Taking On Alzheimer’s

By STEPHANIE SAUL
IN the book “Mrs. Frisby and the Rats of NIMH,” a group of lab rats acquire human intelligence through a genetic experiment. Every child recognizes the charming tale as pure fantasy, yet something similar is occurring at a major pharmaceuticals company, Wyeth, where rodents tested in its labs have, indeed, taken on some features of the human brain.
Unlike the fictional rats that learned to read, write and operate machinery, Wyeth’s animals are slow-witted, confused and forgetful because they suffer from the crippling dementia of Alzheimer’s disease, which they acquired from a transplanted human gene.
Something else extraordinary is going on at Wyeth. The company’s scientists not only can give rodents Alzheimer’s — they have also figured out how to take it away. Curing mice is a lot simpler than curing people, but the results are a tantalizing development that offers hope to humans suffering from the disease. The work also advances what Wyeth executives describe as their war on Alzheimer’s.
Wyeth’s team faces a formidable foe. In an industry often criticized as making pricey “me too” drugs that involve minor tweaks to competitors’ products, as well as promoting medicines of marginal value, Wyeth has decided to go full bore against Alzheimer’s, a disease that has defied effective treatment since it was first identified a century ago. The company has dedicated more than 350 scientists exclusively to Alzheimer’s research, and they are working on 23 separate projects for medicines to possibly treat the disease.
About five million people in the United States are living with Alzheimer’s, according to the Alzheimer’s Association, an advocacy group funded by individual donors as well as foundations and major corporations, including drug makers. Without a cure or new treatments, the number of those with the disease could grow to 13.2 million by 2050, the National Institute on Aging estimates.
“I think this is going to be the disease, and maybe one of the biggest health care political issues of my generation,” says Robert Essner, 59, Wyeth’s professorial chief executive. “It’s hard for anyone to envision how to provide health care in the United States if you’re going to have to deal with the burden. You just start to add up the cost, 20 years from now as my generation gets old — it’s phenomenal.”
Mr. Essner will have more than a host of grateful baby boomers awaiting him if Wyeth’s crusade is successful. The company could snare a big financial payoff from what still amounts to a risky bet, one that has already cost Wyeth about $450 million in research funds. But with a treatment that slows progress of the disease possibly selling at more than $20,000 a year, the company’s Alzheimer’s program is one reason that some analysts are voicing renewed enthusiasm about Wyeth’s stock, which had been weighed down for years by costly fen-phen diet drug litigation.
Wyeth is hardly the only company looking for Alzheimer’s treatments. Virtually every large drug maker and a number of smaller biotechnology companies are working to develop Alzheimer’s drugs, with several hundred ideas under study. Several companies are expected to announce results of clinical studies during an international Alzheimer’s meeting that is under way in Washington. “There seems to be a current of excitement,” said Peter Davies, a biochemist at the Albert Einstein College of Medicine in the Bronx, who has studied Alzheimer’s for 30 years. Dr. Davies is working with Eli Lilly and Applied NeuroSolutions on a possible course of treatment that is such a secret that he will not say anything about it. “I wouldn’t say it’s a race,” Dr. Davies said, “but this is novel and we want to get a jump on therapeutics.”
The four Alzheimer’s treatments now on the market work by regulating the action of chemical neurotransmitters in the brain. The drugs — Aricept by Eisai and Pfizer, Exelon by Novartis, Razadyne by Johnson & Johnson and Namenda by Forest Laboratories — have shown mixed results treating Alzheimer’s symptoms and do nothing to stop the disease’s progress.
Dr. Todd Golde, professor of neuroscience at the Mayo Clinic, says that the drugs are not very effective, and that consumers’ large expenditures for them — about $1.4 billion in the United States alone last year, according to data from Verispan — reflect the desperation of patients and their families to treat the disease.
“It’s scary if you look at the trials that got these drugs approved,” Dr. Golde said. “The change in mental status was so small, the average caregiver of a patient would have no way of knowing there was any difference.” While there is no evidence that any of the drugs stem the underlying disease, they were approved based on studies showing temporary improvement or stabilization in some patients with Alzheimer’s. The changes can be as minor as a better ability to dress oneself or to take out the trash.
In one study of people taking Namenda and Aricept combined for six months, 60 percent of patients either improved or did not deteriorate. “I would say that physicians do believe these drugs are of benefit to patients with Alzheimer’s,” said Stephen M. Graham, senior director of clinical development at Forest.
Spokesmen for the other companies with Alzheimer’s drugs echoed that assessment in regard to their products, pointing to clinical studies demonstrating that they help patients.
Wyeth is wagering that it can find more promising treatments for a nebulous, stealthy disease that does more than rob people of their health and well-being. It also steals some of their most precious memories.
AT first blush, Robert Essner seems an unlikely flag bearer for a corporate assault on Alzheimer’s. The son of a college professor, Mr. Essner studied humanities as an undergraduate and in graduate school, intending to teach college history. But after he graduated from the University of Chicago in 1971 with a master’s degree in history, he soon realized that jobs in his field were scarce. He says he stumbled into pharmaceuticals by answering an ad in The Wall Street Journal.
Today, he is on the leading edge of a generation that is facing a huge emotional and financial burden from a disease that leaves victims requiring full-time nursing care. He is urging a national mobilization against what he describes as a looming Alzheimer’s “epidemic.”
Mr. Essner often speaks publicly about the disease, stepping outside his role as corporate chief and into the public policy arena. Last month, he testified at a Senate hearing, recommending that the National Institutes of Health double its current annual funding of $643 million for Alzheimer’s research.
Seated recently at a conference table at the company’s headquarters on pastoral property near Madison, N.J., Mr. Essner said he has taken to the podium because he thinks Alzheimer’s should garner the same attention that AIDS received during the 1980s and 1990s, when a coalition of government and industry worked feverishly to find treatments.
He says he is concerned as much about the disease’s dehumanizing effects as he is about its costs. “You see mothers who don’t recognize their daughters,” he says.
Mr. Essner also speaks from experience. While he requested that details be kept private, he confides that a relative has been caught in the disease’s maw. In fact, Mr. Essner is just one of several senior managers involved in the Alzheimer’s drug discovery program at Wyeth whose families have been affected by the disease.
Among the others is Menelas Pangalos, the company’s vice president for neuroscience research and a biochemist. He remembers visiting his grandmother in Greece while she was in the throes of the disease. While people may expect the elderly to lose their memories, Dr. Pangalos says that this is a false assumption that has gained traction only because Alzhiemer’s is so prevalent.
“The problem is that it’s so common,” he said in an interview at Wyeth’s research laboratory near Princeton, N.J., where much of its Alzheimer’s work is conducted. “You assume it’s normal and it’s natural, but it’s not.”
MR. ESSNER understands history well enough to recognize that big scientific breakthroughs generally accrue to those willing to take a chance. With the high failure rates in drug development, it is unlikely that any single compound now under study will make it to the market. But Mr. Essner says he believes that with so many drugs under study, at least one is likely to succeed.
Wyeth announced last month that it was moving early into advanced human trials of one experimental treatment, a biological product that many scientists view as the most promising new product under study for Alzheimer’s. Wyeth made a presentation about its Alzheimer’s work the centerpiece of the company’s annual shareholders meeting in April, as well as its annual report, which included the stories of seven Alzheimer’s sufferers.
Among those chronicled in the Wyeth accounts was Gilbert Brown, 80, a retired auto parts salesman for Sears in New Jersey. His son, Michael S. Brown, noticed changes in his father several years ago.
“We would talk on the telephone several times a week and he would sometimes say things that didn’t make sense,” said the younger Mr. Brown, who runs a state-funded program that assists low-income students at Montclair State University in Montclair, N.J. At one point, in a subtle but sure sign that something was amiss, Mr. Brown told his son in 2004 that he had lost his checkbook and insisted that he was going to Kmart for a new one.
About three years ago, his father’s gradual decline prompted the younger Mr. Brown, 59, to move him into his home in Irvington, N.J. Today, the elder Mr. Brown can no longer carry on a conversation, dress himself or shave. In fact, he cannot remember the word for shaving. Yet the elder Mr. Brown can still play church hymns on the organ, remembering old favorites like “Rock of Ages” and others that he regularly performs at a senior program. But his son struggles each morning to help his father shower and dress.
“It really hurts,” the younger Mr. Brown says. “He is a very intelligent man. He was the kind of person that his family, my mom’s family, would depend upon to do anything, conduct any business. Then to go from that to not being able to do anything.”
Mr. Brown took Aricept, one of the four Alzheimer’s drugs currently available, until his insurance company said his disease had progressed too far and he was no longer eligible.
“You don’t know what the progression of the deterioration is, so it’s hard to tell if the medicine is helping or not,” Michael Brown says.
A paucity of effective Alzheimer’s treatments reflects how difficult it remains for scientists, doctors and other medical researchers to understand and combat brain disease. Alzheimer’s research began about a century ago, when the Bavarian psychiatrist Alois Alzheimer first diagnosed a 51-year-old patient suffering from dementia, delirium and hallucinations.
The patient, whom Dr. Alzheimer called Auguste D., entered the Frankfurt asylum in 1901. The doctor’s notes on her condition reveal that she was unable to answer simple questions. “At lunch, she eats cauliflower and pork,” the notes say. “Asked what she is eating, she answers, ‘spinach.’ ” Mrs. D. complained to her doctor: “I have lost myself.”
Mrs. D. died five years later, and an autopsy revealed abnormalities in her brain, including the presence of sticky plaque and tangled fibers in nerves. The condition that Dr. Alzheimer described in Mrs. D. was later named after him. While the exact cause of the disease is still unknown, researchers believe that genetic factors play a role and that heavy plaque deposits like those Dr. Alzheimer discovered in Mrs. D.’s brain may contribute to tissue deterioration — leading to memory and recognition loss, linguistic problems and degraded motor skills. But scientists continue to debate whether plaque is a symptom or a cause of Alzheimer’s.
With more and more people living into their 80s and 90s, Alzheimer’s is more common today than it was 100 years ago. Estimates of its frequency vary, but it strikes one out of every 5 people between ages 75 and 84 and 42 percent of those over age 85, according to the Alzheimer’s Association. The organization estimates the current direct and indirect costs of the disease at nearly $150 billion a year, a figure that includes medical and nursing home costs as well as lost job productivity for family members who serve as caregivers. Two drug companies that have progressed to late-stage tests of Alzheimer’s treatments are Neurochem and Myriad Genetics. Neurochem says it may disclose results of its late-stage trial this month. Its drug, Alzhemed, aims at the plaque.
Myriad Genetics’ product, Flurizan, is similar to an anti-inflammatory drug, and it may lower the production of the protein found in plaque. Dr. Golde of the Mayo Clinic was involved in developing the compound.
The National Institutes of Health, the primary federal agency that oversees and helps fund biomedical research, is currently supporting 22 studies involving Alzheimer’s.
John Hardy, a neurogeneticist at the National Institute on Aging, a branch of the National Institutes of Health, says some of the ideas under study as Alzheimer’s treatments have little chance of success. “There’s some pretty wacky things that people try because we’re desperate,” he says.
Dr. Hardy helped to develop a leading theory, known as the “amyloid cascade,” about the biological process that results in Alzheimer’s. The hypothesis holds that Alzheimer’s brain plaque, which contains a protein called beta amyloid, causes symptoms of the disease. According to the theory, plaque develops when something goes awry in the breakdown of a substance called an amyloid precursor protein, or A.P.P.
Scientists came to believe that A.P.P. had something to do with Alzheimer’s by analyzing the genes of Alzheimer’s patients. They also discovered that people with Down syndrome — a group that commonly develops Alzheimer’s-like symptoms — are born with extra A.P.P. And mutations in A.P.P. genes are among the genetic abnormalities found in families with a hereditary form of early-onset Alzheimer’s.
A.P.P. exists in many human cells. It is normally broken down in the body without incident. But scientists believe that in Alzheimer’s patients, enzymes interfere with the breakdown, causing A.P.P. to glob together and form the sticky, toxic beta-amyloid plaque that interferes with activities in the brain.
Among the many companies going after Alzheimer’s, Wyeth is regarded as a leader. Wyeth’s biggest Alzheimer’s bet, in partnership with Elan Pharmaceuticals, involves biological products that would actually slow or reverse the progress of the disease by attacking beta-amyloid. While most researchers believe that the accumulation of beta-amyloid in the brain is the instigating factor of Alzheimer’s, that theory is not without its critics.
Dr. Davies of Einstein, who also directs an Alzheimer’s research center at North Shore-Long Island Jewish Health System, says he believes that plaque is a symptom of the disease rather than a cause. He questions whether eliminating plaque will help those with Alzheimer’s. “It’s like trying to clear up scar tissue and expecting things to get better,” he says.
He subscribes to an alternative theory that focuses on tau, a protein found in the tangled nerve fibers in the brain of Alzheimer’s patients, as the real culprit. His interests also frame a larger divide in the Alzheimer’s world. Those who embrace the beta-amyloid protein theory are nicknamed “Baptists.” Those who finger tau as the villain are called “Tauists.” The two sides recently have moved closer together, more willing to say that beta-amyloid and tau may be working together in Alzheimer’s.
If the two camps continue to merge, it may mean that in the long run Alzheimer’s patients will be treated with more than one drug, the way multipronged treatment regimens are used for cardiovascular problems.
WYETH itself is keeping a research foot in both treatment camps, on the theory that it is better not to place all its bets on one disease pathway. It is working on compounds aiming at tau, as well as brain enzymes that have been implicated in Alzheimer’s. Its partnership with Elan began in 2000, when several key Wyeth scientists came to Mr. Essner, describing Elan’s work and asking him to sign off on a partnership.
“I asked, ‘What’s the probability of success?’ ” Mr. Essner recalls, laughing. “The first guy said 30 percent. I said: ‘Really? 30 percent, that’s very high.’ He said, ‘Well maybe 10 percent,’ then finally, ‘I have no idea.’ ”
But Mr. Essner says that it was hard to apply a financial calculus to such an undertaking. “I really came away with the impression that their passion for this was so great, that if I had said no, I would have had a mutiny,” he says.
In a development that illustrates the vicissitudes of drug development, the Wyeth-Elan partnership suffered a major setback in 2002, when the first human trial of an Alzheimer’s vaccine, called AN-1792, had to be halted. About 18 patients, or 6 percent of those enrolled, suffered inflammation in their brains. It was an apparent reaction to the vaccine, which used a strand of human protein to prompt an immune response.
Despite the severe reactions of some patients, others in the interrupted trial may have responded positively to the vaccine, according to Wyeth’s follow-up examinations. The symptoms of some patients who fared well in the trial appeared to have stabilized, a contrast to the inexorable decline usually experienced in Alzheimer’s. Autopsies of five trial participants who later died of natural causes revealed evidence of plaque-clearing in their brains.
The results supported the idea that Alzheimer’s plaque can be attacked with immunotherapy. “It looked like the vaccine was doing the same thing we’ve seen in the animals,” Dr. Pangalos says.
After the failure of AN-1792, Wyeth and Elan worked to develop a safer vaccine and also focused on another form of immunotherapy: passive immunization.
Instead of vaccinating patients with a strand of amyloid protein and letting them form their own antibodies, passive immunization injects pre-made antibodies directly into patients. In theory, the antibodies then attach themselves to harmful plaque and dissolve it. Wyeth would deliver its antibody product, bapineuzumab, to patients through infusion, in a process much like chemotherapy for cancer patients.
In a joint announcement last month, Wyeth and Elan said a late-stage trial of the drug would begin in the second half of this year. Although history shows that the odds are against the success of any individual drug, the progress is an encouraging sign for a drug that many scientists regard as the most promising treatment in development for Alzheimer’s.
“It’s going to be the first test of what we call the amyloid hypothesis of Alzheimer’s,” says David Morgan, an Alzheimer’s researcher at the University of South Florida. “Elan and Wyeth clearly are in the lead in developing immunotherapy.”
AT Wyeth’s research lab near Princeton, scientists have tested bapineuzumab and other compounds on genetically altered mice, using a special swimming pool equipped with an invisible platform.
When a mouse is placed in the pool, it instinctively begins swimming around to find a resting place. Once a normal mouse finds the platform the first time, it can find its way back on follow-up swims. But the genetically altered mice become lost.
“The Alzheimer’s mouse cannot remember the location of the platform,” says Reka Hosszu, a research scientist at Wyeth who works with the animals. She says that an Alzheimer’s mouse will paddle aimlessly in the pool.
After treatment, the Alzheimer’s mice can find the platform more easily. And their brains look better. In before-and-after images, it is clear that globs of toxic plaque have cleared. “You can get rid of pretty much all of the amyloid,” says Dr. Pangalos as he displays a three-dimensional image of a mouse brain on his computer. “And you can reverse their memory to normal, like a young mouse.”
If all goes according to Wyeth’s plan, it should work in humans, too. “We’re going after this,” Dr. Pangalos says, “and we’re not stopping until we’ve nailed it.”