Several Drugs Show Promise For Alzheimer's

Scientists are exploring several promising avenues in drug research that could strengthen the battery of weapons used to slow the scourge of Alzheimer's disease.

A handful of drugs -- some originally approved for other diseases -- are showing some success in clinical trials at slowing the cognitive decline that is the hallmark of Alzheimer's. A few, including a prostate-cancer drug, a diabetes drug and a medicine derived from an old class of anti-inflammatory drugs, are in late-stage trials. Their makers say they expect to seek regulatory approval for the treatment of Alzheimer's within a few years. Other compounds, including cholesterol-lowering statins and antibodies that bolster the immune response against the disease, are also showing promise.

If approved for Alzheimer's, the drugs could be a huge breakthrough because they seek to modify the brain processes that cause Alzheimer's, even though those processes aren't fully understood. In contrast, none of the currently approved medicines attack the underlying mechanisms of the disease, offering only limited relief from some symptoms. The four drugs currently approved for Alzheimer's -- Aricept, Exelon, Razadyne and Namenda -- are a huge business. Alone, sales of Aricept, co-marketed in the U.S. by Pfizer Inc. and Eisai Inc., totaled $1.06 billion in the year ended March 31. But typically, patients gain only modest cognitive improvement for less than 18 months. Then, they start to deteriorate again.

Many leading researchers say they believe at least some of the drugs being studied are likely to win approval for Alzheimer's. "I can't promise," says Sam Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University. But "there could be compounds in as few as three years."

In the meantime, a growing number of doctors are experimenting with new ways to use existing Alzheimer's drugs. In particular, doctors are giving medications such as Aricept earlier in the course of the illness -- often before patients are even sick enough to be diagnosed with Alzheimer's. Recent studies of patients with so-called mild cognitive impairment, which involves loss of mental function and sometimes progresses to include dementia and full-blown Alzheimer's, have turned up some evidence that the deterioration into Alzheimer's could be delayed by starting treatment.

The need for better treatments has never been more pressing, as the first members of the Baby Boom generation reach their 60s, the age at which the risk of developing Alzheimer's starts to climb. An estimated 4.5 million Americans have the disease, more than double the 1980 number, according to the Alzheimer's Association.

Here is a look at some of the emerging trends in Alzheimer's research:

-- Existing Alzheimer's Drugs

Wayne Lindley, an 83-year-old North Carolina retiree, started to notice a few years ago that he was having trouble remembering how to perform certain computer functions for his part-time record-keeping job. When Mr. Lindley and his wife, Sarah, consulted an Alzheimer's specialist last year, Mrs. Lindley says, "his opinion was, you don't have Alzheimer's but I'm going to put you on Aricept."

Mr. Lindley is among those people showing early signs of Alzheimer's who are taking approved Alzheimer's drugs before a firm diagnosis. Despite recent evidence that early treatment with Alzheimer's drugs can stave off cognitive decline, Mr. Lindley says he hasn't noticed any improvement: "The other day, I looked at all the pills and wondered, do I still need all these things?" he says. Still, he says he will continue participating in a neuroimaging study at Duke University in which his doctor enrolled him, and he hopes that tests he is undergoing will give his family more information about his prognosis. "I don't want to be in the dark about anything," he says.

Researchers caution that patients with mild cognitive impairment should think carefully before starting on Alzheimer's medication before there is a diagnosis. The drugs can have side effects ranging from mild nausea to stomach bleeding. Some neurologists consider mild cognitive impairment to be early-stage Alzheimer's if it is progressive and not caused by a different health problem, but the condition doesn't necessarily progress to Alzheimer's.

Nevertheless, "over the last year or so, we've seen a dramatic increase in the number of people who don't yet meet the criteria for Alzheimer's and are coming in on medication already," says Gregory Jicha, an assistant professor of neurology at the Alzheimer's Disease Center at the University of Kentucky.

-- Drugs for Other Conditions

Most researchers say a protein called beta-amyloid is at the root of Alzheimer's. The protein appears to build up into plaques in the brain and progressively kill neurons, or nerve cells, in a process known as the "amyloid cascade." Many of the drugs being studied aim to interrupt this cascade.

Some of the most promising results to date involve Flurizan, which is derived from an anti-inflammatory and is being tested by Myriad Technologies. The drug targets an enzyme, called gamma secretase, that is believed to play a role in the build-up of amyloid. The company is scheduled to finish its final U.S. study in the spring of 2008, and hopes to apply to the Food and Drug Administration that summer, says Executive Vice President Bill Hockett.

Some researchers think that the best approach may turn out to be a cocktail of different compounds. Different drugs may also work better for different patients, depending on gender and genetics. For example, leuprolide, the prostate-cancer drug that is being tested in Alzheimer's patients by Voyager Pharmaceuticals Inc. of Raleigh, N.C., has appeared more effective in women than in men. Leuprolide, approved as Lupron for prostate cancer, targets luteinizing hormone, a pituitary hormone believed to promote the production of beta-amyloid.

In a study of 50 women presented this summer in Madrid, women with mild to moderate Alzheimer's disease who took the drug for 48 weeks saw a dramatic slowing of their deterioration, compared with women who didn't get the drug. "The men's study was not as compelling," says Brian Reynolds, Voyager's director of medical information. That could be in part because while luteinizing hormone increases dramatically in women after menopause, its increase is more gradual in men. A Phase III trial will wrap up next fall, Mr. Reynolds says, and the company hopes to have data by early 2008 to prepare an application to the FDA.

Patient responses to a form of the GlaxoSmithKline diabetes drug Avandia suggest that genetics may play a part in determining treatment. In an earlier trial of the drug involving 511 people, patients with a gene that made them more susceptible to Alzheimer's didn't benefit, while those lacking the gene showed improvement. The diabetes drug is believed to play a role in how brain cells metabolize glucose, a process that GlaxoSmithKline researcher Allen Roses believes will eventually prove to be the culprit in Alzheimer's. Dr. Roses says he is "optimistic" that Phase III trials now getting under way will pave the way for approval of the drug for Alzheimer's. Those trials will enroll about 2,800 patients in the U.S. and 32 other countries, according to a Glaxo spokesman.

Cholesterol-lowering statin drugs are also showing some promise. Through the National Institute on Aging, the NIH has funded a recently completed study to test whether the statin Zocor, from Merck & Co., can stall Alzheimer's in patients with normal cholesterol levels. "The idea is that lipid lowering seems to also lower the amount of amyloid in the brain," says Mary Sano, director of the Alzheimer's Disease Research Center at Mount Sinai Hospital in New York. In addition, Pfizer is recruiting patients for a study of Lipitor in Alzheimer's patients.

A note of caution: While these drugs are already on the market for other conditions, doctors and researchers say it would be unwise to prescribe or use any medicines "off-label" for Alzheimer's. The patients who are taking them now are in the controlled environment of a clinical trial with heavy oversight, researchers note, and problems could still crop up, even during the last rounds of testing.

-- New Drugs

Researchers also tout Alzhemed, a drug being developed by a Canadian company, Neurochem Inc., in a Montreal suburb. In an earlier study, patients with mild Alzheimer's remained stable for 20 months. Some patients who participated in an extended study have been getting the medication for three years and "have stayed the same," says spokeswoman Lise Hebert.

Some researchers are looking at ways to stimulate the immune system to fight the disease. Researchers at Eli Lilly & Co. are in the early stages of trials of an antibody that binds to beta-amyloid and prevents it from building up. That study is still recruiting patients. Lilly investigators are further along in trials of a drug that moderates the activity of an enzyme that appears to promote the production of amyloid, says company researcher Eric Siemers. Also, Wyeth, Madison, N.J., is working with Elan Pharmaceuticals Inc. to develop an injectable protein that would prevent the build-up of beta amyloid.

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Alzheimer's research is focusing on several types of drugs: Medicines approved to treat other illnesses, such as the cholesterol drug Lipitor. Drugs approved for Alzheimer's treatment -- such as Aricept -- but used in new ways. Drugs in development, including some that stimulate the immune system to fight the disease.