It was heralded in news articles as a “breakthrough”, a “turning point” and a “gamechanger” for Alzheimer’s disease. Some experts went so far as to call the drug, donanemab, the “beginning of the end” for the debilitating condition.
Pharmaceutical company Eli Lilly in May 2023 released data from a clinical trial they said showed 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 drugs regulators to rapidly approve the treatment for use in patients.
But despite reports the US drugs regulator was set to approve donanemab “any day”, the Food and Drug Administration (FDA) instead announced on 8 March that it had delayed its decision.
The FDA said it wants an independent panel to further scrutinise data on the safety and efficacy of donanemab, with a decision now expected later in 2024. UK, European and Australian regulators are also still assessing the drug.
In a statement, the executive vice-president of Eli Lilly, Anne White, said: “We are confident in donanemab’s potential to offer very meaningful benefits to people with early symptomatic Alzheimer’s disease”.
“It was unexpected to learn the FDA will convene an advisory committee at this stage in the review process, but we look forward to the opportunity to further present the [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 with Sorbonne University in Paris, says this delay comes as no surprise to him.
He says the benefits of donanemab, and similar, much-hyped drugs, including aducanumab and lecanemab, have proved harder to quantify than their potential harms.
“Under this narrative of drug success, there are some really strong side-effects,” Daly told Guardian Australia.
These are a type of drug 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 around three-in-10 people taking lecanemab or donanemab in clinical trials developed a condition known as amyloid-related imaging abnormalities, abbreviated to ARIA, a condition which can cause brain swelling or haemorrhaging.
“Mostly these seem to be minor, not come with any symptoms, and follow-up scans show they appear to have resolved,” Dr Sebastian Walsh, a public health doctor researching dementia risk reduction with the University of Cambridge in the UK, says.
“In a small percentage of participants it does seem to be much more serious, and there have been some deaths – particularly for those on blood-thinning-type medications.”
Some trial participants also experienced brain shrinkage – and the long-term effects of that are unknown.
‘It’s pure speculation’
In the donanemab trial, patients receiving the drug declined on average by 10 points on a 144-point scale that combined cognitive and functional scores. The placebo group who were not receiving the drug declined by 13 points.
This data was 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 means the effects of the drug have been overblown in media reports.
“Whilst it is understandable that people want to think of other ways to present these numbers, it still needs to be scientifically valid,” he says.
“Those who have reported it being ‘an extra six months at higher function’ are on shaky ground scientifically I think. The trials didn’t measure recognition of a loved one, ability to drive, any of these things – extrapolating in this way is not really justified by the evidence we have. It’s pure speculation.”
A professor of neurology at Radboud University Medical Centre in the Netherlands, Edo Richard, told news channel Al Jazeera the drugs “clearly remove” 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.
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 don’t have dementia, and who never go on to develop it, Richard told Al Jazeera.
While many drugs trialled in the past have reduced amyloid levels, donanemab, aducanumab and lecanemab appear to be the first to have also led 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 advised against its approval because of what they believed was a lack of efficacy data resigned. One of the people who resigned described it as “probably the worst drug approval decision in recent US history”.
When it came to implementation, the US health insurance program Medicare said it would not cover it, and clinicians have also been cautious, with little use of the drug.
The Australian regulator, the Therapeutic Goods Administration, in June found “there is no evidence of clinically meaningful efficacy” of aducanumab.
A ‘collective desperation’
As well as minimal meaningful clinical benefits from donanemab, patients also need to receive the drugs via an intravenous infusion at a medical clinic or hospital once every two to four weeks at a cost of about US$26,500, or A$40,500, a year plus undergo regular testing. It 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 a commentary written for the Conversation, Walsh said if, when prescribed in the real world, “the drug eligibility is restricted to match the trial eligibility, then very few people will be eligible. If eligibility is broader, then already small effects are likely to be even smaller and side-effects more pronounced”.
The director of internal medicine and clinical epidemiology at the Princess Alexandra hospital in Queensland, Australia, Prof Ian Scott, published a paper in the February edition of the journal Age and Ageing 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 has been reductive, as it has seen less attention being paid to alternative hypotheses of what is causing the disease, and ways to tackle it.
A 2020 report from the Lancet commission on dementia estimated 40% of cases of age-related dementia are associated with 12 potentially modifiable risk factors across the lifetime, including air pollution, obesity, depression, and less education.
Daly says 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 oppression and things that can’t as easily be seen as a dementia risk are just as important in preventing disease,” Daly says.
“There is an iceberg here – don’t just look at the surface at drugs and lifestyle. There are living conditions and social structures that represent deeper contributions to risk in the population, and interventions targeting these 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 this cannot cloud objectiveness when we look at the evidence,” he says.
