It has been heralded in news reports as a “breakthrough”, a “turning point” and a “game changer” for Alzheimer’s disease. Some experts have gone so far as to call the drug, donanemab, the “beginning of the end” for the debilitating condition.
Pharmaceutical company Eli Lilly released data from a clinical trial in May 2023 they said that donanemab slowed cognitive and functional decline in people with early symptomatic Alzheimer’s disease by 35% over 18 months.
The findings saw the head of Alzheimer’s Research UK and other experts call on drug regulators to quickly approve the treatment for use in patients.
But despite reports the US drug regulator would approve donanemab “any day”.instead, the Food and Drug Administration (FDA) announced on March 8 that it had postponed its decision.
The FDA said it wants an independent panel to further examine data on the safety and effectiveness of donanemab, with a decision now expected later in 2024. British, European and Australian regulators are also still assessing the drug.
In a statement, Eli Lilly executive vice president Anne White said: “We are confident in donanemab’s potential to provide very meaningful benefits to people with early symptomatic Alzheimer’s disease.”
“It was unexpected to learn that the FDA would convene an advisory committee at this stage in the review process, but we look forward to the opportunity to [trial] results and put donanemab’s strong efficacy in the context of safety,” she said. “We will work with the FDA and the stakeholders in the community to make that presentation and answer all questions.”
Dr Timothy Daly, a dementia researcher at the Sorbonne University in Paris, says this delay comes as no surprise to him.
He says the benefits of donanemab, and similar drugs, including aducanumab and lecanemab, are harder to quantify than their potential harms.
“Underneath this narrative of drug success, there are some very strong side effects,” Daly told Guardian Australia.
These are a type of medicine known as novel monoclonal antibodies, and they target amyloid proteins in the brain. Many researchers believe the buildup of these proteins contributes to Alzheimer’s disease.
The drugs have been shown to reduce amyloid levels in the brain. But about three-in-10 people who took lecanemab or donanemab in clinical trials developed a condition known as amyloid-related imaging abnormalities, abbreviated ARIA, a condition that can cause brain swelling or bleeding.
“Most of the time it seems to be minor, without any symptoms, and follow-up scans show it seems to have resolved,” said Dr Sebastian Walsh, a public health doctor who researches dementia risk reduction at the University of Cambridge in the UK. .
“In a small percentage of participants it appears to be much more severe, and there have been some deaths – particularly for those on blood thinners.”
Some trial participants also experienced brain shrinkage — and its long-term effects are unknown.
‘This is pure speculation’
In the donanemab trial, patients who received the drug dropped an average of 10 points on a 144-point scale that combined cognitive and functional scores. The placebo group that did not receive the drug dropped 13 points.
These data were used by researchers to state that the drug slowed cognitive and functional decline by “more than one third” and offered people “extra months” or “up to one year of life” without further disease progression.
Walsh says efforts to translate clinical data into terms more meaningful for people to understand mean the effects of the drug are exaggerated in media reports.
“While it’s understandable that people want to think of other ways to present these numbers, they still need to be scientifically valid,” he says.
“Those who have reported that it is ‘an extra six months at higher function’ are in my opinion scientifically on shaky ground. The trials didn’t measure the recognition of a loved one, the ability to drive, any of these things – extrapolating in this way is not really justified by the evidence we have. This is pure speculation.”
A professor of neurology at the Radboud University Medical Center in the Netherlands, Edo Richard, told the news channel Al Jazeera the drugs “clearly clear” amyloid proteins from the brain “very successfully”.
But a reduction in amyloid proteins does not necessarily lead to a slowing of cognitive decline, he said.
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Research into the disease dating back more than 25 years has found that amyloid proteins are present in the brains of people with dementia. But they are also found in people who do not have dementia, and who never go on to develop it, Richard told Al Jazeera.
While many drugs tested in the past have reduced amyloid levels, donanemab, aducanumab and lecanemab appear to be the first to also lead to a change in cognitive decline. But Richard claimed that change was “statistically significant but clinically irrelevant”.
When the FDA approved aducanumab in 2021, three FDA advisory committee members who had advised against its approval because of what they believed was a lack of efficacy data resigned. One of the people who resigned describe it as “probably the worst drug approval decision in recent US history”.
As for implementation, the US health insurance program Medicare said it would not cover it, and clinicians were also cautious, with little use of the drug.
The Australian regulator, the Therapeutic Goods Administration, found in June that “there is no evidence of clinically meaningful efficacy” of aducanumab.
a ‘collective desperation’
In addition to minimal significant clinical benefits from donanemab, patients must also receive the drugs through an intravenous infusion at a medical clinic or hospital once every two to four weeks at a cost of approximately US$26,500, or A$40,500, per year plus undergo regular. test. That is a lot to ask of vulnerable people and their families.
Those who participate in clinical trials are also a highly selective group. In the donanemab trial, 1,320 participants with amyloid and early disease symptoms completed it. For every 10 people screened for eligibility for the trials, about eight were found to be ineligible.
In wrote a commentary for the ConversationWalsh said that if, when prescribed in the real world, “the drug eligibility is narrowed to fit the trial eligibility, then very few people will be eligible. If eligibility is wider, already small effects are likely to be even smaller be and side effects more pronounced.”
The director of internal medicine and clinical epidemiology at the Princess Alexandra Hospital in Queensland, Australia, Prof Ian Scott, a paper in the published February issue of the journal Age and Aging with similar concerns. He wrote trials of amyloid-targeting monoclonal antibodies to date “do not provide high-quality evidence of clinically meaningful impacts at an affordable cost”.
Daly believes that significant focus on the potential of drugs that target amyloid buildup despite a lack of efficacy was reductiveas it has seen less attention paid to alternative hypotheses of what causes the disease, and ways to tackle it.
A 2020 report from the Lancet Commission on Dementia an estimated 40% of cases of age-related dementia are associated with 12 potentially modifiable risk factors over the lifetime, including air pollution, obesity, depression and less education.
Daly says that while such findings make it tempting to list lifestyle changes people can make to reduce dementia risk, this is also too simplistic, as it puts the onus on individuals rather than governments.
“Working conditions, forms of suppression and things that are not so easily seen as a dementia risk are just as important to prevent disease,” Daly said.
“There’s an iceberg here – don’t just look at the surface of drugs and lifestyle. There is living conditions and social structures which represent deeper contributions to risk in the population, and interventions targeting them are needed by governments to make our society fairer and more dementia-resilient.”
Walsh says there is understandably “a collective desperation” among scientists and patients for better treatments and preventive options for Alzheimer’s disease, which is the most common cause of dementia in Western societies and which has no cure.
“But that cannot cloud objectivity when we look at the evidence,” he says.
