After 18 months, both groups had experienced decline, as would be expected in people with dementia. Those taking lecanemab had scores which had declined by an average of 1.21 points. And those on the placebo had deteriorated more, by an average of 1.66 points over the course of the trial. That’s a difference of 0.45 points on an 18-point scale, described as “moderate” in the paper.
It is also important to note that the people who were recruited to the trials were only those with the “purest” forms of Alzheimer’s. For every 10 patients put forward, seven or eight were rejected. Those who were accepted had high amyloid levels but were relatively young and free of other diseases. To pick these patients, according to Dr Seb Walsh, a public-health doctor researching dementia at Cambridge University, is to misrepresent how the disease occurs among the vast majority of the population. Most people’s dementia is complex, occurring when they are in their eighties, and caused by several disease processes.
“By selecting amyloid-only patients,” he says, “they were giving the drug the best possible chance to show an effect, and yet even so they found an effect (after 18 months of fortnightly infusion treatment) that was so small it probably wouldn’t be noticeable to a doctor.” If the drug were given to a broader range of people diagnosed with Alzheimer’s disease, the already-small improvements might even disappear altogether.
And there’s another problem. The side effects.
Over a quarter of the participants in the lecanemab trial suffered drug infusion reactions, while there was brain swelling (which can be mild, such as flushing, or more severe, with changes in breathing and heart rate) in 13%. Others experienced headache, confusion and visual disturbance. Donanemab had similar side effects and three people also died in the trial — something researchers ascribed to the treatment.
So, while the press releases make a persuasive case for the effectiveness of the drugs, the overall difference is so small as to invite the question as to whether patients or families would even notice. What sort of improvement would these small differences represent in the real-world? And more important: are they worth the risk?
“My view,” says Professor Robert Howard, Professor of Old Age Psychiatry at University College London, “is that we’ve just about reached the point where we couldn’t have treatments that remove amyloid more aggressively because of the side effects of brain bleeds and swelling.”
It is this finding that is exercising — and dividing — scientists. For what does it mean for the new drugs if, as the trial showed, a big reduction in brain amyloid doesn’t translate into a hugely impressive reduction in or slowing down of symptoms.
One body of clinicians continues to hold to the hypothesis. Craig Ritchie, a Professor of the Psychiatry of Aging at the University of Edinburgh, worked on the donanemab trial and claims it has “a profound effect on the core pathology of Alzheimer’s disease namely cerebral amyloid”. He maintains that the slowing of the progression of the disease coupled with a reduction in amyloid build-up is not a coincidence. He believes that more time is needed to show the full impact of the reduction in amyloid on symptoms. “These drugs give us hope that we can do something, that these are the first drugs of an important new generation of treatments.” In order to push out this treatment, he has quit the NHS and set up Scottish Brain Sciences as an “independent research company” to run studies and give patients free access to the latest diagnostic tests and medications through trials funded by the drug industry. He, too, is funded by the industry.
These proponents of the new drugs also insist that monoclonal antibodies will show more impact if they are given before amyloid has damage to the brain. Therefore, they say, it needs to be given earlier — possibly even before someone has any symptoms of dementia.
That’s where the proposal that screening people — the so-called “Alzheimer’s blood test” would come in. It would test people before they have any memory problems for their future dementia risk. But, offered as a “check up”, it would come with wide ethical issues. There would inevitably be false positives and negatives — causing needless anxiety or false reassurance. Nor would a result necessarily lead to people being offered treatments that could lower their chances of getting dementia later. But could it make sense in a research setting, as an opportunity to try these new treatments to see if they could make a difference if given earlier?
Professor Howard is sceptical. The amyloid treatment, he says, “is a cul de sac, a dead end. And, worse, it means that the money and energy in drug development and trials isn’t being put into something that might work.” he says. “The argument that maybe the drugs need to be given earlier to make a difference is really just a wish or a hope. There is no data to suggest that it is true,” he says. “I worry that the “treat earlier” argument has become a way of saying ‘don’t blame the drugs for not working, blame the patients’.”
Various Alzheimer’s charities have heavily advocated for these drugs to be made available quickly. When lecanemab was approved in the US, a public letter hosted by the US Alzheimer’s Association in 2023 described it as “a foundational gamechanger”, saying: “No barrier can be allowed to stand between our patients and a treatment that has a reasonable risk-benefit ratio.” There may be a less philanthropic reason why they are so enthusiastic about the new treatments. A closer look at the signatories revealed that some had drug industry connections. And the charity itself received over $750,000 from Eisai and $430,000 from Biogen in 2023, who make lecanemab.
The inevitable result of these two amyloid-removing drugs being licensed means all drug companies will want to make and market their own versions, regardless of the criticisms. After all, it’s harder for regulators to say “no” when there are similar drugs on the market and the big charities are rooting for them.
But that hasn’t stopped the charities from investing £5 million in developing a blood test that will “revolutionise dementia diagnosis”. They say that currently only 2% of people get the detailed diagnosis they need and that significant investment is needed to ensure the NHS can identify people with Alzheimer’s disease far sooner. The Blood Biomarker Challenge, available within five years, will help do that. “If we can fix diagnosis, we open the door for a cure. It’s a bold ambition but, with someone developing dementia every three minutes in the UK, we must aim high,” they say.
But Dr Seb Walsh, a public health doctor researching dementia at the University of Cambridge, says the hype and hope is unkind: “For 20 years we have been promised wonder drugs within 5 years — but still we wait,” he says.
He also says it’s bad research practice to pre-empt your results before you do the research. “We don’t know how useful these tests will be, how well they’ll perform in the ‘typical’ NHS dementia patient (more complex than the people in existing research studies), that’s the whole point of doing the research.”
But the key question, and the one that Nice will be weighing up over the course of the year, is whether any of these new drugs represent the best use of public money. Given the small benefits, the risk of side effects, but the lack of other decent alternatives, the question will be how to weigh that up as independently as possible. Spending similar sums on social care might well provide greater benefits for patients and families than the drugs. Is it right that a drug — with minimal benefits — should be funded when the same money invested into social care might do more good for patients and families getting more practical help?
Obviously, a drug that worked would have massive, global market potential. But the hyperbole from doctors and researchers in this area — especially those with industry funding — is unhelpful. It means that the pressure to upsell the effectiveness of a drug is particularly intense. This, then, diverts money into look-alike drug development and drains it from continued research. Clearly the pharmaceutical industry and its relationship with the private and public sectors has a lot to answer for. Currently, Alzheimer’s has no cure and treatment has progressed little despite decades of research and billions of pounds. As our investigation shows, we should be cautious about the promise of these new “wonder” drugs which risk benefiting only the drugs companies.
“There is still much we don’t know, but we really need to know,” Dr Walsh says. “We are unlikely to ever, truly ‘cure’ dementia — this is more false hope.”
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