Alzheimer's prevention seen promising as drug cures fail

 

NEW YORK

Three studies set to explore the use of experimental drugs that may become the first to change the course of Alzheimer's disease aren't looking to cure the illness. Their goal is to prevent it altogether.

The independent trials will begin in 2013 and run for three to five years, testing as many as five drugs in almost 1,500 volunteers who haven't shown any of Alzheimer's mind-altering symptoms, yet carry a strong genetic risk for the disease or display early physical evidence in the brain. A decision on the final study drug is expected in December.

The newest strategy abandons a drive that failed to stop Alzheimer's once memories recede. Instead, as with heart disease, scientists are exploring if the mind-robbing ailment can be prevented or at least delayed using drugs that act roughly like Pfizer's Lipitor and other statins. The idea, driven by new information that tracks the disease's progression back through time, is to act years before symptoms occur to rid the brain of proteins that can later destroy nerve cells.

"We now can see changes 10 to 15 years before symptoms develop," said Neil Buckholtz, director of the division of neuroscience at the National Institute on Aging in Bethesda, Maryland. "If you can stop them, you have a chance of slowing down or possibly even stopping progression."

A breakthrough can't come soon enough. The number of Alzheimer's cases globally is expected to double within 20 years as the world's population ages, to as many as 65.7 million people in 2030 and 115 million by 2050, the Geneva- based World Health Organization said in April.

At the same time, studies completed as recently as the last three months involving drugs made by Pfizer and Johnson & Johnson, the world's two biggest makers of health products, and Eli Lilly & Co. showed virtually no progress in slowing or stopping the disease in patients in the later stages of the disease.

Lilly said on Oct. 8 that its drug, solanezumab, provided no benefit to advanced victims in a trial. The research did suggest the medicine may help in a small way in those with early symptoms. J&J and Pfizer reported on Sept. 11 that while their drug, bapineuzumab, showed signs of reducing physical damage, it didn't affect symptoms.

The next step, Buckholtz said, is to determine if pushing the use of drugs like these back in time, when the disease is just beginning to form, will make a difference.

"Really what's happened is over the past 10 years, investigators have tried to go earlier and earlier in the disease process," Buckholtz said.

Enabling researchers to get an ever earlier look at the progression of Alzheimer's has been the development of new imaging agents, such as Pittsburgh Compound B or PiB, that highlights the activity of beta amyloid, the hallmark protein that makes up the brain's tell-tale tangles.

Researchers studying those with a genetic propensity for early Alzheimer's, which can take hold by age 40, have also tracked changes in brain size and cerebrospinal fluid that can occur as early as 25 years before symptoms develop.

That work has allowed scientists to think of Alzheimer's as a kind of chain reaction, much like that leading up to heart disease, said Randall Bateman, a neurologist at the Washington University in St. Louis who is leading one of the three studies.

"The questions are how long do you treat, when do you start, and how do you measure effectiveness," Bateman said in a telephone interview. "It took thousands of patients over many years to show statins have a benefit in heart disease. We're going as early in Alzheimer's as we practically can."

While the three studies won't help those with the disease now, they may be able affect the lives of generations to come, the researchers said.

Researchers in two of the trials have already determined they'll use Lilly's solanezumab and two products made by Roche Holding that are in earlier stages of testing.

One of these trials is led by Bateman and the other by Eric Reiman of the Banner Alzheimer's Institute in Phoenix. These studies will test about 460 people, all of whom have rare genetic mutations that almost certainly will trigger the disease early in their lives.

Bateman's team will, over at least three years, test as many as three drugs in 160 people with parents who fell victim to the disease early.

Reiman's group will study a group of families in Colombia who often suffer severe memory loss by their early 40s. The five-year $100 million study has interim tests that may indicate whether the drug is having an effect within two years.

The third trial, dubbed A4, will be conducted by a team led by Reisa Sperling at Harvard Medical School in Boston. It will test a drug on about 1,000 older people over three years whose brains show the beginning of physical signs of Alzheimer's characteristic beta amyloid protein deposits, and who haven't yet displayed the disease's symptoms.

A4 is the most representative of the general population, and researchers plan to decide in December which drug they will test, Sperling, a neurologist, said in a telephone interview. She declined to say which medicines are being considered.

"It's challenging to make a decision," she said. "We're looking for a combination of evidence of biologic activity and a hint of clinical efficacy. That's much more difficult because the drugs right now are all being tested in dementia, so it's hard to know how to extrapolate the findings back 10 years."

The researchers also want to make sure the drugs are safe, because the study group is composed of clinically normal older adults, Sperling said.

The trials are exploratory, said Maria Carrillo, the vice president of medical and scientific relations at the Alzheimer's Association, a Chicago-based advocacy organization. Any drug that's at least being studied in a Phase 2 trial targeting amyloid is fair game, she said.

"The question is, if we can really effect and impact that in a significant way," Washington University's Bateman said. "It would be a fantastic breakthrough for these family members, and having that demonstration we can treat and prevent the disease will embolden the field."

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