Two U.S.-based research groups are planning clinical trials of drugs to prevent Alzheimer’s disease, using volunteers who are cognitively normal but genetically at high risk for the disease. Aside from testing the preventive effects of individual drugs, the trials will aim to show that such studies can be done relatively quickly, by targeting “biomarkers” of the disease in the blood and brain long before dementia symptoms appear.
“The main roadblock to the discovery of effective prevention therapies has been the lack of techniques to evaluate them rapidly,” says Eric Reiman, who directs one of the prevention-trial groups, the Alzheimer’s Prevention Initiative (API) of the Banner Alzheimer’s Institute in Phoenix, Arizona.
Prevention trials are necessary, but problematic
Alzheimer’s begins insidiously, many years before its outward signs appear. In those early, presymptomatic stages, the disease seems to be driven by the accumulation in the brain of small, soluble, toxic clumps, or “oligomers” of amyloid beta (A-beta) protein. There are several candidate drugs that might be able to prevent Alzheimer’s by reducing this early accumulation of A-beta oligomers, much as statin drugs prevent heart disease by blocking cholesterol. In fact, this presymptomatic period may be the only time these drugs will work: Just as statins cannot reverse severe heart failure, anti-A-beta drugs in clinical trials have been unable to stop Alzheimer’s once dementia has set in (see “Seeking Earliest Signs of Alzheimer’s”).
“By the time the dementia is there, the pathology is much more than just an A-beta dysregulation; there are many other [degenerative] processes at work,” says John Morris, a neurologist and Alzheimer’s researcher at the Washington University School of Medicine who heads another prevention-trial initiative.
But how can researchers test anti-A-beta drugs as preventives of dementia? In an ordinary elderly population, a definitive prevention test would require the treatment and monitoring of tens of thousands of elderly patients, beginning when they are cognitively normal and running for at least a decade. Aside from the huge expense, and the lack of incentive for pharmaceutical companies—whose drug patents normally expire 20 years after the patent application—there is a serious ethical issue: One cannot give drugs of uncertain risks and benefits, over many years, to large numbers of apparently healthy people who may never get disease. Therefore, such a trial “isn’t going to happen,” concludes Reiman.
On the other hand, a prevention trial would be ethical, affordable, and relatively quick if it could be done in a smaller group of people who are almost certain to develop dementia within a narrow age-range. Such people now can be identified—and these are the people Reiman’s and Morris’s groups plan to enroll in their prevention trials.
The Banner API trials
In and around Medellin, Colombia lives an extended family of some 5,000 people, about a third of whom carry an otherwise rare, Alzheimer’s-causing mutation (see sidebar). The mutation disrupts the normal function of the gene for presenilin-1, part of an enzyme complex involved in the production of A-beta—and in so doing boosts the production of A-beta-42, a form of A-beta that is relatively prone to form harmful clusters. Those who have even a single copy of the mutant presenilin-1 gene typically start to show signs of cognitive impairment in their mid-forties.
Reiman and his co-director Pierre Tariot are now trying to set up a trial in this extended family that they hope will start in 2012. From a registry of gene-tested family members, they would randomly assign about 150 cognitively normal carriers of the presenilin-1-mutation to receive a candidate drug—to be determined soon—and an equal number of carriers to receive a placebo. They also would give placebos to non-carriers in the registry, so as not to identify the mutation carriers by exclusion. “They consider the mutation a curse,” says Reiman.
The researchers would monitor each subject for two years from enrollment, not only with standard cognitive tests but also with the latest brain-imaging and fluid biomarkers tests, including tests of levels of A-beta in their cerebrospinal fluid. “If the biomarkers budge in the right direction, we’d continue to monitor them until we show that we can slow cognitive decline—which we’ve estimated we might be able to do in two to five years,” says Reiman.
If successful, this small, relatively quick trial would likely lead to large-scale confirmatory tests of the drug. Almost as importantly, it might persuade the FDA and European Medicines Agency to allow future Alzheimer’s prevention trials based on relatively fast-changing biomarker evidence—instead of the much-longer-term cognitive score changes that make up the current standard.
Reiman and his colleagues are trying to set up a second, U.S.-based trial in late middle-aged people who have a weaker but more common risk factor for Alzheimer’s: a gene variant known as apo-E4. That trial would enroll at least several hundred people in the treatment and control groups, and would employ a similar strategy involving biomarkers and standard cognitive tests.
The DIAN study
Morris and colleagues, with funding from the National Institute on Aging, have been setting up a registry of other families around the world who have inherited, early-onset forms of Alzheimer’s—a registry known as the Dominantly Inherited Alzheimer’s Network (DIAN), “dominant” being a genetics term for a mutation that can cause disease even when inherited from only one parent.
Since last year, DIAN researchers also have been meeting to plan dementia prevention trials in these families, and so far, says Morris, nine companies have submitted a total of ten candidate drugs for testing in these trials—to begin with one, biomarker-focused trial.
“We hope that by the ICAD conference in Paris this July, the DIAN clinical trials committee will decide on a lead drug compound,” says Morris. “When that’s approved by the DIAN steering committee, then I think we’ll start working in earnest with the sponsoring company to develop the trial design, with an idea of launching the trial next year.”
One of the most promising prevention drug candidates, because it showed a hint of effectiveness in ordinary clinical trials and seemed mostly safe, is bapineuzumab, a monoclonal antibody that targets and helps remove A-beta “plaques” in the brain. “We know that bapineuzumab lowers the fibrillar amyloid burden in the brain,” says Sam Gandy, an Alzheimer’s researcher at Mount Sinai School of Medicine. “The main unknowns are how early we’d have to give it [as a preventive], how long we’d have to give it, and whether it would also eliminate A-beta oligomers.”
The issue of when to start treating early-onset Alzheimer’s patients with a preventive drug may be a thorny one. “Very preliminary evidence suggests that biomarker abnormalities can be detected in these subjects at least ten years before their expected age of onset of dementia,” says Morris. Ideally, then, candidate preventive drugs should be given—if they are safe—when early-onset subjects are still in their late 20s and early 30s. Yet drug companies for business reasons may insist on shorter trials, starting very close to the expected age of dementia onset. “We’ll want to intervene before there’s substantial brain damage, but not so early that we have to follow these people for decades,” says Morris.
Another unresolved issue is the precise relevance of these rare, inherited forms of Alzheimer’s to the much more common, “sporadic” forms. But Gandy says that, for now, there is a broad consensus that prevention-drug effects in carriers of presenilin-1 and similar early-onset Alzheimer’s mutations should give solid clues to the performance of the same drugs in ordinary elderly people. “If amyloid-lowering beginning prior to dementia onset does not succeed in these familial Alzheimer’s cases, then the likelihood that amyloid-lowering will succeed in sporadic Alzheimer’s will be diminished,” he says.