Prevention is goal of Alzheimer's drug trial

Prevention is goal of Alzheimer's drug trial

If the drug can forestall memory or cognitive problems, it will show that delay is possible

In a clinical trial that could lead to treatments that prevent Alzheimer’s, people who are genetically guaranteed to develop the disease – but who do not yet have any symptoms – will for the first time be given a drug intended to stop it, according to federal officials.

Experts say the study will be one of the few ever conducted to test prevention treatments for any genetically predestined disease. For Alzheimer’s, the trial is unprecedented, “the first to focus on people who are cognitively normal but at very high risk for Alzheimer’s disease,” said Dr Francis S Collins, director of the National Institutes of Health.

Most participants will come from the world’s largest family to experience Alzheimer’s, an extended clan of 5,000 people who live in Medellin, Colombia, and remote mountain villages outside that city. Family members with a specific genetic mutation begin showing cognitive impairment around age 45, and full dementia around age 51, debilitated in their prime working years as their memories fade and the disease quickly assaults their ability to move, eat, speak and communicate.

Three hundred family members will participate in the initial trial. Those with the mutation will be years away from symptoms, some as young as 30. “Because of this study, we do not feel as alone,” said Gladys Betancur, 39, a family member. Her mother died of Alzheimer’s, three of her siblings already have symptoms, and she had a hysterectomy because of her fears that she has the mutation and would pass it on to her children. “Sometimes we think that life is ending, but now we feel that people are trying to help us.”

The $100 million study will last five years, but sophisticated tests may indicate in two years whether the drug helps delay memory decline or brain changes, said Dr Eric M Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix and a study leader.

Alzheimer’s experts not involved in the study said that though only a small percentage of people with Alzheimer’s have the genetic early-onset form that affects the Colombian family, the trial was expected to yield information that could apply to millions of people worldwide who will develop more conventional Alzheimer’s.

“It offers a tremendous opportunity for us to answer a large number of questions, while at the same time offering these people some significant clinical help that otherwise they never would have had,” said Dr Steven T DeKosky, an Alzheimer’s researcher who is vice president and dean of the University of Virginia School of Medicine. DeKosky was part of a large group consulted early on, but is not involved in the study.

The drug trial is part of the federal government’s first national plan to address Alzheimer’s, which was unveiled by Kathleen Sebelius, the secretary for health and human services. The government took the unusual step of assigning $50 million from the current year’s NIH budget to research considered too promising to wait, including the Colombia trial and a study on whether inhaled insulin can ease mild cognitive impairment, Collins said. Another $100 million is proposed for 2013, mostly for research, but also for education, caregiver support and data collection.

Success for the Colombia trial is, of course, no sure thing. Many trials fail, and Alzheimer’s research has so far found no treatment effective for more than several months. But experts say that trying drugs years before symptoms emerge could have greater potential because the brain would not yet be ravaged by the disease.

Private donors

The trial will be financed with $16 million from the National Institutes of Health, $15 million from private donors through the Banner Institute and about $65 million from Genentech, the drug’s American manufacturer.

The drug, Crenezumab, attacks amyloid plaques in the brain. If it can forestall memory or cognitive problems, scientists will know that prevention or delay is possible and appears to lie in targeting amyloid years before dementia develops. Many, but not all, Alzheimer’s researchers believe amyloid is an underlying cause of Alzheimer’s.

“The first thing I did was to ask myself the question, Are we taking advantage of these folks?” said Richard H. Scheller, Genentech’s executive vice president of research and early development. “The answer was clearly no.” The risks, he said, are balanced by the fact that if nothing is done, “they’re going to get this terrible, terrible disease for sure.”

The few trials of prevention therapies – involving ginkgo biloba, women’s hormone replacement treatment and anti-inflammatory drugs – have involved people not guaranteed to get the disease. These therapies either failed or caused adverse side effects.

Testing drugs on that kind of population takes “too many healthy volunteers, too much money, and too many years,” Reiman said. The Colombian population is ideal because it is large enough to provide solid results, and it is easy to identify whom the disease will strike and when.

Crenezumab was chosen for the Colombia trial partly because it appears to have no negative side effects, unlike other drugs designed to clear amyloid from the brain, said Dr. Francisco Lopera, a Colombian neurologist who has worked with the family for decades and is a leader of the study. Other anti-amyloid treatments have caused edema in the blood vessels, an imbalance of fluid that can have serious consequences.

Crenezumab is currently being given in two clinical trials to people with mild to moderate symptoms of dementia in the United States, Canada and Western Europe to see if it can help reduce cognitive decline or amyloid accumulation, according to Genentech.

In the Colombia study, expected to start early next year, 100 family members with the mutation will receive the drug every two weeks in an injection at a hospital. Another 100 carriers will receive a placebo. And because many people do not want to know if they have the mutation, researchers will include 100 noncarriers in the study; they will receive a placebo.

Researchers have developed a sophisticated battery of five memory and cognitive tests that have been shown in other studies to detect subtle alterations in recall and thinking ability that usually go unnoticed. Dr Pierre N Tariot, director of the Banner Institute and a leader of the study, said the measurements would involve recalling words, naming objects, nonverbal reasoning, remembering time and place, and drawing tests involving copying complex figures.

The scientists will take physiological measurements, including PET scans that measure amyloid and how glucose is metabolized in the brain, MRI scans that measure whether the brain is shrinking, and cerebral spinal fluid tests that measure amyloid and tau, a protein in dying brain cells.

If any of these indicators are improved by the drug, Reiman said, scientists may then be able to treat one of these early physiological changes, just as high blood pressure and cholesterol are treated to prevent heart disease.

In Medellin, Marcela Agudelo, 17, has Alzheimer’s on both sides of her family because her parents are distant cousins. Marcela watched her maternal grandmother die, and her father, 55, once a vibrant livestock trader, has deteriorated so much that he can no longer walk, talk or laugh. With the research, “we have more hope for a cure,” Marcela said, “or at least a better life.”

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