An Outcast Among Peers Gains Traction on Alzheimer’s Cure –


After years of effort, researcher Dr. Claude Wischik is awaiting the results of new clinical trials that will test his theory on the cause of Alzheimer’s.

Some people collect stamps, others vintage cars. As a young Ph.D. student at Cambridge University in the 1980s, Claude Wischik was on a mission to collect brains.

It wasn’t easy. At the time, few organ banks kept entire brains. But Dr. Wischik, an Australian in his early 30s at the time, was attempting to answer a riddle still puzzling the scientific community: What causes Alzheimer’s disease? To do that, Dr. Wischik needed to examine brain tissue from Alzheimer’s patients soon after death. That meant getting family approvals and enlisting mortuary technicians to extract the brains, he says, “no matter the time of day or night.” And it wasn’t just a few brains: he collected more than 300 over about a dozen years.

He also embraced an idea that, if he is right, could ultimately spin Alzheimer’s research on its heels—and raise new hopes for the roughly 36 million people world-wide afflicted with Alzheimer’s or dementia.

Alzheimer’s researcher Claude Wischik has long backed a minority view: that a protein in the brain called tau-not plaque-is largely responsible. WSJ’s Shirley Wang spoke with Dr. Wischik about his work on a new drug to treat the devastating disease.

The 63-year-old researcher believes that a protein called tau—which forms twisted fibers known as tangles inside the brain cells of Alzheimer’s patients—is largely responsible for driving the disease. It is a theory that goes against much of the scientific community: For 20 years, billions of dollars of pharmaceutical investment has supported a different theory that places chief blame on a different protein, beta amyloid, which forms sticky plaques in the brains of sufferers. But a string of experimental drugs designed to attack beta amyloid have failed recently in clinical trials, including two this summer from Eli Lilly & Co. and a partnership involving Pfizer Inc., Johnson & Johnson and Elan Corp.

After years on the sidelines, Dr. Wischik, who now lives in Scotland, sees this as tau’s big moment. The company he co-founded 10 years ago, TauRx Pharmaceuticals Ltd., has developed an experimental Alzheimer’s drug that it will begin testing in the coming weeks in two large clinical trials. Slowly, other companies are boosting investment in tau research, too. This summer, Roche Holding AG bought the rights to a type of experimental tau drug from Switzerland’s closely held AC Immune SA.

History is peppered with examples of scientists who struggled against a prevailing orthodoxy, only to be proved right. In 1854, British doctor John Snow traced a cholera outbreak in London to a contaminated water supply, but his discovery was rejected by other scientists, who believed bad vapors in the air caused the disease. In the 1880s, cholera was finally pegged to bacteria found in contaminated water. In 1982, when two Australian scientists declared that bacteria caused peptic ulcers, conventional wisdom had it that stress and lifestyle were to blame. The scientists won the 2005 Nobel Prize in medicine for their discovery.

It is far from clear whether Dr. Wischik will join their ranks. Although interest in tau is building, opinions about the cause of Alzheimer’s remain deeply divided. Some scientists believe an interaction between beta amyloid and tau plays a central role. Others think there are many possible triggers, including some beyond beta amyloid or tau.

Dr. Wischik says he and other tau-focused scientists have been shouted down over the years by what he calls the “amyloid orthodoxy,” a hard-charging group of researchers who believed passionately that beta amyloid was the chief cause of the disease. “Science is politics,” he says. “And the politics of amyloid won.”

Yet Dr. Wischik has also been hampered by inconclusive research. A small clinical trial of TauRx’s drug in 2008 produced encouraging, but mixed, results. What’s more, plenty of influential scientists still are backing the idea that beta amyloid plays a central role. Although Roche is investing in tau, Richard Scheller, head of drug research at Roche’s biotech unit, Genentech, says the company still is a strong believer in beta amyloid. He thinks amyloid drugs need to be tested on Alzheimer’s patients much earlier in the disease cycle in order to prove effective; Roche recently announced plans to conduct such a trial.

Drugs tied to conventional theories on Alzheimer’s causes haven’t been effective.
Meanwhile, scientists Dr. Wischik accuses of wrongly fixating on beta amyloid, such as Harvard neurologist Dennis Selkoe, say the evidence for pursuing amyloid is strong. “Claude I think sees the world somewhat darkly…if we’ve made our case more potently for [beta amyloid], there is nothing wrong with that,” Dr. Selkoe says. He adds that he supports tau research, as well, and believes drugs to attack both beta amyloid and tau will be necessary.

Alzheimer’s disease is the leading cause of dementia in the elderly, and according to the World Health Organization, the cost of caring for dementia sufferers totals about $600 billion each year world-wide. The disease was first identified in 1906 by German physician Alois Alzheimer, who studied the brain of a deceased woman who had suffered from dementia and documented the plaques and tangles that riddled the tissue. The following decades brought few advancements in understanding the disease, in part because of the difficulty of studying the human brain, which unlike other tissues cannot be biopsied and examined until after death.

Still, in the 1960s, British scientist Martin Roth and colleagues showed that the degree of clinical dementia was worse for patients with more tangles in the brain. In the 1980s, Dr. Wischik joined Dr. Roth’s research group at Cambridge University as a Ph.D student, and was quickly assigned the task of determining what tangles were made of, which launched his brain-collecting mission, and years of examining tissue.

Finally, in 1988, he and colleagues at Cambridge published a paper demonstrating for the first time that the tangles first observed by Alzheimer were made at least in part of the protein tau. Later research identified tau as the main ingredient. Like all of the body’s proteins, tau has a normal, helpful function—working inside neurons to help stabilize the fibers that connect nerve cells. But when it misfires, tau can clump together to form harmful tangles that kill brain cells.

Dr. Wischik’s discovery was important news in the Alzheimer’s field: identifying the makeup of tangles made it possible to start developing ways to stop their formation. But by the early 1990s, tau was overtaken by another protein: beta amyloid.

Signs of Decline

Several pieces of evidence convinced an influential group of scientists that beta amyloid was the primary cause of Alzheimer’s. Among these was the discovery of several genetic mutations that all but guaranteed a person would develop a hereditary type of the disease. These mutations also appeared to increase the production or accumulation of beta amyloid in the brain, leading scientists to believe that amyloid deposits were the main cause of the disease.

The so-called “amyloid hypothesis” quickly gripped the field, and attacking the protein became the main strategy for fighting Alzheimer’s. Athena Neurosciences, a biotech company whose founders included Harvard’s Dr. Selkoe, focused in earnest on developing drugs to attack amyloid. Meanwhile, tau researchers say they found it hard to get research funding or to publish papers in medical journals.

“It was very difficult to have a good publication on tau, because the amyloid cascade was like a dogma,” says Luc Buee, a tau-focused researcher at the French National Institute of Health and Medical Research. “For 15 years if you were not working in the amyloid field you were not working on Alzheimer’s disease.”

Dr. Wischik and his colleagues fought to keep funding from the UK’s Medical Research Council for the repository of brain tissue they maintained at Cambridge, he says. The brain bank became an important tool. In the early 1990s, Dr. Wischik and his colleagues compared the postmortem brains of Alzheimer’s sufferers against those of people who had died without dementia, to see how their levels of amyloid and tau differed. They found that both healthy brains and Alzheimer’s brains could be filled with amyloid plaque, but only Alzheimer’s brains contained aggregated tau. What’s more, as the levels of aggregated tau in a brain increased, so did the severity of dementia. “We decided that amyloid isn’t what is making people demented,” Dr. Wischik says.

In the mid-1990s, Dr. Wischik discovered that a drug sometimes used to treat psychosis dissolved tangles in a test tube. He tried to set up a company to develop the drug as a treatment for Alzheimer’s, but found that American and British venture capitalists wanted to invest in amyloid projects, not tau.

By 2002, Dr. Wischik scraped together about $5 million from Asian investors with the help of a Singaporean physician who was the father of a classmate of Dr. Wischik’s son in Cambridge. TauRx is based in Singapore but conducts most of its research in Aberdeen, Scotland.

As his tau effort launched, early tests of drugs designed to attack amyloid plaques were disappointing. A vaccine developed by Athena Neurosciences failed to improve patients’ cognitive function in a trial that ended in 2002.

To better understand these results, a team of British scientists largely unaffiliated with Athena or the failed clinical trial decided to examine the brains of patients who had participated in the study. They waited for the patients to die, and then, after probing the brains, concluded that the vaccine had indeed cleared amyloid plaque but hadn’t prevented further neurodegeneration.

Commitment to the amyloid hypothesis persisted, however. Peter Davies, an Alzheimer’s researcher at the Feinstein Institute for Medical Research in Manhasset, NY, recalls hearing a researcher at a conference in the early 2000s concede that his amyloid research results “don’t fit the hypothesis, but we’ll keep going till they do.”

“I just sat there with my mouth open,” he recalls.

In 2004, TauRx began a clinical trial of its drug, called methylene blue, in 332 Alzheimer’s patients. Around the same time, a drug maker called Elan Corp., which had bought Athena Neurosciences, began a trial of an amyloid-targeted drug called bapineuzumab in 234 patients.

A key moment came in 2008, when Dr. Wischik and Elan presented results of their studies at an Alzheimer’s conference in Chicago. The Elan drug failed to improve cognition any better than a placebo pill, causing Elan shares to plummet by more than 60% over the next few days.

The TauRx results Dr. Wischik presented were more positive, though not unequivocal. The study showed that, after 50 weeks of treatment, Alzheimer’s patients taking a placebo had fallen 7.8 points on a test of cognitive function, while people taking 60 mg of TauRx’s drug three times a day had fallen one point—translating into an 87% reduction in the rate of decline for people taking the TauRx drug.

But TauRx didn’t publish a full set of data from the trial, causing some skepticism among researchers. (Dr. Wischik says it didn’t to protect the company’s commercial interests). What’s more, a higher, 100-mg dose of the drug didn’t produce the same positive effects in patients; Dr. Wischik blames this on the way the 100-mg dose was formulated, and says the company is testing a tweaked version of the drug in its new clinical trials, which will begin enrolling patients late this year.

Meanwhile, drugs designed to attack beta amyloid have continued to disappoint. This summer, a trio of companies that now own the rights to bapineuzumab—Elan, Pfizer and Johnson & Johnson—scrapped development of the drug after it failed to work in two large clinical trials.

Then in August, Eli Lilly & Co. said its experimental medicine targeting beta amyloid, solanezumab, failed to slow the loss of memory or basic skills like bathing and dressing in two trials involving 2,050 patients with mild or moderate Alzheimer’s. Just recently, Lilly disclosed that in one of the trials, when moderate patients were stripped away, the drug slowed cognitive decline only in patients with mild forms of the disease. Lilly said it would talk to regulators before deciding what to do next with the experimental drug.

The trial failures have tempered support for the amyloid hypothesis, but there are still fervent believers who say beta amyloid needs to be attacked very early in the disease cycle—perhaps before symptoms begin—for such medicines to work. This spring, the U.S. government said it would help fund a $100 million trial of Roche’s amyloid-targeted drug, crenezumab, in 300 people who are genetically predisposed to develop early-onset Alzheimer’s but who don’t yet have symptoms. Dr. Selkoe, one of the authors of the amyloid hypothesis, says this trial should help provide a “definitive” answer about the theory.

Scientists and investors, meanwhile, are turning more attention to tau. Roche this year said it would pay Switzerland’s AC Immune an undisclosed upfront fee for the rights to a new type of tau-targeted drug, and up to CHF400 million in additional payments if any drugs make it to market.

Dr. Buee, the longtime tau researcher in France, says Johnson & Johnson asked him to provide advice on tau last year, and that he’s currently discussing a tau research contract with a big pharmaceutical company. (A Johnson & Johnson spokeswoman says the company invited Dr. Buee and other scientists to a meeting to discuss a range of approaches to fighting Alzheimer’s.)

With its new clinical trial program under way, TauRx is the first company to test a tau-targeted drug against Alzheimer’s in a large human study, known in the industry as a phase 3 trial. With his passionate beliefs, Dr. Wischik admits he may be just as much a zealot about tau as he accuses others of being about beta amyloid. “I may be,” he says. “In the end…it’s down to the phase 3 trial.”

Write to Jeanne Whalen at

~ by Butch on November 24, 2012.

One Response to “An Outcast Among Peers Gains Traction on Alzheimer’s Cure –”

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