Henry Magendantz, a participant in the Aduhelm clinical trial, finishes receiving an infusion of the drug at Butler Hospital in Providence, R.I. on May 27, 2021.Kayana Szymczak/The New York Times News Service
Ever since U.S. officials approved a new drug for Alzheimer’s disease last month, Vancouver neurologist Robin Hsiung has been fielding questions from patients eager to know how and when they can get it.
Their excitement for the drug has been understandable. Aducanumab, developed by pharmaceutical company Biogen and marketed as Aduhelm, is the first Alzheimer’s drug the U.S. Food and Drug Administration has approved in nearly two decades, and it’s the first aimed at altering the course of the disease. While existing medications help treat the symptoms, temporarily improving memory or reducing confusion, they don’t halt the illness. Aducanumab, by contrast, is intended to tackle a possible cause of Alzheimer’s disease and slow patients’ decline.
But Dr. Hsiung, who has been involved in trials for the drug, is having to rein in his patients’ expectations. Aducanumab doesn’t yet have Health Canada’s approval – a necessary step before patients on this side of the border can access it. And not everyone is convinced Canadian authorities should follow the FDA’s lead.
While some doctors and patients herald aducanumab as a long-awaited and much-needed beacon of hope for the growing number of Canadians with the devastating neurodegenerative disease, others say the potential benefits of the drug don’t justify the costs and challenges it presents.
Dr. Hsiung, an associate professor at the University of British Columbia and president of the non-profit Consortium of Canadian Centres for Clinical Cognitive Research, is among those with reservations about the drug. He said many of his colleagues agree with him. “We all feel the FDA approval is premature,” he said. “We do not disagree that it may have potential benefits, but I don’t think the current data is strong enough to have an approval.”
According to a Biogen Canada spokesperson, Health Canada accepted the company’s submission for aducanumab in June. The health regulator is now expected to review the submission before deciding whether to approve the drug.
Aducanumab’s road to FDA approval was a rocky and unusual one. In 2019, Biogen halted its two phase III trials for the drug when interim data suggested they were unlikely to succeed.
The company later revived the project, after an analysis of the final dataset found one of the two trials showed a slowing of patients’ clinical decline – but the second trial, which was meant to be identical, did not.
But then further analysis showed that some patients in the latter trial did, in fact, show similar slowing of the disease, said Sharon Cohen, a neurologist and director of the Toronto Memory Program, one of the international trial sites for aducanumab. Those second-trial patients had all received higher doses of the drug for longer durations than others in their study group, she said, meaning the difference between the two trials could be accounted for in large part by differences in dosing.
The FDA’s approval has been controversial. Several members of an FDA advisory committee resigned in protest, saying there wasn’t enough evidence to support green-lighting aducanumab. The U.S. authority also drew scrutiny for initially not specifying which Alzheimer’s patients the drug was for. In an update earlier this month, it narrowed the group to patients in early stages of the disease.
Still to be resolved is the question of how well the drug works. The FDA is requiring that Biogen complete a post-approval trial to verify its clinical benefit.
Aducanumab, which is administered by intravenous infusion, clears a precursor protein called amyloid beta from the brain. Amyloid beta clumps together to form amyloid plaques, one of the hallmarks of Alzheimer’s disease. For decades, many researchers believed a buildup of amyloid was the main cause of the disease, and that reducing the amyloid burden in the brain would stop or slow the disease from progressing.
But there is growing doubt as to whether amyloid causes Alzheimer’s disease. Many researchers think the protein may be partly responsible, but not the entire cause, said Howard Chertkow, chair in cognitive neurology and innovation at Baycrest, a geriatric hospital and long-term care centre in Toronto.
Dr. Chertkow said the data released so far on aducanumab do not meet several of Health Canada’s criteria for drug approval. To obtain Canadian approval, there should be a dose response – that is, a higher dose should produce a greater effect. But with aducanumab, there isn’t a clear dose response, he said.
And the drug’s effect size should be large enough to be clinically detectable. In other words, Dr. Chertkow explained, “People should be able to tell that patients who are treated are doing better than patients who are not treated. And that’s not clear to me at all in the data that’s been presented.”
And there should be reproducibility between trials, he added.
Dr. Chertkow and others also say Canada simply isn’t ready for the drug. In a meeting in June, he and other prominent members and leaders of Canada’s dementia research organizations drafted a statement, which they expect to release soon, to outline their position and provide guidance to Health Canada about aducanumab.
Among the Canadian dementia researchers’ concerns is the fact that most of the medical care for the more than half a million older Canadians currently living with dementia is provided by family doctors, most of whom are not equipped to administer intravenous infusions of aducanumab. Meanwhile, specialized clinics – which have the appropriate equipment and expertise – already have lengthy wait lists, Dr. Chertkow said.
And there are challenges to identifying which patients to put on the drug. Currently, the only way to determine whether a patient has an accumulation of amyloid in their brain is to either perform a spinal tap or a positron emission tomograph (PET) scan, which is costly and not widely available, Dr. Hsiung said.
There are also obstacles to monitoring those treated with the drug. About 30 per cent of people who take aducanumab develop a side effect called amyloid-related imaging abnormalities, or ARIA, which commonly involves temporary brain swelling. The symptoms of ARIA are hard to detect, Dr. Hsiung said, and the only way to tell whether someone has it is to do a magnetic resonance imaging (MRI) scan.
Another major issue is whether Canada’s health care system can afford the drug, Dr. Hsiung said. He noted that some estimate aducanumab will cost US$56,000 per year, per patient – and doctors and researchers don’t know how long to keep patients on the drug.
To combat Alzheimer’s disease, Dr. Chertkow said there are easier and cheaper ways. For instance, managing hearing loss in midlife helps lower the risk of dementia, he said.
“If we gave everyone in Canada hearing aids who needs them, that would have far greater benefit, at far less of a cost than giving 100 or 200 thousand people in Canada a drug like aducanumab,” he said. “We’re talking about savings of billions of dollars to get the same benefits.”
Dr. Chertkow said he also worries that the U.S. approval of aducanumab will slow the development of better drugs. The moment a drug is released to the public, it becomes harder to recruit participants for other clinical trials, he said.
And there’s a danger that aducanumab lowers the standards for approving other drugs, he said. “We want a drug that hits the home run, and this is a drug that barely makes it onto first base. I mean, how low do you want to set the bar?”
Dr. Cohen sees it differently. As the first approved drug of its kind, aducanumab provides a foundation upon which the medical field can build, she said.
While aducanumab may be expensive, so is Alzheimer’s disease, Dr. Cohen said. As the disease progresses, the cost to families and the health care system increases. The expenses include emergency department visits and nursing homes, and family members who spend time caring for patients may lose wages if they have to take time off from work.
“If you can keep people in the mild stage, you can have a lot of cost savings by a treatment that slows down disease,” Dr. Cohen said.
Trial data showed a 40-per-cent slowing of the disease in terms of participants’ day-to-day function, which is “a very substantial amount,” she added.
Donald MacIntosh, 68, one of Dr. Cohen’s patients, was part of the placebo group in one of the phase III aducanumab trials. For the past year, the retired Toronto lawyer has been receiving the drug as part of a study to provide long-term data.
It will be “a game-changer” if aducanumab can give him a few more years in his present condition, he said.
Mr. MacIntosh said patients like him had little to feel optimistic about until last month’s FDA approval, and he now hopes Health Canada will do the same.
“It provides all the hope in the world for those of us who are inflicted with this insidious disease,” he said.
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