Alzheimer's Drug Shows Promise in Small Trial

A new drug trial that some researchers are calling the most promising yet in the fight against Alzheimer’s suggests it may be possible to clear the brain of the amyloid protein that is characteristic of the disease.

The study was small and researchers caution that it’s far too soon to declare victory against a fatal disease that robs people of their memories and ability to function in daily life. But despite repeated failures of Alzheimer’s drugs in the past, there was room for enthusiasm about the trial, the results of which were published today in Nature. “This is the best news we’ve had in my 25 years of doing Alzheimer’s research,” says Stephen Salloway, a professor of clinical neurosciences and psychiatry at Brown University and a co-author of the paper.

The longer an early-stage Alzheimer’s patient took the drug aducanumab, and the higher the dose, the less clogged their brain was with amyloid a year later. The 21 subjects who made it through the study on the highest dose had no detectable amyloid deposits left in their brains after a year. “The effect size of this drug is unprecedented,” says paper co-author Roger Nitsch, president and founder of Zurich-based Neurimmune, which initially developed aducanumab.

The drug also increased the risk of brain hemorrhage and potentially dangerous fluid shifts in the brain, however, forcing a balancing act between its effectiveness and patients’ ability to tolerate a high-enough dose. Researchers were able to catch early signs of the side effect, known as amyloid-related imaging abnormalities (ARIA), through MRI brain scans, Salloway says, and no one in the trial suffered irreversible harm.

The trial was too small to show whether the reduction in brain amyloid made a difference in the everyday functioning of the participants, although there were some indications the drug slowed cognitive and functional decline in those who received the highest dose for more than six months. Most of the trial results have been released previously at public meetings. The new publication offers more depth and marks the first time the results have been peer-reviewed and presented comprehensively, the authors said in an August 30 news conference.

The small trial showed promise, but the real test of aducanumab is underway in two much larger studies funded in collaboration with the drug company Biogen, which has partnered with Neurimmune to bring aducanumab to market. Those trials, begun last year, will include 2,700 participants in North America, Europe and Japan, who will take the drug for 18 months. If the trials are successful, the companies will go on to apply to the U.S. Food and Drug Administration for permission to sell aducanumab to patients.

Salloway and others said they do not expect aducanumab, even if it works well, to be “the” solution to Alzheimer’s. As with other complex diseases like cancer and HIV, a cocktail or series of drugs will likely be necessary. The drug will also likely be most useful at the disease’s earliest stages, when removing amyloid can hopefully make a difference in Alzheimer’s trajectory, said Biogen Group Executive Vice President and Chief Medical Officer Alfred Sandrock, who led the research and press conference.

Aducanumab is an antibody, a natural substance the body produces to fight disease. The compound was derived from healthy older people who had not developed Alzheimer’s, under the presumption that they carried some kind of protective factors in their immune systems. It is still not completely clear how aducanumab works, although the study shows it targets amyloid in the brain but not in the bloodstream. The hypothesis suggests antibodies that attack amyloid in the bloodstream get sidetracked and never make it into the brain. By focusing on brain amyloid, aducanumab seems to be able to cross into the brain to reach its target, researchers said at the press conference.

In the two larger studies participants will start on a lower dose to minimize their risk of ARIA, which is more likely to occur early in treatment, and people who carry at least one copy of the APOE ε4Alzheimer’s risk gene, who are more vulnerable to ARIA, will probably remain on a lower dose, according to Salloway.

Participants must have evidence of excessive amounts of amyloid in their brains, as shown in a PET scan, before being allowed into the study. This should help avoid a problem that may have doomed earlier drug trials. Those trials failed in part, researchers think, because they included too many people without excessive amyloid in their brains and must therefore have had a form of dementia other than Alzheimer’s. Earlier trials are also believed to have failed because they tested patients whose disease was too advanced and the damage irrevocable. In contrast, aducanumab is being tested in patients with only very early evidence of disease.

Others in the Alzheimer’s field expressed enthusiasm this week for the paper and the ongoing study of aducanumab. “The results are very impressive and very encouraging,” says Rudolph Tanzi, a neurologist at Harvard University and a longtime leader in Alzheimer’s research. “The fact is [the authors are] the first ones to show some level of proof that an anti-amyloid therapy is a way to treat or prevent Alzheimer’s.”

If the drug performs well in the larger trials, Tanzi says he expects it could be used in people in their 40s and 50s who are starting to show the first evidence of amyloid buildup. Clearing out amyloid then and keeping levels low with another type of drug that Tanzi is working to develop might prevent them from ever having Alzheimer’s, he says.

James Hendrix, director of global science initiatives for the Alzheimer's Association, also praised the trial, saying he was impressed with its design as well as its results. He said the study also shows how crucial it is for people to volunteer for Alzheimer’s research studies, to help better understand the disease and how to treat it. Because of the stigma surrounding Alzheimer’s, researchers typically struggle to find enough volunteers to fill studies, he says, adding that the Alzheimer’s Association offers information on ongoing trials on its Web site.

Alzheimer’s trial supports β amyloid origin of disease

Results from an Alzheimer's drug trial that targets β amyloid plaques (yellow) in the brain are raising cautious hopes.

selvanegra/iStockphoto

By Emily Underwood

Despite some of the headlines that may speed around the internet today, there is still no cure for Alzheimer’s disease, a degenerative brain disease that causes memory loss and dementia. Pharmaceutical companies have sunk billions of dollars into drugs aimed at preventing or reducing the disease’s hallmark plaques, abnormal brain deposits of a protein fragment called β amyloid, but a long list of failed clinical trials has led many to question that strategy. Now, newly published results from a closely watched clinical trial are being hailed as a big win by some in the Alzheimer’s treatment field. The trial data hint that an anti–β amyloid antibody drug called aducanumab warded off cognitive decline in people diagnosed with early Alzheimer’s. But the trial, an early test of the antibody’s safety, is still too small to prove conclusive, leading many others to caution against false hope.

Nearly all the data from new study, published today in Nature, have been publicly presented before at conferences such as the 2015 Alzheimer’s Association meeting in Washington, D.C. This is the first time the results have been written up in a peer-reviewed journal, however, providing a “coherent, comprehensive, carefully vetted presentation of the data,” says neurologist Stephen Salloway of Brown University, one of the study investigators. “This is first time that a β amyloid–lowering drug is associated with a potential clinical benefit.”

Pharmaceutical companies and academic researchers racing to develop anti–β amyloid drugs fervently hope that a fundamental misunderstanding of Alzheimer’s disease is not at the root of past clinical failures. To troubleshoot potential glitches, they’re trying many β amyloid–targeting strategies, from preventing its buildup and removing existing clumps to giving the drugs earlier in the disease. Aducanumab, an antibody made by the pharmaceutical company Biogen, binds to and clears clumps of β amyloid from the brain like many other antibodies that have been tested. But its origin is unique: It was derived from healthy older people who may have some natural resistance to Alzheimer’s disease, Salloway says.

In the yearlong clinical trial, 165 participants with mild cognitive impairment or dementia from Alzheimer’s took either a 1-, 3-, 6-, or 10-mg/kg dose of aducanumab once a month, or a placebo. After 54 weeks, positron emission tomography brain scans revealed that those who had received the drug had fewer β amyloid deposits; the higher the dose, the greater the reduction in β amyloid. That represents a major breakthrough, says Robert Vassar, a neuroscientist at the Northwestern University Feinberg School of Medicine in Chicago, Illinois. “This is a remarkable therapeutic achievement and a tremendous advance for the field.”

More tantalizing, the new trial also produced some indications of a cognitive benefit. Participants who took the largest 10-mg dose showed less decline on one of two memory tests than those receiving lower doses, or the placebo.

Troublingly, however, 40 patients dropped out of the trial midway—half because of adverse side effects such as small hemorrhages and brain swelling. The side effects were more common at higher doses. That has been a persistent problem for those trying to target β amyloid using immunotherapies—a β amyloid vaccine trial many years ago was halted because it triggered dangerous brain inflammation.

Overall, Alzheimer’s researchers are urging caution about the new drug results—even those who are co-authors on the paper. The study was “grossly underpowered” to determine whether cognition was actually better in people who took aducanumab, or a statistical fluke, notes David Knopman, a neurologist at the Mayo Clinic in Rochester, Minnesota, and another trial investigator. Two much larger, 18-month-long phase III trials are now in progress to determine whether the memory benefits hold up in bigger groups—the point at which many other promising Alzheimer’s drugs have failed. 

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