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First Alzheimer’s Prevention Trial in Full Swing

April 23, 2013
In the early 1980s, behavioral neurologist Francisco Lopera at the University of Antioquia met families from a remote mountain village surrounding Medellín, Colombia, who were affected by dementia that resembled Alzheimer’s. In these families symptoms struck much sooner than is typical for the disease, as early as mid-40s. By the late 1980s, Lopera and his colleagues knew the cause: a rare, autosomal dominant mutation of the presenilin 1 gene. Those with the mutation were sure to develop Alzheimer’s.

Now Colombian patients with the mutation-of which there are thousands-will become part of the Alzheimer’s Prevention Initiative (API), which includes a double-blind placebo-controlled study investigating an anti-amyloid β therapy. The trial is funded through a $100 million investment and an international partnership between scientists at the University of Antioquia, the Phoenix-based Banner Alzheimer’s Institute, and Genentech in South San Francisco, California. The National Institutes of Health has given $16 million of that sum, as part of the U.S. National Plan to address Alzheimer’s Disease.

There are a lot of hopes riding on this high-profile study, which is the first to evaluate an Alzheimer’s treatment before it has ravaged patients’ brains.

“There’s no guarantee that this treatment will work. But there’s only one way to find out, and based on the current thinking in the field, [the Colombian families] have a chance,” says Eric Reiman, executive officer of BAI and lead investigator of the trial with Lopera and BAI’s director Pierre Tariot.

So far, thanks to the close relationship that Lopera has with the families, the team has enrolled 2,500 family members, 30 percent of whom have the mutation, says Reiman, and are beginning to conduct detailed memory and cognitive assessments on the participants, as well as brain imaging and biomarker measurements in a smaller subset.

A smaller trial will take place in the U.S., and the BAI is working with the Dominantly Inherited Alzheimer’s Network (DIAN) an international research partnership that is conducting its own prevention trial in early-onset AD-to vet possible locations. In the meantime, in Colombia, the team is busy installing a cyclotron to make radioactive imaging agents and positron emission tomography and magnetic resonance imaging scanners. The team is also establishing a radiochemistry lab and training healthcare providers.

“It’s been going great. It’s been a concerted team effort involving a lot of different stakeholders,” says Reiman. After the study concludes in 2018 or sooner, results and clinical samples will be released to the broader research community.

Experts are hoping this trial provides a better test of the amyloid hypothesis-that a buildup of amyloid deposits in the brain cause the disease. Many think anti-amyloid therapies have not panned out so far because the treatments were given to individuals whose brains had already become too damaged.

In the new trial, Genentech’s crenezumab, an investigational anti-amyloid antibody will be given to mutation carriers, 30 and older, 15 years before they develop symptoms, and a battery of biomarkers, from brain scans, and cerebrospinal fluid and blood tests of amyloid, will be assessed throughout the trial.

In two studies published last November in Lancet Neurology, the group showed that amyloid begins to accumulate in the cerebrospinal fluid of Colombian family members with the mutation, in the late 20s. Brain imaging shows that plaques form in the brain by age 28 and reach a plateau before the individuals typically show mild cognitive impairment by 45 and dementia by their 50s. Although amyloid levels are on the rise in participants of the upcoming trial, the researchers believe crenezumab will target it before it produces too much damage.

Crenezumab was chosen by the BAI, with help from an independent academic advisory committee, from a range of different candidates. One reason it was picked was because it seems to have a good safety profile in a few hundred people it has been administered to so far. As a result, researchers can administer crenezumab at higher doses than is commonly used for antibodies-another important consideration because only a small fraction of antibodies are thought to cross the blood-brain barrier.

Besides hope for delaying a devastating illness, and new clues as to Alzheimer’s causes, the API team expects to lay the groundwork of evidence needed to qualify a biomarker as a reasonably likely surrogate endpoint in future prevention trials, effectively paving a regulatory approval pathway for drugs tested in 2-year prevention trials based on biomarkers alone, says Reiman.

Other prevention trials are also watching biomarkers. The Alzheimer’s Association-funded DIAN Trials Unit-which will investigate three potential therapies, among them Eli Lilly’s solanezumab and Roche’s gantenerumab and the A4 trial, managed by the NIH’s Alzheimer’s Disease Cooperative Study, which will also study solanezumab in people with earlier-stage Alzheimer’s, are starting this year. (See ‘Q&A with Eli Lilly’s Eric Siemers.’)

“These innovative trials will serve not only to test the therapeutic interventions, but also as a way of testing the biomarkers we now believe are important in Alzheimer’s,” says Maria Carrillo, vice president of Medical and Scientific Relations at the Alzheimer’s Association. “An increase of funding is critical now in order to accelerate these types of trials to determine if we can delay or prevent dementia symptoms.”

In the meantime, results of the crenezumab trial could come as early as 2015, after the study’s independent data safety monitoring board evaluates the effects on the patients’ cognitive and biomarker measurements and determines whether the research will continue.

So far, says Reiman, working with these families has been a humbling experience. “It’s not possible to meet families and come home unmoved,” he adds.