Alzheimer’s cure elusive as promising drugs fall short
In February, pharmaceutical companies Roche and Eli Lilly announced two experimental drugs they had developed for Alzheimer’s disease had failed in clinical trials. Roche’s drug, gantenerumab, and Eli Lilly’s solanezumab joined more than 100 other potential Alzheimer’s drugs that have flopped, including aducanumab, a much-heralded drug from Biogen.
In March 2019, Biogen announced it had halted two clinical trials of the drug early after an interim analysis showed they weren’t working, but the company has since changed course, saying it intends to seek approval from the Food and Drug Administration based on a new analysis of the data.
A lot is riding on Biogen’s experimental drug. If approved, it “would be the first disease-modifying drug ever,” said George Vradenburg, chairman and co-founder of the advocacy group UsAgainstAlzheimer’s. The last time a drug was approved specifically for Alzheimer’s was 2003, and since then, the Alzheimer’s drug pipeline has spit out a bunch of duds.
More than 200 promising leads have fallen through in the past decade. There has been an ongoing search for Alzheimer’s drugs since the 1990s, but “the long and short of it is that it’s not been successful,” says Lon Schneider, an Alzheimer’s researcher at the University of Southern California’s Keck School of Medicine.
These failures aren’t for lack of trying. Instead, they are evidence the disease and its causes are much more complex than researchers first appreciated. “We were blind to this [complexity]. Things looked simpler than they really are,” said Richard Hodes, director of the National Institute on Aging.
Dementia, confusion and personality changes are hallmark symptoms of Alzheimer’s, but the disease can be definitively diagnosed only by examining the brain in an autopsy. The brains of people with Alzheimer’s show a loss of nerve cells and the connections between them along with signature plaques and tangles of proteins called beta amyloid and tau.
Until relatively recently, the search for a drug largely centered around the idea that Alzheimer’s develops and progresses in a specific pattern.
Toxic plaques of beta amyloid clump together between neurons in the brain. As these accumulate, they’re accompanied by a buildup of tangled masses of tau inside neurons. These changes are accompanied by inflammation and cell death in the brain. Many drug candidates have aimed to clear or disarm beta amyloid, under the logic that eliminating amyloid plaques would halt or reverse the process and thus Alzheimer’s itself.
Biogen’s drug is just one of many designed to clear beta amyloid, and so when its trials were halted last spring, it initially seemed like another repudiation of the “amyloid hypothesis.”
But interest was reignited when Biogen announced in October that it had reanalyzed the data from the two halted clinical trials of aducanumab and found that patients receiving the highest doses of the drug seemed to experience less cognitive decline than the placebo group in one of the trials. If aducanumab really works, it would be a triumph for the amyloid approach.
“The Biogen results are the most exciting results we’ve seen in a while,” said Howard Fillit, executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation.
Others in the field remain skeptical, however.
The benefits were found in only one of the two trials, and the company’s analysis broke “all the rules, really, about how you analyze data and report it,” University College London Alzheimer’s researcher Robert Howard told the journal Science.