An late-stage trial of an Alzheimer’s drug that will deliver results in a matter of weeks is shaping up to be a turning point in a three-decade quest to show that removing the brain’s sticky amyloid plaques can slow the disease.
The phase 3 trial is 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 clear plaques known as amyloid beta that are at the center of an increasingly acrimonious scientific debate about the causes of Alzheimer’s.
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. It would be encouraging for Eli Lilly and Roche, which are running trials of similar drugs that could generate tens of billions of dollars in sales if they are shown to slow the progression of Alzheimer’s disease.
But scientists say the disappointing test results would deal a significant blow to the so-called amyloid hypothesis, the idea that removing clumps of toxic cells that clump together in the brain can slow the rate of cognitive decline in patients.
Alberto Espay, a professor of neurology at the University of Cincinnati, said some researchers had become too attached to the amyloid hypothesis, which has been tested in dozens of studies that have failed to provide conclusive evidence that plaque removal slows the cognitive impairment.
“We have run into a dogma,” he said. “And it’s very difficult to test new ideas when the overall theme of funding is centered around the idea that removing amyloid should be the only way forward.”
The disappointing results could also act 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 displaced by Big Pharma’s focus on amyloid.
The amyloid hypothesis is the most proven of the many theories about the causes of Alzheimer’s, ranging from inflammation of some types of brain cells to the presence and formation of various proteins in the brain. It has been the focus of more than a fifth of the more than 2,000 clinical trials related to the disease as of 2019.
The failed launch last year of Biogen’s aducanumab, the first amyloid-stripping drug to gain approval and the first new treatment for the disease in nearly two decades, has only served to heighten doubts about similar drugs.
Aducanumab, which is sold under the brand name Aduhelm, was fast-tracked by US regulators despite doubts about its efficacy and the strength of two late-stage clinical trials that supported its approval. Widespread skepticism among doctors deepened further when the company priced the treatment at $56,000 a year, a move that also sparked backlash among politicians and lawmakers.
In April, US authorities dealt Aduhelm a serious blow by severely restricting reimbursement from government-funded health plans, a measure that limits their use to a few thousand people taking part in clinical trials. Any similar amyloid treatment approved under the FDA’s fast-track procedure would face the same restrictions, a hurdle Eisai acknowledges complicates lecanemab’s approval process.
“Yes, I admit it raises the bar. Hence the trial design. . . it’s so important,” Ivan Cheung, Eisai’s US CEO, said in an interview.
In a bid to win the public’s trust, Eisai is conducting one of the largest trials ever conducted on an Alzheimer’s drug, enrolling 1,795 patients in the early stages of the disease. He has also sidelined his partner Biogen by assuming what Cheung describes as “final decision-making authority” as the drug moves through the regulatory process.
Eisai aims to match or improve on the results of an earlier trial that showed that giving patients a 10-mg dose of lecanemab every two weeks for 18 months can reduce the rate of cognitive decline by 26 percent, compared with those who received a placebo.
It uses the Clinical Dementia Rating scale to measure dementia symptoms in patients in six categories, including memory, judgment, and problem solving.
Critics argue that this scale is an imprecise mechanism and question whether it is worth approving amyloid drugs that can only slightly slow the rate of cognitive decline and can cause life-threatening side effects.
But patient groups like the Alzheimer’s Association say even relatively small delays in disease progression can bring significant benefits to people who are terminally ill.
“It could mean six more months at that stage where you can maintain your independence, enjoy your family and attend a wedding,” said Maria Carrillo, chief science officer for 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 findings from clinical trials.
Eisai said that after the Aduhelm controversy, a result showing a slowdown rate below 25 percent could “trouble” his FDA application for accelerated approval of lecanemab, a process that is due to conclude in January.
Under this fast-track process, the FDA could approve the drug on the basis that it reduces amyloid plaque and is only “reasonably likely” to predict clinical benefit. Those were the same criteria used to approve Aduhelm, a controversial decision that prompted the resignation of three members of a committee that advises 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 passing judgment. “Everything must be based on facts. . . I hope we have a fair debate,” he said.
For Biogen, success could help rebuild its tarnished reputation after the disastrous launch of Aduhelm, which led to a $1 billion cost cut, the departure of its CEO and research by various US government agencies.
Ronald Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center, said that if the lecanemab trial was “totally negative,” then it wouldn’t be good for the “amyloid hypothesis.” But he said he wouldn’t bury the theory entirely because of upcoming results from late-stage trials of three drugs from Roche and Eli Lilly.
Petersen said his best guess was that one of the trials would show a positive clinical impact, albeit modest in magnitude.
“This would give us a foot in the door for treatments because, ultimately, a combination therapy will be needed in the future to have a voila kind of effect,” he said.
“If all four of these [trials] they don’t really show evidence of any kind of clinical impact. . . it can only suggest that we should probably be looking elsewhere for clinical targets,” she added.