Estee Lauder died of heart failure in 2004) and told him to forget about requiring complex grant proposals. "They gave me an office, a desk, and a pot of money," says Fillit, the institute's director. "I go to meetings, hear an interesting presentation, and tell the scientist, Call me. I'll give you money.'"

That's the story behind Allon Therapeutics Inc. ( NPC.TO) in Vancouver. Some five years ago, Allon's founding scientist, Ilana Gozes of Tel Aviv University, had collected meager funds from friends and family to finance her research into a protein fragment necessary for brain formation. She had a hunch the fragment might shield neurons from the damage inflicted by Alzheimer's.

Gozes was just starting her company when Fillit learned about her work. Based on a few conversations, he handed her $350,000. "No one else would have made an investment at that point," says Allon CEO Gordon C. McCauley, who came on board in 2004 when his venture capital fund provided the next round of financing. Allon's treatment has since proven safe in people and is about to enter a larger trial. And Allon has enough capital to keep the trials going—the company went public in 2004.

JUST THE BEGINNING

Dr. Paul S. Aisen oversees the care of some 1,000 Alzheimer's patients as director of the Memory Disorders Program at Georgetown University School of Medicine, and there is little he can offer them. Consequently he is willing to test any reasonable-sounding experimental treatment that comes along, and his program is one of the nation's leading centers for Alzheimer's trials.

Unfortunately, clinical trials often turn into exercises in futility, since fewer than 10% of experimental drugs survive the three-stage process to win FDA approval. Aisen knows this all too well. He spent 15 years testing anti-inflammatories such as Aleve and Vioxx against Alzheimer's because studies seemed to show a link between the popular drugs and a lower incidence of the disease. But in 2003 he admitted defeat after a rigorous trial found that anti-inflammatories did no good. He published the results and moved on, searching for something else that would work. "It is the patients' plight that gives everyone on our team a great appreciation for the tremendous need for better treatments," says Aisen.

Today, Aisen is the lead investigator for Alzhemed. His clinic is also running trials on Flurizan, antibodies from Wyeth/Elan and Eli Lilly, and the generic anti-seizure medicine Valproate. But he'll look far afield from advanced biotech labs for treatments. That's why he is testing a drug derived from a Chinese moss that has been used for more than 2,000 years in the Middle Kingdom to treat fevers.

Aisen learned in 1999 that doctors in China had been using the drug, called Huperzine A, for some 20 years to relieve symptoms of Alzheimer's. Now made by Neuro-Hitech Inc. (NHPI), the drug improves memory in much the same way as Pfizer's Aricept and other existing Alzheimer's treatments, without the gastrointestinal problems associated with these older drugs. But Aisen was most intrigued by evidence that, in mice, Huperzine A protected brain cells from the ravages of plaque and tangles, something the other drugs can't do.

Aisen is now in charge of a mid-stage trial of Huperzine A. But he does not expect it, or any of the drugs he is testing, to be the definitive cure the world craves. Ultimately, scientists and physicians say today's research is laying the groundwork for treatments that can prevent Alzheimer's from taking hold in the first place. "I'm hoping we'll put ourselves out of business in 20 years," says Dr. Reisa A. Sperling, head of Alzheimer's clinical trials at Brigham & Women's Hospital in Boston. "I'm 47, and before I retire, I believe I'll be looking for another disease to study."

Corrections and Clarifications

"Decoding Alzheimer's" (Special Report, Jan. 8) misspelled the names of Dr. Howard Fillit, director of the Institute for the Study of Aging, and Illana Gozes of Tel Aviv University.

Corrections and Clarifications

"Decoding Alzheimer's" (Special Report, Jan. 8) misspelled the names of Dr. Howard Fillit, director of the Institute for the Study of Aging, and Illana Gozes of Tel Aviv University.

By Catherine Arnst


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