Cochrane review: No ‘meaningful difference’ with anti-amyloid Alzheimer’s drugs

The debate over anti-amyloid drugs for Alzheimer’s disease has erupted once more after a Cochrane review concluded they make no ‘meaningful difference’ while increasing the risk of swelling and bleeding in the brain.

Analysis of data from 17 clinical trials with 20,342 participants, looking at impact of anti-amyloid drugs on people with mild cognitive impairment or mild dementia due to Alzheimer’s disease over 18 months found the effects were ‘absent or trivial’.

The Cochrane reviewers said it was important to distinguish between results that were statistically significant but ‘do not translate into a meaningful clinical difference for patients’.

Some experts said the results of the new class of drugs had been disappointing, but evidence was showing the ability to remove amyloid from the brain did not automatically translate into clinical benefit.

However, others said the approach taken by the Cochrane reviewers was flawed because they had included trials looking at lecanemab and donanemab but also five other amyloid antibodies that did not pass clinical trials and make it to market.

It comes a fortnight after NICE reopened a consultation into the use of donanemab and lecanemab on the NHS.

The reassessment following an appeal from the manufacturers is expected to be done under the new cost effectiveness thresholds agreed as part of the USA-UK trade deal last year.

Professor Edo Richard, professor of neurology at Radboud University Medical Centre in the Netherlands and senior author of the Cochrane review said: ‘I see Alzheimer’s patients in my clinic every week and I wish I had an effective treatment to offer them.

‘Existing approved drugs offer some benefit for some patients, but there remains a high unmet need for more effective treatments. Sadly, anti-amyloid drugs do not offer this and bring additional risks.’

Professor Robert Howard, professor of old age psychiatry, at University College London (UCL) said the results should not come as a surprise to those who have appreciated the very small benefits of treatment seen in clinical trials.

Emerging data from longer term trials suggests that after three years there is no difference between early and delayed-start participants, he added.

‘This 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.’

But Professor Bart De Strooper, group leader at the UK Dementia Research Institute at UCL, said the review had not clarified the evidence but blurred it.

‘By mixing failed drugs with the only antibodies that have actually changed clinical practice, it turns therapeutic progress into statistical noise.

‘Anti-amyloid antibodies are not one uniform group of medicines. They are different molecules, developed at different times, directed against different forms of amyloid, and associated with very different trial outcomes,’ he said.

Professor Paresh Malhotra, head of the division of neurology at Imperial College London, said the findings to-date do not justify ‘throwing the baby out with the bathwater’.

‘The results of ongoing amyloid-targeting trials will help us understand these treatments better, and we should continue to explore all promising avenues for the treatment of Alzheimer’s and other dementia-causing diseases.’

Charities also criticised the approach of the review.

Dr Richard Oakley, associate director of research and innovation at Alzheimer’s Society, said it was not the case that all amyloid-targeting drugs are ineffective.

‘This review’s conclusions make the picture look bleaker than it really is, as authors combined results for a majority of failed drug trials with a small number of more recent successful trials.

‘It’s essential that we interpret this review with nuance and avoid taking a sledgehammer to decades of pioneering scientific study.’