Eli Lilly and Eisai have backed their Alzheimer’s disease drugs despite research finding the mechanism of action may be less clinically meaningful than suggested.
A review by Cochrane found that the absolute effects of anti-amyloid drugs on cognitive decline and dementia severity were “absent or trivial,” falling “well below established thresholds for the minimum clinically important difference”.
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Lead author Francesco Nonino, neurologist and epidemiologist at the IRCCS Institute of Neurological Sciences of Bologna, Italy, said: “There is now a convincing body of evidence converging on the conclusion that there is no clinically meaningful effect. 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.”
The review also found that anti-amyloid drugs likely increase the risk of swelling and bleeding in the brain, known as amyloid-related imaging abnormalities (ARIA). This was observed in brain scans without any apparent symptoms for most patients, although any long-term effects remain unclear since reporting of symptoms was inconsistent across trials. ARIA is a well-known adverse event (AE) associated with anti-amyloid drugs, with patients requiring intermittent follow-up scans to check for ARIA development during and after treatment.
It examined data from 17 clinical trials with a total of 20,342 patients, all looking at the impact of anti-amyloid drugs on people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Proponents of these drugs have theorised that they would be more effective at these earlier stages before the disease has progressed.
On the basis of the Cochrane review, the authors suggested that future trials targeting amyloid beta removal are unlikely to provide a clear benefit to patients and asked researchers to consider alternative modalities.
Pharma backs approach
The reviews included data from trials of two approved drugs, Eli Lilly’s Kisunla (donanemab) and Biogen and Eisai’s Leqembi (lecanemab). Both companies have backed their drugs, which were the first disease-modifying therapies approved for the disease.
A spokesperson for Eli Lilly said: “Donanemab received marketing authorisation in the UK in October 2024, following a thorough, independent assessment of the clinical evidence. Alzheimer’s disease is a progressive neurodegenerative disorder. Donanemab demonstrated slowing of cognitive and functional decline in people with early symptomatic Alzheimer’s disease in the 18-month Phase III TRAILBLAZER-ALZ 2 trial (NCT04437511). We remain steadfast in our confidence in the clinical effectiveness of donanemab and the value it brings to patients.”
“The Cochrane review pools data from multiple anti-amyloid therapies, including molecules that failed in clinical development and were never granted regulatory approval. This grouping is a significant methodological limitation that undermines the review’s conclusions about approved therapies,” they concluded.
Meanwhile, a spokesperson for Eisai described the analysis as “scientifically questionable” due to it “inappropriately” combining ineffective antibodies and failed studies with effective, regulatory-approved anti-amyloid treatments such as lecanemab.
They added, “Extensive long-term clinical data with patients treated for up to four years and real-world experience with over ten thousand patients globally show that patients who receive lecanemab continue to benefit from this treatment. Globally, lecanemab has been approved by more than 50 regulatory authorities.”
