Deborah Brauser

July 25, 2012

July 25, 2012 (Vancouver, British Columbia) — Three upcoming treatment trials aim to delay or even prevent the onset of Alzheimer's disease (AD) in individuals who are asymptomatic, according to presentations here at the Alzheimer's Association International Conference (AAIC) 2012.

The researchers noted that disappointing results from other recent treatment trials for AD may be due to the fact that all of these agents have been tested in symptomatic patients. It is widely believed by many in the field that current treatments are administered too late in the disease process.

Although it has not yet been approved for funding, investigators for the 3-year placebo-controlled Anti-Amyloid Treatment of Asymptomatic AD trial (known as A4) hope to assess healthy elderly adults who have biomarker evidence of AD brain changes beginning in the middle of 2013.

"We now have the biomarker measuring tools and experimental drugs to test the hypothesis that reducing amyloid burden in the brain will slow the loss of nerve cells at a stage of Alzheimer's before there's widespread, irreversible neuronal damage," principal investigator Reisa Sperling, MD, from Harvard Medical School and Brigham & Women's Hospital in Boston, Massachusetts, told press briefing attendees.

Dr. Reisa Sperling

In addition, the Dominantly Inherited Alzheimer's Network (DIAN) – Therapeutic Trials Unit (TTU) is preparing to launch prevention trials of 3 treatments in people with young-onset genetic AD. And the Alzheimer's Prevention Initiative (API) is planning to assess the amyloid-modifying treatment crenezumab vs placebo in individuals in both the United States and Columbia who have younger-onset AD gene mutations but no symptoms.

"These 3 trials are in their early stages of development, but what's striking is that they will all be intervening early, when there is the greatest chance of success," press briefing moderator Ralph Nixon, MD, PhD, chair of the Alzheimer's Association Medical and Scientific Advisory Council, told Medscape Medical News.

Dr. Ralph Nixon

"The goal is to prevent the further development of memory or functional decline with anti-amyloid treatments. This will be provide very critical information," said Dr. Nixon.

Targeting Amyloid Buildup

The A4 trial plans to enroll at 50 sites in the United States 1000 patients older than 70 years who, although they test "normal" on memory and thinking tasks, have brain amyloid buildup, as shown in positron emission tomography scans.

According to the investigators, one third of "clinically normal" elderly individuals have cerebral amyloid-beta buildups.

"These amyloid-positive 'normals' demonstrate evidence of functional and structural imaging abnormalities, elevation of CSF [cerebral spinal fluid] tau, and subtle cognitive deficits, consistent with the preclinical stages of AD, and represent an ideal population for a...prevention effort to slow cognitive decline," they write.

All A4 participants will be randomly assigned to receive either placebo or an experimental treatment (expected n = 500 for each arm). Although the choice of treatment has not yet been finalized, Dr. Sperling reported that it "will likely be a monoclonal antibody to fight against amyloid."

The primary outcome measure will be decreasing the rate of decline in cognition and executive function; secondary outcomes will include results on structural and functional imaging and on spinal fluid assays.

"We now have the [means] to test the hypothesis that altering 'upstream' amyloid burden will impact 'downstream' neurodegeneration," write the researchers.

"I think this is our best chance of being able to see whether amyloid really makes a difference or not," added Dr. Sperling.

She noted that in the past, she has been accused of "amyloid-centricity."

"But the success of the A4 trial doesn't require that amyloid is the cause of AD, because it may not be, but only that it is one of the critical factors," she explained.

Review of the trial's funding application by the National Institute on Aging has been completed, with a decision expected in September. If approved, the investigators plan to select partners and the study treatment in December, finalize study protocol with their partners and with the US Food and Drug Administration in January, and begin enrollment in the summer of 2013.

DIAN Treatment

The DIAN-TTU investigators plan to assess 3 pharmacologic treatments over 2 years for delaying, preventing, or restoring cognitive loss in people who carry an AD gene mutation. They hope to start the first stage of the study in late 2012 or early 2013.

"Autosomal dominant AD accounts for less than 1% of all AD, but has 100% risk and usually occurs in the third to fifth decade of life," write the investigators.

"Scientists believe that there is significant overlap of the causes and progression in people with dominantly inherited Alzheimer's and other forms of the disease," added lead author Randall Bateman, MD, from Washington University School of Medicine in St. Louis, Missouri, in a release.

Dr. Randall Bateman

DIAN was created in 2008 so that research centers around the world could collaborate and "investigate AD caused by mutations."

As reported by Medscape Medical News, the DIAN investigators published results from their first study on July 11 in the New England Journal of Medicine. That study showed that changes in cerebrospinal fluid and brain amyloid deposition could be detected up to 25 years before symptoms of AD appear.

Dr. Bateman reported that the new trial will consist of 4 treatment arms: 1 for placebo and 1 for each of 3 different active drugs (expected n = 40 per arm). If there are positive results, the investigators plan on extending the study past the initial 2-year period.

"Each of the proposed drugs has their own unique mechanism of action and their own target to test the idea of which of these drugs, if any, have significant impact on the disease processes of the brain," he explained during his presentation.

"The participants and patients are quite eager. They've been asking for a very long time to participate in drug trials. We think there is very strong scientific rationale, and the regulatory agencies have been very supportive of these kinds of treatment studies."

Dr. Nixon noted that the DIAN trial represents "an important direction" for the field to moving toward.

"It's important because of what it will tell us about how to treat sporadic Alzheimer's and what it's telling us already about the natural course of the disease and when biomarkers first appear," he said.

Assessing Crenezumab

The third prevention trial, from the API, plans to enroll 300 individuals older than 30 years in Colombia and 24 individuals in the United States who carry the AD gene mutations PS1 E280A or APOE but who are asymptomatic for the disorder.

All participants will be randomly assigned to receive either crenezumab or placebo for 5 years. Crenezumab is a humanized monoclonal antibody that is intended to remove different forms of brain amyloid and is "engineered to minimize the risk of certain adverse effects."

"We feel that it is important to give persons at highest risk access to promising investigational treatments, and to conduct the study in a way that provides the greatest possible benefit to the field," said co–lead investigator Eric Reiman, MD, from the Banner Alzheimer's Institute in Phoenix, Arizona, and the Translational Genomic Research Institute at the University of Arizona, in a release.

Dr. Eric Reiman

He noted during his presentation that the API also plans to create Web-based Alzheimer's Prevention Registries, with the goal of including more than 3300 mutation carriers in Antioquila, Colombia, and more than 250,000 people in North America.

"We are excited about our progress, plans, current timelines, and the chance to work with other researchers, programs, and stakeholders," said Dr. Reiman.

"Together, we have a chance to set the stage of a new era in AD prevention research, develop the resources, biomarker endpoints, and accelerated regulatory approval pathway needed to rapidly evaluate the range of promising presymptomatic treatments, and find ones that work as soon as possible," he added.

The trial is scheduled to begin in late 2012 in the United States and in mid-2013 in Columbia.

Dr. Nixon noted that it is interesting that both the API and DIAN trials will focus on patients who carry the gene mutation "that guarantees that they will develop Alzheimer's at a later age."

"All of the studies involve patients who are at risk, although the A4 patients will not be at the same level of risk as the other populations," he added.

Pushing the Envelope

Investigators from all 3 studies said they plan to share data with each other — and with other AD researchers.

"We've all been working together through the Collaboration for Alzheimer's Prevention, or CAP. This will let us try and coordinate and maximize information across the studies," said Dr. Sperling.

"These trials will present important information for defining more definitively the earliest stage of Alzheimer's and to push the envelope further and earlier," added Dr. Nixon.

The DIAN-TTU is funded by the Alzheimer's Association, the National Institutes of Health, and the DIAN Pharma Consortium. The API is funded by Genentech (the manufacturer of crenezumab), by Banner Alzheimer's Institute, and by the National Institutes of Health. The study authors and Dr. Nixon have disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2012. Abstracts F3-04-1, F3-04-02, and F3-04-03. All presented July 17, 2012.


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