The first clinical trial of a drug aimed at preventing Alzheimer's disease was announced Tuesday. If successful, the study would not only confirm important theories about the causes of the devastating degenerative disease and advance a new class of treatments, but serve as a template for preventative drug trials for other conditions like cancer and diabetes as well.
Alzheimer's disease patient Isidora Tomaz (R), 82, is carried to bed by Otilia Canarias (L), an aid worker from the Portuguese Alzheimer Association, a charity, as her husband Amilcar Dos Santos, 82, watches in their house in Lisbon September 15, 2009
"We've had a lot of failures in Alzheimer's drugs. But you learn from them," says Guy Eakin, the vice president of scientific affairs at the American Health Assistance Foundation, which funds research seeking cures for several age-related degenerative diseases (though it is not involved in the newest trial).
This newest venture -- a $100 million collaboration between the U.S. National Institutes of Health, the Arizona-based Banner Alzheimer's Institute, drug giant Genentech and the University of Antioquia in Colombia -- is approaching the disease from an unusual angle. Instead of testing drugs on patients with full-blown dementia, the trial will focus on around 300 people in the U.S. and Colombia that carry a genetic mutation that usually triggers Alzheimer's symptoms around age 45. Most of the study subjects are from a single large extended family.
The mutation in question affects the gene PSEN1, which makes a protein that forms an important link in a chain of activity that makes another protein, beta amyloid. Clumps of beta amyloid proteins, known as "plaques," and smaller aggregations of amyloid known as 'ligomers' are thought to play a key role in Alzheimer's disease when they build up in the brain.
Crenezumab, the drug being tested, is an antibody that binds to beta amyloid and helps clear out those excessive deposits.
"This is significant in that it's the first time we really are going to be looking at cognitively normal yet extremely high-risk individuals," says the NIH's Laurie Ryan, who manages more than 30 clinical Alzheimer's drug trials for the agency.
Most drug trials focus on mitigating existing symptoms in patients with moderate to late-stage Alzheimer's. But the subjects in this new study are, at the outset, cognitively normal.
"If we intervene early in these people that we know are at risk for Alzheimer's, does that change their course?" If so, "that's a big proof of concept right there," Ryan says.
Each subject will get either an injection of the drug crenezumab or an injection of placebo at regular intervals for two years. All of the subjects that have the PSEN1 mutation -- many of whom do not want to know that they carry it, trial administrators say -- will receive crenezumab, while relatives of the subjects that are not carriers for the Alzheimer's mutation will receive the placebo.
Meanwhile, researchers will be evaluating the subjects with brain scans, tests of cerebrospinal fluid, and other cognitive measurements to look for signs of early-onset Alzheimer's. The researchers will then make the call after two years whether or not to continue the crenezumab treatment for the full five-year period.
If crenezumab succeeds in averting patient's genetically predestined fate, it would be a significant confirmation that beta amyloid is a crucial player in the disease and a well-deserved target for Alzheimer's drugs.
But there are other possible molecular players that have attracted attention in recent years -- most notably tau, another protein that when defective can aggregate into "tangles" and destroy brain cells. Just going after amyloid might not be enough to stop patients' decline, but drugs that target tau are much further behind in the pipeline.
"I think the general consensus is that amyloid is still a very important molecule and it's the biggest lever we have to pull on Alzheimer's disease right now," Eakin says.
Ryan said truly comprehensive Alzheimer's treatments may adopt the model that's found success in HIV - a cocktail of multiple drugs with multiple targets. The cocktail might have to be adjusted for a person's genetic makeup, or other factors like pre-existing heart conditions.
"Alzheimer's is a complex disease. It's likely there won't be a single treatment that'll work for everyone," Ryan says.
Even if this crenezumab trial is successful, the drug won't be on shelves for years. Pharmaceuticals have to go through three phases of clinical trials, and this one isn't even a "full-blown" phase III, Ryan says. What will be needed is a subsequent trial testing the drug in a general population.
And even once the drug's been approved, how will physicians know who to give it to? Doctors can now measure beta amyloid levels in patients using body-scanning technology, but more amyloid doesn't necessarily equal Alzheimer's disease.
But Ryan drew a parallel to heart disease: "Not everyone who has high cholesterol will have a heart attack. But we know it's a risk factor."
If the drug is safe enough, it could be worthwhile to give crenezumab as a preventative measure to patients that are showing signs of beta amyloid buildup, in the same way that statins -- a class of cholesterol-lowering drugs -- are given to patients with high cholesterol to guard against cardiovascular disease.
Pierre Tariot, one of two scientists from BAI, one of the Alzheimer's institutes leading the Colombian trial, says crenezumab beat out nearly three dozen other drugs to win the spot in the trial. One of the primary reasons crenezumab won, he says, is the drug's potency -- it appears to be particularly good at binding beta amyloid fragments -- but another big factor that pushed crenezumab ahead of the competition is its apparent safety.
According to Tariot, crenezumab has also been engineered in part to avoid the adverse effects that have plagued other Alzheimer's drugs in clinical testing -- brain inflammation, tiny strokes called microbleeds, or the development of water pockets in the brain.
But the researchers will still be watching for adverse events very carefully over the next two years.
"I've adopted this mantra: We have many rivers to cross," Tariot says.
The push to find a potent Alzheimer's treatment or cure has an element of urgency - the huge cost of taking care of Alzheimer's patients, combined with a enormous cohort of aging Baby Boomers, looms large on Eakin's mind.
"This truly stands a chance of crippling our health care system if we don't get a disease-modifying treatment soon," Eakin says.
Regardless of how crenezumab fares, a lot of people will be looking at the trial design and thinking of ways to apply it to other diseases, he says.
Ryan emphasizes that the NIH isn't putting all of its medicinal eggs in the prevention basket.
"We're not abandoning those Alzheimer's patients that already have dementia," she says.
Meanwhile, other drugs are steadily winding their way down the pipeline.
Eli Lilly's solanezumab and Pfizer's bapineuzumab - which, like crenezumab, target beta amyloid, are set to publish data from their own phase III trials later this year. Another treatment from Baxter International called Gammagard, which is already approved for use in various immune deficiency disorders is set to wrap up the first of two phase III trials in Alzheimer's patients in early 2013.
"It's kind of a really exciting summer," Eakin says.
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