Drug Firms Pursue Efforts To Block Plaques That Mark Alzheimer's
Dow Jones Online News, Thursday, July 08, 1999 at 00:38
(Published on Wednesday, July 07, 1999 at 21:35)
By Robert Langreth, Staff Reporter of The Wall Street Journal
When a researcher at a small California drug company first suggested vaccinating people against Alzheimer's disease, his fellow scientists thought the idea nutty enough to put it on an office bulletin board of outlandish comments.
But today, they are reporting that a vaccine the company made has kept laboratory mice from getting amyloid plaques, the telltale protein clumps found in the brains of Alzheimer's victims. Within months, Elan Pharmaceuticals expects to begin human testing of the vaccine, which it describes in the latest issue of the scientific journal Nature.
Also this year, Bristol-Myers Squibb Co. and a partner hope to start human tests of a pill they developed that makes mice produce less of the same unruly protein.
This is the kind of news the medical world is waiting for, as are millions of patients and their anguished relatives. Four million Americans are estimated to have Alzheimer's disease, and they currently have no way to block the long and ultimately fatal decline in brain function. "If the prevention of amyloid plaques slows the disease, it will be a truly remarkable advance," says Zaven Khachaturian, senior medical adviser at the Alzheimer's Association.
For a drug company, needless to say, it could be a blockbuster. The goal of defeating amyloid plaques is so alluring that pharmaceutical companies are rushing in. Among those pouring money and researchers' energies into the race are Eli Lilly & Co., Merck & Co., Novartis AG and Pharmacia & Upjohn Inc.
Yet in doing so, the industry is taking a major gamble. The problem, in essence, is this: Although it has long been known that Alzheimer's patients' brains clog up with amyloid plaques, no one can be sure that those deposits are the cause of the disease or a prime contributor to it, instead of just a byproduct.
"We are putting a lot of money into something we hope is the answer, but we won't know for sure until we've done large clinical trials," says Geoffrey Dunbar, who will head Bristol-Myers's human tests.
Since it was first recognized at the beginning of the century, Alzheimer's disease has remained one of the most confounding disorders. Even today, a definitive diagnosis of it can be made only after death.
Not only is it impossible to look into patients' brains while they are still alive and see what is happening on a microscopic level, but symptoms vary from patient to patient and are rather subjective.
"Ways to interfere with the disease process have been lacking for a long, long time," says Bernd Sommer, head of research in neurodegenerative diseases at Novartis. But now, Novartis plans to have a plaque-blocking drug in human trials in two to three years.
Yet some prominent scientists fear that this intense and costly industry focus is misguided.
One theory blames "tangles" of a hairlike protein -- not amyloid but another one called tau -- that pile up inside neurons. This theory's proponents argue that the number of tangles found in autopsied brains correlates much better with the degree of dementia than does the number of amyloid plaques.
Still another school of thought traces Alzheimer's -- and perhaps tangles -- to a gene. Patients carrying one called APOE-4 are statistically more likely to get Alzheimer's.
There is also a theory that Alzheimer's patients' brain cells fail because they are deprived of key nutrients over a period of years. Meanwhile, two prescription drugs are approved for helping patients function a little better. But they don't stop the brain-cell death.
In the early 1980s, some scientists theorized that the plaques known to clutter Alzheimer's sufferers' brains might actually be the cause of their condition. Among those intrigued by this notion was Dennis Selkoe, a young Harvard neurologist. To pursue it, Dr. Selkoe, while remaining at Harvard, co-founded a start-up company called Athena Neurosciences -- now the Elan Pharmaceuticals subsidiary of Ireland's Elan Corp. PLC. (Accounting for the takeover was among issues the Securities and Exchange Commission asked Elan Corp. about earlier this year; Elan says the issues concerning the subsidiary have been resolved.)
Athena set up shop just south of San Francisco. Few drug companies focused on Alzheimer's at that time, the mid-1980s, because they had no molecular targets to attack.
But slowly, circumstantial evidence to indict the amyloid plaques began to build. A Harvard researcher, Bruce Yankner, showed that in test tubes, amyloid protein could damage nerve cells.
Athena and Harvard researchers also discovered that amyloid wasn't produced solely in a diseased brain, as was thought, but also in small amounts by normal cells, at least in the test tube. Researchers at Athena and at Lilly -- which long funded Athena but no longer does -- began randomly mixing chemicals in test tubes containing brain cells, checking to see if any reduced amyloid production.
Others at Athena attacked one huge obstacle facing all Alzheimer's researchers: the lack of a laboratory animal that gets the disease, on which tests could be done.
Their attempts to genetically engineer such an animal proved difficult. But in 1994, a letter arrived from an obscure biotech company in Massachusetts that was going out of business -- a company that had created many strains of mice, with various genes. One strain had the gene that produces amyloid protein, and the company offered some of these mice for sale. Athena bought some, and autopsied them. Sure enough, their brains were speckled with Alzheimer's-like plaques.
Athena scientists began trying to figure out how they could use this information. At a brainstorming session, one scientist, Dale Schenk, suddenly had a bright idea. "Maybe we can immunize" the mice against the plaque, he blurted out. "Everyone looked at me like I was crazy," he recalls.
It was certainly possible theoretically. But there seemed to be reasons why a vaccine wouldn't work, among them the notorious "blood-brain barrier," which not all substances can get across.
Athena eventually tested the approach on the special mice, though, and in late 1997, the results it found were startling: The vaccine almost completely prevented formation of plaques in the mice's brains.
The company reports in Nature today that monthly amyloid shots given to young mice as an inoculation almost completely prevented plaque formation as the mice aged. In older mice that already had amyloid clusters in their brains, the inoculation stopped additional ones from forming, and even appeared to eliminate some of the old ones.
Until now, most people thought that vaccines couldn't stimulate a robust immune response in the brain. Elan's finding "is more than surprising -- it is unprecedented in biology," says Sangram Sisodia, a neurobiologist at the University of Chicago. "The entire community of Alzheimer's disease researchers will look at this carefully."
All this while, Bristol-Myers was chasing after a way to fight those same amyloid plaques with a pill. Like the vaccine researchers, Bristol-Myers was both stalled by setbacks and spurred by serendipity.
Its approach was to screen a vast collection of compounds on brain cells in the test tube, in search of something that checked amyloid. Bristol-Myers collaborated with a small La Jolla, Calif., biotech company called Sibia Neurosciences Inc. Together, they pinpointed several promising substances, and then chemists spent years tweaking two of them to improve potency and eliminate side effects. In early 1997, the companies put the substances up against mice genetically engineered to develop amyloid plaques in the brain.
They didn't work. Not, that is, until a Bristol-Myers biologist checking the mice late one night decided to measure the amyloid in their brains -- earlier than was scheduled. To her surprise, the compounds had drastically reduced the protein's level. It turned out researchers had been waiting too long to take the measurement, allowing the drugs' effectiveness to subside.
Then came more obstacles. Some compounds had to be dropped because they didn't penetrate the brain well. Another was abandoned after tests showed it damaged the stomach lining.
But now, barring unexpected setbacks, Bristol-Myers will begin an ambitious program of human trials by year-end, and if initial safety tests go well it will quickly move into large-scale tests of effectiveness. In a high-risk gambit to get a drug to market faster, the company will simultaneously conduct four large trials comparing its drug with a dummy pill, rather than the more typical procedure of conducting consecutive rounds of efficacy trials.
The trials will involve several thousand patients and last as long as two years.
Elan, meanwhile, thinks its mouse findings are so striking that a single human trial of its vaccine in several hundred patients may show enough effects to win drug-marketing approval. Elan plans another trial to see if the vaccine can prevent Alzheimer's disease in people who don't have it but are at high risk for it.
Are the animal results raising hopes too high? The mice on which the Elan and Bristol-Myers/Sibia compounds have been tested don't really get Alzheimer's. The mice were genetically engineered simply to get amyloid plaques, and when they get them, they don't suffer the same degree of brain damage associated with Alzheimer's in humans. Moreover, the mice don't develop the tangles seen inside the brain cells of Alzheimer's patients.
The University of Chicago's Dr. Sisodia, impressed as he is by Elan's results, says it is far too soon to tell whether it will ever be an effective human therapy.
Such cautions aren't stopping the drug industry or its spending. For instance, Lilly, although it won't discuss its Alzheimer's effort, is known to have kept several promising amyloid-blocking compounds after ending its alliance with Elan.
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