Alzheimer’s drugs which pharmaceutical firms hoped could revolutionise dementia treatment ‘likely have no clinically meaningful benefit’, review finds
A new generation of Alzheimer’s drugs “likely have no clinically meaningful benefit”, according to a gold-standard review.
It suggests billions of pounds globally may have been wasted in researching the so-called amyloid hypothesis – which assumed that reducing the build-up of the key protein in the brain could halt the progression of dementia.
There had been huge hope among dementia patients and experts after pharmaceutical firms posted data from clinical trials claiming that two groundbreaking drugs, known as monoclonal antibodies, were the first to slow the degeneration seen in dementia patients. Until then drugs could only mask or lessen symptoms.
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But now a Cochrane Review of 17 studies including 20,000 dementia patients on the first seven amyloid-targeting monoclonal antibodies said there appears to be no link between clearing amyloid from the brain – and benefit in thinking skills that patients or carers would actually notice.
Author Dr Francesco Nonino, neurologist at the IRCCS Institute of Neurological Sciences of Bologna in Italy, said: “Unfortunately, the evidence suggests that these drugs make no meaningful difference to patients. There is now a convincing body of evidence converging on the conclusion that there is no clinically meaningful effect.”
Co-author Prof Edo Richard, of the Radboud University Medical Centre in the Netherlands, said: “The results of our meta-analysis show that removing amyloid from the brain does not improve cognition or slow cognitive decline.”
Monoclonal antibodies bind to the amyloid-beta protein, reducing plaques that have been seen in patients who experience dementia symptoms and helping the immune system clear them from the brain.
Two such drugs called lecanemab and donanemab were heralded as the first ever drugs to tackle the progression of dementia. They have been licensed to be sold in Europe and the US however the NHS initially refused to prescribe them. The National Institute for Health and Care Excellence (NICE) concluded the apparent benefits to thinking skills was too small to justify the cost and risk of severe side effects, such as a bleed on the brain. This advice is currently under review.
The review’s conclusion centres on how pharmaceutical firms assessed the success of the amyloid targeting drugs, using PET scans to check the presence of the protein in the brain as well as cognitive assessments of thinking ability. It found that the slowing of the degeneration in thinking skills was so small that patients and care givers would not even notice it. The review suggests that the small “statistically significant” benefit could be down to chance or accidental bias in the studies.
Dr Nonino said: “While early trials showed results that were statistically significant, it is important to distinguish between this and clinical relevance. It is common for trials to find statistically significant results that do not translate into a meaningful clinical difference for patients.”
Some 70% of all dementia patients have the form caused by Alzheimer’s disease. It has long been known that while amyloid plaques are seen in brain scans of Alzheimer’s patients, those same plaques are sometimes identified in patients who experience no symptoms.
Prof Richard added: “I see Alzheimer’s patients in my clinic every week and I wish I had an effective treatment to offer them. Sadly, anti-amyloid drugs do not offer this and bring additional risks. Given the absence of correlation between amyloid removal and clinical benefit, we need to explore other pathways to help address this devastating disease.”
The Cochrane Review has been criticised for including five drugs that did not succeed in their clinical trials in combination with the drugs that did and have been licensed. Dr Richard Oakley, research director at the Alzheimer’s Society, said: “It’s not the case that all amyloid-targeting drugs are ineffective. This review’s conclusions make the picture look bleaker than it really is.
“Authors combined results for a majority of failed drug trials with a small number of more recent successful trials. This includes the trials for lecanemab and donanemab which the UK medicines regulator agreed bring a modest but meaningful benefit for people with early-stage Alzheimer’s. It’s essential that we interpret this review with nuance and avoid taking a sledgehammer to decades of pioneering scientific study.”
Prof Paresh Malhotra, head of neurology at Imperial College London, said: “These findings do not justify ’throwing the baby out with the bathwater’ and dismissing all the results of well-conducted individual studies. The results of ongoing amyloid-targeting trials will help us understand these treatments better.”
Six studies are currently ongoing into amyloid targeting drugs which were not included in the review.
Robert Howard, professor of old age psychiatry at University College London, said: “This should be seen as a potential corrective to some of the misinformation that has come to surround what can be realistically expected from these drugs. It suggests that the drugs do not modify disease course and appear much more likely to be acting as a symptom-improving treatment, in much the same way as seen with the earlier ‘symptomatic’ treatments that we have had for nearly 30 years.”
