Plans Under Way for Alzheimer's Prevention Trial

Neurology Today
21 June 2012; Volume 12(12); p 1–14

Eastman, Peggy

At an NIH summit meeting, investigators announced plans to launch a trial to study the benefits of early intervention for subjects who are amyloid positive and at risk for developing Alzheimer's disease.

DR. FRANCIS COLLINS noted at the opening of the two-day summit that the number of Americans with Alzheimer's is likely to balloon from 5.1 million today to 15 million by 2050.

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BETHESDA, MD—The goal of treating older patients at risk of developing Alzheimer's disease while they are presymptomatic is moving closer to reality, according to speakers at a research meeting at the NIH here. If all goes as hoped, the Anti-Amyloid Treatment in Asymptomatic AD (A4) Trial, a secondary prevention trial, will be reviewed this summer and researchers will start screening subjects for eligibility in 2013.

The NIH meeting, Alzheimer's Disease Research Summit 2012: Path to Treatment and Prevention, was hosted by the U.S. Department of Health and Human Services (HHS) and the National Institute on Aging (NIA) — funder of the A4 trial — with private support from the Foundation for NIH. The summit was one of the first steps in responding to the National Alzheimer's Project Act, signed into law in January 2011. That law requires the HHS secretary to adopt and implement a national strategy for Alzheimer's research and care.

Without such a strategy the number of Americans with Alzheimer's is likely to balloon from 5.1 million today to 15 million by 2050, said NIH Director Francis Collins, MD, PhD, who opened the two-day event, noting that there is a “sense of optimism” emanating from recent scientific advances and opportunities.

“I think the biggest problem with clinical trials is timing; we need to study compounds at the beginning, not at the end,” said Paul Aisen, MD, professor of neurosciences at the University of California, San Diego, and director of the Alzheimer's Disease Cooperative Study (ADCS), a consortium funded by the NIA to develop assessment instruments and conduct clinical trials.

What is needed, said Dr. Aisen, is “preclinicaltrials.gov,” a national system of enrolling patients at risk of developing Alzheimer's before cognitive symptoms — even those from mild cognitive impairment (MCI) — have appeared. Dr. Aisen noted that amyloid-beta deposition (Abeta) in the brain can precede Alzheimer's disease by as long as 15 years. “If there are 15 years, it can't make sense to wait until the development of Alzheimer's disease to treat,” he said.

“Intervening at the stage of dementia is too late” because by the time of dementia too many neurons have been destroyed, agreed Reisa Sperling, MD, director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital; an associate professor in neurology at Harvard Medical School; principal investigator on the NIA Program Project-funded Harvard Aging Brain Study; and chair of the NIA/Alzheimer's Association working group on preclinical Alzheimer's disease.

“We need to define the critical window for therapeutic intervention,” added Dr. Sperling — who along with Dr. Aisen leads the A4 trial. “Alzheimer's disease is a continuum....Ultimately we want to move to primary prevention, of course; we need to start secondary prevention trials now and lay the groundwork for primary prevention trials,” she said.

In an interview, Dr. Sperling said that a drug has not yet been chosen for the A4 trial, but that a decision on that drug — a compound which has shown anti-amyloid activity in humans — will likely be made by December 2012. She said that study subjects (who must be age 70 or older) will be sought who are clinically normal and have no cognitive symptoms, and added that patients from minority groups will be actively recruited. “We don't want MCI or dementia,” she said.

As for the ethical issue of enrolling presymptomatic patients, Dr. Sperling told Neurology Today that subjects have to be amyloid-positive as shown on PET amyloid imaging, and thus at risk of developing Alzheimer's disease. She also said that the compound chosen for the trial must have at least several years of demonstrated safety data — an important consideration since the study population will not have an identified genetic mutation for Alzheimer's disease.

Dr. Sperling said study subjects will be treated for three years with the chosen anti-amyloid drug or placebo, and then followed — to see whether preclinical treatment to reduce amyloid burden can have an impact on neurodegeneration and cognitive function — for at least two years beyond treatment.

Asked by Neurology Today if CSF testing will be included in the trial, she said, “We will not require CSF, but we will encourage it.” Study subjects will be also be asked to consider having their brains autopsied upon death.

Dr. Aisen said the investigators expect to find a ready number of study subjects eager to enroll. “I have no doubt of it. We have already found a willingness to participate. Right now what we need is money,” he said.

A4, which hopes to recruit about 1,000 US patients, is part of the NIA-funded ADCS chaired by Dr. Aisen, which will provide most of the money for the trial. But the study will likely require industry partners for the drug and PET imaging aspects of the trial, noted Dr. Sperling.

Speakers at the NIH summit agreed with Drs. Aisen and Sperling that in order to make a major difference in cognitive decline, Alzheimer's disease will likely have to be treated much earlier on its neurodegenerative continuum.

“Amyloid targets may ultimately require primary prevention even assuming the underlying cascade hypothesis is correct,” said Michael L. Hutton, PhD, chief scientific officer for the neurodegeneration team at Eli Lilly. Dr. Hutton noted that most drug discovery programs are currently focused on Abeta aggregation as a hypothesized target in Alzheimer's.

“I think that Abeta is unequivocally a causal factor for some forms of Alzheimer's,” said Dennis Selkoe, MD, the Coates Professor of Neurologic Diseases at Harvard Medical School and Brigham and Women's Hospital. “Therapies most likely to work in chronic diseases are those that target the earliest molecular change. ...What we need are better compounds and earlier trials in the disease process,” he noted.

James L. Bernat, MD, the Louis and Ruth Frank Professor of Neuroscience and Professor of Neurology and Medicine at the Geisel School of Medicine at Dartmouth in Hanover, NH, and former chair of the AAN Ethics, Law and Humanities Committee, said he is confident that three ethical principles that apply to all clinical trials will be applied in the prevention trial: 1) that the human subjects give their free and informed consent about the trial including an understanding of its potential risks and benefits; 2) that the experimental agent chosen has a favorable risk-benefit ratio; and 3) that respect is given to the human research subjects — meaning, they are told that they can withdraw or change their minds about participating at any time, and further, that if they become ill, they can report their symptoms and receive treatment.

“If the investigators incorporate these principles — and I'm sure they will do so for the trial to be approved by their institutional review boards — from my perspective, the prevention trial would be ethically sound,” said Dr. Bernat, who is also a member of the editorial advisory board of Neurology Today.

“Of course, at this point, we don't know which agent they will choose,” Dr. Bernat continued. “If it's a monoclonal antibody, for example, that could have significant risks in otherwise healthy people, that might raise an ethical question about its risk-benefit ratio. But these investigators are fully aware of the ethical principles involved in these trials, and I'm sure they'll meet the requirements.

“Given that the plans are to include subjects who are normal now but who may end up with this devastating disease, I think it is rational and ethical to see if there are therapies that can prevent it.”