NATIONAL INSTITUTE ON AGING/NATIONAL INSTITUTES OF HEALTH
“Futile”—that’s the devastating label now attached to two highly anticipated clinical trials of a drug that targets β-amyloid, the neuron-killing protein fragment littering the brains of people with Alzheimer’s disease. Biogen in Cambridge, Massachusetts, and Eisai in Tokyo, the pharmaceutical partners developing the drug, called aducanumab, today announced their decision to halt a pair of ongoing phase III trials after seeing the results of a “futility analysis,” in which an independent committee found that the drug was unlikely to slow cognitive decline as intended. This latest blow to the β-amyloid approach has left researchers asking: Do any of the remaining antiamyloid drug trials have a better chance, or is it time to declare the whole approach, well, futile?
“Amyloid definitely has something to do with Alzheimer’s—there’s far too much evidence to dismiss,” organic chemist Derek Lowe wrote today on his drug industry blog In the Pipeline. (The blog is hosted by Science Translational Medicine, which, like ScienceInsider, is published by AAAS.) “But the situation is clearly more complicated than people have hoped, because otherwise, all the attempts to address amyloid … would have yielded some tiny bit of clinical benefit.”
There were reasons to think that aducanumab might succeed where antiamyloid drugs from Merck & Co., Eli Lilly and Company, and others had failed. The drug is an antibody designed to bind to and eliminate sticky β-amyloid plaques that build up around neurons, block their communication, and, ultimately, kill them. And it was clear from a smaller clinical trial that this drug was very effective at clearing plaques—“that’s one of the reasons we were sanguine about this trial,” says neurologist Dennis Selkoe of Brigham and Women’s Hospital in Boston, who treats patients who were enrolled in one of the trials. Studies also suggest aducanumab can attack the most noxious form of amyloid—so-called oligomers—that other drugs may have left untouched.
What’s more, the now-canceled aducanumab trials, called ENGAGE and EMERGE, were among the first to recruit people who had both cognitive impairment and confirmed amyloid plaques in their brains, notes Heather Snyder, senior director of medical and scientific operations at the Alzheimer’s Association in Chicago, Illinois. It’s estimated that 20% to 30% of patients in previous trials of antiamyloid drugs didn’t actually have significant amyloid buildup, she says, which could help explain their failure.
But those advantages couldn’t keep aducanumab afloat. There’s no indication from the companies’ press release of what went wrong in the trials, though they note that today’s decision wasn’t based on safety concerns. Even though the trials recruited people with mild, early forms of Alzheimer’s, it’s possible that the disease was already too advanced for the amyloid-clearing effects of aducanumab to help, Selkoe says.
If that’s the case, the most promising trials may be those aimed at preventing Alzheimer’s in people who have no clinical symptoms but are at increased risk of developing dementia. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study, set to conclude in 2020, is testing the antibody solanezumab (which failed in a previous trial sponsored by Eli Lilly) in people who show amyloid buildup in brain scans but have no signs of memory loss. And in the Dominantly Inherited Alzheimer Network trial, companies and academic institutions have teamed up to test solanezumab and another amyloid-targeting antibody in people with an Alzheimer’s disease—causing mutation but no symptoms. Another failed drug candidate, crenezumab, has also been revived in a trial aimed at people with an Alzheimer’s mutation who are still in the “preclinical” phase of disease.
Meanwhile, other, nonamyloid approaches are making their way through clinical testing, including drugs that target the protein tau that builds up inside neurons of the Alzheimer’s brain. “It’s critical as we await more information about [the aducanumab] study … that we continue to actively and broadly pursue multiple candidate targets,” says Richard Hodes, director of the National Institute on Aging in Bethesda, Maryland.
Selkoe plans to put some of his patients into trials of the antitau approach once the aducanumab is out of their systems. But he isn’t ready to give up on antiamyloid treatments for patients with mild symptoms—and neither are some drug companies. Swiss drugmaker Roche continues to test the antibody gantenerumab after it failed in trials at a lower dose. Biogen and Eisai continue to collaborate on two other antiamyloid drugs. One is BAN2401, an antibody that failed to meets its primary endpoint in a phase II trial but may yet have benefit, the companies claim. The other is elenbecestat, a molecule that blocks amyloid production. The companies have not yet said whether the aducanumab results change their plans for testing these other two drugs.
“We must continue to advance [candidates] that are in the pipeline,” Snyder says of the antiamyloid drugs still in trials. “They’re there because that’s what science has suggested.”
Source: Science Mag