Meta analysis: No breakthrough in Alzheimer’s disease with β-amyloid antibodies

Lecanemab and donanemab have little benefit with high risks and enormous costs

The introduction of new antibody drugs such as lecanemab and donanemab is supposed to mark a potential turning point in Alzheimer’s research. However, these therapies, which aim to slow down the progression of the disease by reducing amyloid protein deposits in the brain, are the subject of highly controversial debate. On the one hand there are hopes of a breakthrough, on the other serious concerns about efficacy, cost and safety. A new, comprehensive meta-analysis now reveals that patients can expect high costs, marginal improvements and a multitude of side effects.

The systemic analysis from the Universities of Georgia and Michigan, which appeared in Annals of Family Medicine, reviewed 19 randomized, placebo-controlled trials involving more than 23,000 people affected by Alzheimer’s disease who were treated with eight different monoclonal amyloid antibodies. The review found that these therapies showed little benefit at the cognitive and functional level. No drug achieved a “minimally clinically significant difference” (MCID) for any of the scores assessed. Instead, treatment was always associated with significant risks such as brain edema and bleeding.

Anti-amyloid antibodies in Alzheimer’s therapy: high expectations, results not clinically meaningful

The meta-analysis of previous studies on anti-amyloid antibodies in the treatment of Alzheimer’s disease has delivered sobering results. Although significant improvements were found in some cognitive and functional tests, these advances were not considered clinically meaningful.

This is in contrast to the high frequency of side effects. Since the approval of aducanumab and lecanemab in the USA, the topic of anti-amyloid antibodies has been omnipresent in the discussion about neurodegenerative diseases. In particular, the approval of aducanumab has already caused fierce controversy, as a clinical benefit could only be proven in one of the two studies for approval. The approval was ultimately based on the positive influence of surrogate markers, in particular the reduction of amyloid deposits in the brain.

Aducanumab has since been discontinued by the manufacturer, while lecanemab has received regular approval from the FDA and is expected to be approved by the EMA in Europe this year. Donanemab, another candidate among the anti-amyloid antibodies, is about to be approved following promising study results.

Ahead of launch in Europe: Critical questions about patient safety and cost-effectiveness

The upcoming launch of the new antibodies raises critical questions regarding cost-effectiveness and safety. With an annual price of around 27,000 dollars in the USA – and probably similar sums in Europe – the costs for lecanemab are enormous. This represents a considerable financial burden, particularly in view of the fact that the therapy is regularly associated with side effects. Of particular concern are the so-called ARIA (Amyloid-related Imaging Abnormalities), specific side effects of this drug class that are visible on imaging and raise serious concerns about patient safety.

The new antibody therapies for Alzheimer’s disease cause cerebral edema and hemorrhages that often remain asymptomatic, but the long-term effects are unknown due to a lack of long-term data. These changes, visible on MRI, require careful monitoring and, if necessary, discontinuation of therapy, which entails additional logistical effort and increased economic costs. The justification for the high costs and the risk of serious side effects therefore depends heavily on the clinical benefit that the therapy offers to patients.

None of the therapies can achieve clinically relevant improvements

The meta-analysis and the individual assessments of the approved or pending antibodies showed that none of these therapies were able to achieve a clinically relevant improvement. At the same time, cerebral edema and hemorrhage occurred in one in ten patients, leading the authors to conclude that no anti-amyloid antibody has yet demonstrated a clinically relevant benefit that outweighs the side effects. These findings call into question the efficacy and safety of antibody therapies and emphasize the need for further research to find effective and safe treatments for Alzheimer’s disease.

The research team concludes that the hope of using β-amyloid antibodies to significantly reduce the disease burden and personal suffering caused by Alzheimer’s in the future is not supported by the results of the meta-analysis.

The authors led by Mark H. Ebell, University of Georgia, write: “Alzheimer’s disease causes enormous suffering for those affected, heavy burdens for their families and caregivers, and enormous costs to the health care system. Each of these groups hopes for effective tools to alleviate these burdens and extend the period of meaningful life. However, our meta-analysis shows that anti-amyloid monoclonal antibodies offer no clinically meaningful benefit, are associated with significant harms and are costly.”