Another major drug candidate targeting the brain plaques of Alzheimer's disease has failed. What's left? | Science

"Futile": it's the devastating label that is now badociated with two highly anticipated clinical trials of a drug that targets β-amyloid, the killer protein fragment of neurons spanning the brains of people with Parkinson's disease. Alzheimer. Aducanumab, a pharmaceutical partner that is developing the drug, at Biogen in Cambridge, Mbadachusetts, and Tokyo, Tokyo, announced today its decision to suspend two ongoing Phase III trials after taking knowledge of the results of a "futility badysis" in which an independent panel found that it was unlikely that the drug would slow cognitive decline as expected. The researchers are wondering what will happen in the anti-amyloid drug trial that remains, or is it time to declare the complete approach, well, futile?

"Amyloid certainly has something to do with Alzheimer's disease – there is too much evidence to reject," says organics chemist Derek Lowe today on his blog In the Pipeline on pharmaceutical industry. (The blog is hosted by Translational medicine sciencewho, like ScienceInsider, is published by AAAS.) "But the situation is clearly more complicated than people expected, because otherwise, all attempts to fight against amyloid … would have produced a minimal clinical benefit."

There was reason to believe that aducanumab could succeed where the antiamyloid drugs of Merck & Co., Eli Lilly and Company and others had failed. The drug is an antibody designed to bind to and eliminate β-amyloid sticky plaques that accumulate around neurons, block their communication and ultimately kill them. And it's clear from a smaller clinical trial that this drug was very effective at cleansing plaques – "that's one of the reasons we're optimistic about this trial," says neurologist Dennis Selkoe of the Brigham and Women's Hospital in Boston, which treats patients enrolled in one of the trials. Studies also suggest that aducanumab can attack the most harmful form of amyloid, called oligomers, that other drugs might have left intact.

In addition, the currently canceled trials on aducanumab, called ENGAGE and EMERGE, were among the first to recruit people with both cognitive impairment and confirmed amyloid plaques in their brains, notes Heather Snyder, Senior Director medical and scientific operations at the Alzheimer's Association. in Chicago, Illinois. It is estimated that between 20% and 30% of patients who had taken anti-amyloid tests had not actually accumulated amyloid, which could explain their failure.

But these benefits could not keep the aducanumab afloat. The company press release gives no indication of what went wrong during the tests, although they note that today's decision is not based on safety concerns. Even though the trials have recruited people with early and mild forms of Alzheimer's, it is possible that the disease is already too advanced for the effects of aducanumab on amyloid clearance can help, says Selkoe.

If this is the case, the most promising trials could be those aimed at preventing Alzheimer's disease in people with no clinical symptoms but with an increased risk of developing dementia. The study on anti-amyloid therapy in the treatment of asymptomatic Alzheimer's disease, due to end in 2020, tests the antibody solanezumab (which had failed in a previous trial sponsored by Eli Lilly) in patients with amyloid accumulation in brain scans, but with no evidence of memory loss. And in the mainstream Alzheimer's Network test, companies and academic institutions have teamed up to test for solanezumab and another amyloid-targeting antibody in people with Alzheimer's disease – causing mutation, but no symptoms. Crenezumab, another failed drug candidate, has also been relaunched in an essay targeting people with Alzheimer's disease who are still in the "preclinical" phase of the disease.

At the same time, other non-amyloid approaches are making their way into clinical trials, including drugs that target the tau protein that accumulates in neurons in the Alzheimer's brain. "It's crucial as we wait for more information on [the aducanumab] to study … that we continue to actively and purposefully pursue multiple candidate goals, "said Richard Hodes, director of the National Institute on Aging in Bethesda, Maryland.

Selkoe plans to put some of his patients into trials of the anti-tart approach once the aducanumab is released from their system. But he is not ready to give up anti-amyloid treatments for patients with mild symptoms, any more than some drug manufacturers. The Swiss drug maker Roche continues to test the gantenerumab antibody after failing it in clinical trials at a lower dose. Biogen and Eisai continue to collaborate on two other anti-amyloid drugs. One of them is BAN2401, an antibody that has not met its primary endpoint in a phase II trial but may still have benefits, say the companies. The other is elenbecestat, a molecule that blocks the production of amyloid. The companies have not yet clarified whether the results of aducanumab would change their plans for testing these two other drugs.

"We must continue to move forward [candidates] in preparation, "says Snyder about the anti-amyloid drugs still being tested. "They are there because that's what science has suggested."