Amyloid gains traction in Alzheimer’s disease treatment debate

The pharmaceutical industry took the idea and started developing drugs to attack amyloid. Until recently, they all failed. Between 2004 and 2021, nearly two dozen drugs have failed clinical trials. With each setback, doubts grew among doctors and scientists about the effectiveness of anti-amyloid drugs.

Late last year, Eisai’s Leqembi became the first drug to clearly show that reducing amyloid could slow Alzheimer’s disease, a progressive form of dementia that affects six million people in the United States. United States and which is one of the main causes of death in the world.

The effectiveness of the drug is modest, but undeniable, doctors say. Patients with early-stage symptoms who received Leqembi for 18 months experienced 27% less cognitive decline than those who received placebos, a timeframe equal to about five months, according to Eisai, who co-developed the drug with Biogen Inc.

“The amyloid hypothesis has basically been proven, it’s not really a hypothesis anymore,” said Dennis Selkoe, professor of neurological diseases at Harvard Medical School and an early proponent of the hypothesis. “The debate now drifts to whether (Leqembi) is effective enough.”

The criticisms remain. They say scientists still don’t know how removing amyloid slows the disease, and that it could be due to side effects such as reducing tangled strands of a protein called tau that’s also found commonly in patients with Alzheimer’s disease.

Newer drugs such as Leqembi are very effective at reducing amyloid – about two-thirds of patients no longer had elevated amyloid after treatment – and yet produce only a minor slowing of Alzheimer’s disease, a said Lon Schneider, an Alzheimer’s disease researcher at the University of Southern California. .

“The clinical change is so small that it’s irrelevant whether the destruction of (amyloid) plaques alters the course of the disease,” Dr. Schneider said. “If the idea was to pop plaque and improve function, then you really haven’t demonstrated that.”

In the past, major drugmakers, including Pfizer Inc.

withdrew from Alzheimer’s disease research following failed studies. Some scientists say the field has focused too singularly on amyloid and needs to reassess its basic assumptions about how to treat the disease.

The amyloid debate intensified following the Food and Drug Administration’s 2021 approval of Aduhelm, an anti-amyloid drug developed by Biogen, in partnership with Eisai. In two large studies, Aduhelm was effective in reducing brain amyloid, but produced mixed results overall, slowing the disease in one study but not the other.

The FDA said that despite uncertainty about its effectiveness, Aduhelm could help patients by targeting amyloid, which it called a key underlying disease process in Alzheimer’s disease.

The endorsement has been criticized by some doctors and scientists, including the American Academy of Neurology, for overstepping the scientific consensus that reducing amyloid will help patients. Several outside experts who had recommended against approval resigned from an FDA advisory committee in protest. Some hospitals refused to administer the drug to patients.

Medicare took the unprecedented step of issuing a general denial of routine coverage for anti-amyloid drugs such as Aduhelm and Leqembi, citing in part the ongoing controversy over the amyloid hypothesis, which it said was still not not proven.

But Leqembi’s data has caused some skeptics to rethink their stance on anti-amyloid drugs, said Sam Gandy, a neurologist at Mount Sinai in New York who criticized Aduhelm’s FDA approval.

“There are skeptics who are closer to believing, who are confident enough that they will use the drug,” said Dr. Gandy, an amyloid researcher who believes the protein is one of multiple factors in gambling in Alzheimer’s disease.

The agency that oversees Medicare officials said it was willing to reconsider coverage policy if it received additional data to answer outstanding questions about anti-amyloid drugs.

David Holtzman, a neurologist at Washington University in St. Louis, said he was skeptical of anti-amyloid drugs because of research showing the protein builds up in the brain decades before anyone does. is diagnosed with Alzheimer’s, in which case it may be too late.

“Because the whole amyloid cascade begins about 20 years before symptoms begin, I didn’t know if it would be too late to remove amyloid this far in the process,” Dr. Holtzman said. “But it seems such that there are clearly effects.”

David Knopman, a Mayo Clinic neurologist, worked on anti-amyloid drug trials for two decades before repeated study failures made him so disappointed with the approach that he argued it should be scrapped. .

“To be frank, reduction (of amyloid) appears to be an ineffective approach, and it’s time to focus on other targets to advance Alzheimer’s disease therapeutics,” he wrote. in a 2019 editorial in the New England Journal of Medicine.

Dr. Knopman said he began to change his mind in early 2021, when Eli Lilly & Co. reported that its anti-amyloid drug, donanemab, significantly reduced brain amyloid in patients with dementia. Alzheimer’s disease and slowed their clinical decline. Lilly expects to have results from a larger Phase 3 study of the drug this year.

Eisai’s Leqembi phase 3 study and, ironically, the failure of a Roche Holding AG

A drug study late last year confirmed that removing amyloid could help treat Alzheimer’s disease, Dr Knopman said. Roche said its drug gantenerumab failed in two studies because it did not remove enough amyloid as the researchers predicted to achieve clinical benefit.

“Together, the studies gave a very clear picture of the degree of amyloid reduction needed to enter a zone of success,” Dr. Knopman said.

Still, Dr Knopman said Leqembi’s success is only a partial vindication of the amyloid hypothesis, which in the minds of many doctors promised to stop Alzheimer’s disease or even reverse it. some symptoms.

“The hope was that removing amyloid would have the same therapeutic benefits as vitamin C for scurvy – you introduce a treatment and you get a cure,” Dr. Knopman said. “The thing is, reducing amyloid doesn’t come close to that.”

Other anti-amyloid drugs are on the horizon, including Lilly’s donanemab, as well as drugs aimed at clearing tau tangles, reducing inflammation and improving neuroplasticity. Current anti-amyloid drugs are so good at removing the protein that stronger drugs are unlikely to be more effective, Dr. Knopman said.

“We may have reached the limit of what amyloid reduction can do,” Dr. Knopman said. “So we need to think about alternatives, such as treating people earlier, looking at combination therapies, and really looking at alternative targets.”

Write to Joseph Walker at joseph.walker@wsj.com

Corrections & Amplifications
A photo accompanying this article shows a series of MRI scans of the brain of a patient with Alzheimer’s disease. An earlier version of the article incorrectly stated that the scans were over time. (Corrected February 27)