Anti-amyloid drugs that were hailed as possible breakthrough treatments for Alzheimer’s patients show ‘no clinically meaningful positive effects’ but increase the risk of bleeding and swelling in the brain, a new Cochrane review has found.
The review said that the absolute effects of anti-amyloid drugs on cognitive decline and dementia severity were ‘absent or trivial’ and fell well below established thresholds for the ‘minimum clinically important difference’.
But Alzheimer’s Research UK said the review had ‘major limitations’ and that much of the evidence it relied upon was from older experimental drugs that were discontinued due to failed trials.
The charity’s executive director of research Dr Susan Kohlhaas said: ‘Only two of the 17 studies included were for the medicines now approved in the UK, lecanemab and donanemab. The rest focused on drugs that were not pursued after failing to show meaningful benefit, inevitably shaping the review’s conclusions.’
Impact of anti-amyloid Alzheimer’s drugs
The Cochrane review, examined data from 17 clinical trials with a total of 20,342 participants, looking at the impact of anti-amyloid drugs on people with mild cognitive impairment or mild dementia due to Alzheimer’s disease.
It included the drugs lecanemab and donanemab, which had been hailed as ‘historic’ breakthroughs following successful clinical trials.
Although they are licensed for use in the UK by Medicines and Healthcare products Regulatory Agency, the National Institute for Health and Care Excellence rejected their use in the NHS in England and Wales on the grounds of cost effectiveness. However, that decision is due to be reconsidered after the drugs’ manufacturers won an appeal.
Francesco Nonino, lead author of the Cochrane review and researcher at the IRCCS Institute of Neurological Sciences of Bologna in Italy, said: ‘There is now a convincing body of evidence converging on the conclusion that there is no clinically meaningful effect [of anti-amyloid Alzheimer’s drugs].
‘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.’
Risk of swelling and bleeding in the brain
People with Alzheimer’s disease have high levels of amyloid beta proteins in their brains that are detectable at increased levels even before symptoms begin, though the role of these proteins in disease progression remains unclear.
Anti-amyloid drugs have been developed to remove these proteins from the brain, under the theory that this could prevent or slow disease progression.
But in addition to the absence of clinically meaningful effects, the Cochrane review found that anti-amyloid drugs likely increase the risk of swelling and bleeding in the brain.
Its authors noted that these effects were observed in brain scans without any apparent symptoms for most patients. They also said that because reporting of symptoms was inconsistent across trials the long-term effects remain unclear.
Based on the evidence, the Cochrane review authors concluded that future trials targeting amyloid beta removal are unlikely to provide clear benefit to patients and recommended that future research should focus on other mechanisms.
Patient priorities
But Dr Kohlhaas said that there was no agreed definition of ‘clinically meaningful’ and that trial measures do not always ‘reflect what matters most to people with dementia’.
‘We regularly hear from families affected by dementia that even a delay of several months in decline could provide valuable, meaningful time with loved ones and that shouldn’t be minimised,’ she explained.
‘Newer, longer-term evidence suggests that the approved treatments may deliver modest but sustained benefits beyond the 18-month horizons of earlier studies, yet this emerging data is not reflected in the review.’
Dr Kohlhaas added that anti-amyloid treatments will not be the ‘whole answer’ to curing Alzheimer’s and that research was already moving towards a wider range of biological targets.
‘But it’s not accurate to dismiss [anti-amyloid drugs’] impact as “trivial”, especially when the analysis has clear constraints that limit what it can tell us,’ she concluded.
A version of this article was originally published by our sister publication The Pharmacist.
