Experts temper hope for new FDA-approved Alzheimer’s drug

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When U.S. authorities approved a new Alzheimer’s drug early in January, Howard Chertkow felt a sense of déjà vu.

In 2021, Dr. Chertkow, the scientific director of the Canadian Consortium on Neurodegeneration and Aging, and his colleagues had warned Health Canada that an Alzheimer’s disease medication approved in the U.S. called aducanumab did not show sufficient clinical benefit, and could, in fact, have detrimental effects for patients. Although many Canadians were eager to receive aducanumab, the drugmaker later withdrew its submission for Health Canada approval.

Then, just a few months later, a new drug, lecanemab, was granted accelerated approval by the U.S. Food and Drug Administration on Jan. 6 – raising some similar concerns.

“This time around, it’s somewhat different and somewhat the same,” said Dr. Chertkow, a senior scientist at Toronto’s Baycrest academic health sciences centre.

Lecanemab, marketed under the brand name Leqembi, is the second Alzheimer’s drug to receive U.S. regulatory approval in two decades. Like aducanumab, it targets amyloid beta, which are sticky protein fragments that accumulate in the brain. And, similarly, some experts are tempering the hope it brings to patients with caveats.

Both drugs are designed to remove amyloid beta from the brains of patients in early stages of the illness, and are intended to slow decline. They are based on what’s called the amyloid hypothesis, a proposed explanation for Alzheimer’s that suggests the buildup of toxic amyloid plaques eventually causes dementia.

But there are growing doubts about the hypothesis, as some believe amyloid may only be part of the puzzle. For other diseases, the removal of too much of a substance, such as copper in patients with Wilson disease or iron in those with hemochromatosis, eliminates the symptoms and cures the illness, Dr. Chertkow said. But this has not been the case for amyloid and Alzheimer’s disease.

Moreover, the amyloid hypothesis suggests that if people have amyloid in the brain, they get dementia. But this, too, has been challenged by the fact many older people with amyloid in their brains don’t have dementia, Dr. Chertkow said.

Neither aducanumab nor lecanemab cures Alzheimer’s disease, but they may give patients more time.

According to the Alzheimer Society of Canada, an estimated 597,300 Canadians had some form of dementia in 2020, and that number is expected to grow to nearly one million by 2030. Alzheimer’s disease is one of the most common forms of dementia, and while there are drugs available that can help treat the symptoms, they do not reverse or stop the progression of the disease.

The evidence that’s been provided for lecanemab is clearer than it was for aducanumab, in that the drug trials showed clinical benefit, Dr. Chertkow said. But it’s uncertain what that means for patients.

“Will it mean anything noticeable? That’s a big question,” he said, explaining patients may progress from mild to severe dementia in four to five years instead of three to four.

According to a December editorial in the Lancet journal, the difference lecanemab made in clinical trials on a test of the severity of participants’ cognitive and functional symptoms “might not be clinically meaningful.” It also pointed out that some participants given the drug developed a side effect, called amyloid-related imaging abnormalities, or ARIA, which commonly involves temporary brain swelling, although most cases were asymptomatic.

The Lancet said it remains to be seen whether lecanemab is the game-changer some have suggested. For now, it said, the key public health message involves targeting modifiable risk factors for dementia, such as hypertension, smoking, diabetes and obesity.

In an e-mail, a spokesperson for Eisai Co., Ltd., the pharmaceutical company that makes lecanemab, said the drug has not yet been submitted to Health Canada for approval to their knowledge, and had no information about when that might occur.

Biogen Canada Inc. withdrew its submission of aducanumab from regulatory review by Health Canada in 2022, stating that the agency indicated the data provided wasn’t sufficient to support marketing approval in this country.

Cathy Barrick, chief executive of the Alzheimer Society of Ontario, expects that it will take some time for both drugs to go through the approval process in Canada. She said it is encouraging that they have been approved in the U.S, and that it would be disappointing if Health Canada does not approve them eventually.

Even if they only buy patients a little more time, that’s better than nothing, she said, and in spite of their limitations, they provide hope that science is moving in the right direction.

“These are not miracle cures. They do come with some pretty serious side effects. But from what I know, and the people that I talk to who are living with dementia, they just want options.”

Ms. Barrick emphasized the need to prepare for the eventual introduction of Alzheimer’s disease-modifying therapies in Canada. She anticipates that wait times to see a neurologist which are already lengthy, will only increase. The health system needs more dementia specialists and better access to diagnostic tools such as MRIs (magnetic resonance imaging), she said, to be able to get these types of drugs to those who need it. Both lecanemab and aducanumab are administered intravenously and require monitoring.

Cost is another consideration. Eisai said it would set a price for lecanemab at USD$26,500 per patient per year. If it is eventually approved in Canada, the question of whether it should be covered under provincial health plans requires serious debate, Dr. Chertkow said.

“In a single-payer system, it becomes a question of: Is it worth making it accessible to everybody?” he said, adding that Canada needs a framework to address the introduction of Alzheimer’s disease-modifying drugs because there will be more new treatments beyond lecanemab.

Dr. Chertkow said he sees lecanemab as a small step in the right direction. But other potential drugs are in the pipeline, including ones that don’t hinge on the amyloid hypothesis.

The future of Alzheimer’s disease treatment may involve various different therapies for different people, he said.

“There are many other irons in the fire. So I don’t want people to lose hope that this was the best that science can come up with, and that’s it.”