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Key lessons in Alzheimer’s drug failures, top Mass researcher says

Testing of several potential Alzheimer’s medications has yielded recent disappointments, but important lessons can be gleaned from those failures, says a top Boston researcher.

An analysis of the research suggests that a key problem with the most closely-watched drugs is that scientists didn’t complete basic laboratory tests before moving on to clinical trials of the medications in humans, said Dr. Dennis J. Selkoe, Coates professor of neurologic diseases at Harvard Medical School and Brigham and Women’s Hospital.

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“I think the field can be accused of being not meticiulous enough,” Selkoe said in an interview. “The scientists try to do their best, but didn’t really think through whether the drugs were good drugs, and had passed all the tests in animal models before they gave them to humans.”

Selkoe’s analysis appears as a special perspective piece today in Nature Medicine.

In the article, Selkoe, who has spent more than two decades researching Alzheimer’s disease, lays out a methodical process for other scientists that, he said, will help close the “important gaps in our knowledge.”

Among the drug trials Selkoe analyzed was one involving R-flurbiprofen, an anti-inflammatory medication. Scientists had hoped the drug would lower the amount of sticky amyloid protein plaques in the brain that are a hallmark of Alzheimer’s disease and are thought to damage nerve cells, leading to dementia.

“That trial was much reported as a failure but the drug was no good,” said Selkoe.

Scientists later realized that the drug was not able to seep into the brain in amounts high enough to be effective, he said.

Another drug that scientists had high hopes for was Alzhemed.

“That failed because it was never shown in animals that it would do what it was supposed to do,” he said.

Selkoe is one of the founders of Elan, a company that has partnered with Johnson & Johnson and Pfizer to conduct trials on another drug known as Bapi, short for Bapineuzumab. He remains a consultant to the company.

William H. Thies, chief medical and scientific officer for the national office of the Alzheimer’s Association, said he agrees with Selkoe that certain basic, necessary science hasn’t been completed.

But Thies said the problem isn’t with the scientists, it’s with the lack of federal research funding for their work.

“This is not a problem of execution, it’s a problem of resources,” Thies said. “The funding is simply not there for the basic work that would tell us about penetration of molecules into the brain, or the value of activating certain receptors.”

Thies said that the National Institutes of Health spends over $6 billion a year on cancer research, over $4 billion annually on heart disease research, and over $3 billion annually on HIV/AIDS, but only $480 million on Alzheimer’s research.

Yet, he said, Alzheimer’s is the only cause of death among the top 10 in the United States without a way to prevent it, cure it or even slow its progress.

Despite progress in the past 50 years in better understanding the brain-robbing disease, scientists still are stymied by basic questions, Thies said.

“We don’t know what starts Alzheimer’s, what moves you down the road from a normal brain to the path that leads to dementia,” he said. “We don’t know what that single event is.”

In today’s article, Selkoe also said that equally important to conducting the appropriate animal and lab tests before moving on to humans is to conduct the human trials on subjects who show only mild Alzheimer’s symptoms or who show no symptoms at all.

That view is shared by a growing number of researchers, who say that the greatest potential for having an impact in slowing the insidious disease is to approach it as scientists have other chronic diseases such as cancer, high blood pressure, and diabetes, which is to attack it at its earliest and likely most treatable stage.

Kay Lazar can be reached at klazar@globe.com.
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