Most patients "won't see benefit" with Alzheimer's drugs

A review of clinical data on amyloid beta-targeting Alzheimer's disease therapies has concluded their efficacy is too modest to show a clinically meaningful benefit for patients.

The report from the influential Cochrane Collaboration, an independent group that analyses clinical data, maintains that these drugs have "absent or trivial" effects on cognitive decline and dementia severity in Alzheimer's, whilst also increasing the risk of bleeding and swelling in the brain.

The authors, led by Francesco Nonino, neurologist and epidemiologist at the IRCCS Institute of Neurological Sciences of Bologna in Italy, drew their conclusions after analysing data from 17 clinical trials of seven amyloid-targeted Alzheimer's drugs with a total of 20,342 participants. That included trials of the only two approved therapies, Eisai/Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab).

"There is now a convincing body of evidence converging on the conclusion that there is no clinically meaningful effect," said Nonino.

"While early trials showed results that were statistically significant, it is important to distinguish between this and clinical relevance," he added. "It is common for trials to find statistically significant results that do not translate into a meaningful clinical difference for patients."

Some researchers have already pushed back against the findings, however. Prof Tara Spires-Jones of the University of Edinburgh and the UK Dementia Research Institute, along with her DRI colleague Prof Jonathan Schott, noted that five of the seven drugs analysed did not succeed in trials, weakening the result.

"By combining studies of different drugs, many of which have long since been disbanded, several of which had little or no effects on beta-amyloid, and most of which have failed in randomised clinical trials, it is almost inevitable that the conclusion will be that as a group they are clinically ineffective," said Schott.

Leqembi and Kisunla are both approved in the UK, but are not recommended for use by the NHS, although, last month the reimbursement authority NICE said it would look again at its original appraisal decisions as a result of changes to its cost-effectiveness thresholds.

For now, anyone seeking treatment with them will have to pay privately, looking at a bill of almost £90,000 for an 18-month course of treatment.

The Cochrane authors conclude that future trials targeting amyloid beta removal are unlikely to provide a clear benefit to patients, and recommend that future research on Alzheimer's treatment should focus on other mechanisms.

"Existing approved drugs offer some benefit for some patients, but there remains a high unmet need for more effective treatments," said senior author Edo Richard, of Radboud University Medical Centre in the Netherlands.

"Sadly, anti-amyloid drugs do not offer this and bring additional risks," he added. "Given the absence of correlation between amyloid removal and clinical benefit, we need to explore other pathways to help address this devastating disease."

Giving another perspective, Prof Paresh Malhotra of Imperial College London (ICL) said the results are not surprising given that most of these trials have negative effects, but does not take into account the key differences between individual drugs and the trials assessing them.

"There are many questions that still need to be answered about the licensed drugs, including methods and duration of administration," he said.

"I agree with the authors that other mechanisms of action beyond targeting amyloid for treatment of Alzheimer's should be explored. However, the findings to date do not justify 'throwing the baby out with the bathwater' and dismissing all the results of well-conducted individual studies."