A late-stage trial of an Alzheimer’s drug intended to generate results within weeks is shaping up to be a pivotal moment in a three-decade quest to prove that clearing sticky amyloid plaques from the brain can slow down the disease.
The phase 3 trial is being led by Eisai, a Tokyo-based pharmaceutical company that has partnered with US biotech Biogen to develop lecanemab. Previous studies have suggested that monoclonal antibody treatment can eliminate the plaques known as beta-amyloid which are at the center of an increasingly acrimonious scientific debate about the causes of Alzheimer’s disease.
A positive result could lead to the approval of a new drug for a disease that affects 50 million people worldwide and has no known cure. That would be encouraging for Eli Lilly and Roche, which are conducting trials of similar drugs that could generate tens of billions of dollars in sales if they are found to slow the progression of Alzheimer’s disease.
But scientists say disappointing test results would be a blow to the so-called amyloid hypothesis, the idea that eliminating clumps of toxic cells that bind in the brain can slow the rate of cognitive decline in people reached.
Alberto Espay, professor of neurology at the University of Cincinnati, said some researchers have become far too attached to the amyloid hypothesis, which has been tested in dozens of studies that have failed to provide conclusive evidence that the amyloid Plaque removal slows cognitive decline.
“We ran into a dogma,” he said. “And it’s very difficult to test new ideas when the overall funding theme is centered around the idea that eliminating amyloid should be the only way forward.”
Disappointing results could also serve as a catalyst for a shift in Alzheimer’s research funding, with some scientists arguing that promising areas of study and potential treatments have been crowded out by Big Pharma’s focus. on amyloid.
The amyloid hypothesis is the most tested of many theories about the causes of Alzheimer’s disease, which range from inflammation of certain types of brain cells to the presence and formation of various proteins in the brain. It was the subject of more than a fifth of more than 2,000 clinical trials linked to the disease in 2019.
Last year’s botched launch of Biogen’s aducanumab – the first anti-amyloid drug to be approved and the first new treatment for the disease in nearly two decades – has only heightened doubts about similar drugs .
Aducanumab, which is sold under the brand name Aduhelm, received the accelerated green light from US regulators despite questions about its efficacy and the robustness of two late-stage clinical trials that backed up its approval. Widespread skepticism among clinicians was further heightened when the company priced the treatment at $56,000 a year, a move that also sparked a backlash among politicians and policymakers.
In April, US authorities dealt a crippling blow to Aduhelm by severely restricting reimbursement by government-funded health plans, a move that limits its use to a few thousand people participating in clinical trials. Any similar amyloid treatment approved under the FDA’s fast track would face the same restrictions, a hurdle that Eisai says complicates lecanemab’s approval process.
“Yes, I admit that it raises the bar. This is why the design of the trial . . . is so important,” Ivan Cheung, Eisai’s US Managing Director, said in an interview.
In an effort to build public confidence, Eisai is conducting one of the largest trials ever of an Alzheimer’s drug, enrolling 1,795 patients in the early stages of the disease. It also sidelined its partner Biogen by assuming what Cheung describes as “final decision-making authority” as the drug progresses through the regulatory process.
Eisai aims to match or improve on the results of a previous trial which showed that giving patients a 10mg dose of lecanemab every other week for 18 months can slow the rate of cognitive decline by 26%, compared to those who received a placebo.
It uses the Clinical Dementia Rating Scale to measure symptoms of dementia in patients across six categories, including memory, judgment and problem solving.
Critics claim that this scale is an imprecise mechanism and question whether it is worth approving amyloid drugs that can only slightly reduce the rate of cognitive decline and can cause life-threatening side effects.
But patient groups such as the Alzheimer’s Association say even relatively small delays in disease progression can provide significant benefits for people with terminal illness.
“It could mean six more months at this point where you can maintain your independence, enjoy your family and attend a wedding,” said Maria Carrillo, scientific director of the Alzheimer’s Association.
Despite the controversy over Aduhelm, Carrillo said it was an encouraging time for Alzheimer’s disease research, pointing to increased government funding and key clinical trial results.
Eisai said that following the Aduhelm controversy, a result showing a slowdown rate of less than 25% could “disrupt” his application for fast-track FDA approval of lecanemab, a process that is due to conclude in January.
Under this expedited process, the FDA could approve the drug on the basis that it reduces amyloid plaque and is only “reasonably likely” to predict clinical benefit. These are the same criteria used to approve Aduhelm, a controversial move that led to the resignation of three members of a committee advising the FDA on the drug.
Cheung said he was confident the lecanemab trial would be a success and asked amyloid skeptics to study the data before making a judgment. “Everything must be based on facts. . . I hope we will have a fair debate,” he said.
For Biogen, the success could help rebuild its tarnished reputation after the disastrous launch of Aduhelm, which sparked $1 billion in cost cuts, the departure of its chief executive and investigations by several US government agencies.
Ronald Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center, said if the lecanemab trial was an “absolutely negative” it wouldn’t be good for the “amyloid hypothesis.” But he said that would not completely bury the theory because of upcoming results from late-stage trials of three drugs from Roche and Eli Lilly.
Petersen said his best estimate was that one of the trials would show positive clinical impact, albeit of modest magnitude.
“It would give us a foot in the door for treatments, because ultimately it will take combination therapy to have a so kind of effect,” he said.
“If these four [trials] really show no evidence of any clinical impact. . . it may just suggest that we should probably look elsewhere for clinical targets,” he added.
