A class of Alzheimer’s drugs that have been available for several years did not appear to have any “clinically meaningful effects,” according to a new review of clinical trial data.
Monoclonal antibodies that target a type of plaque called amyloid beta in the brain showed little impact across 17 trials, Francesco Nonino, a neurologist and epidemiologist who directs the Unit of Epidemiology and Statistics at the IRCCS Institute of Neurological Sciences of Bologna, Italy, and his co-authors wrote in the review.
“The effect of amyloid‐beta‐targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease is trivial, while on functional ability, it is small at best,” they said.
“Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Future research on disease‐modifying treatments for Alzheimer’s disease should focus on other mechanisms of action.”
The review covered 17 studies involving 20,342 participants. The drugs were typically compared with placebos in the trials, which were all funded by pharmaceutical companies.
The monoclonal antibodies in question were first approved by the Food and Drug Administration in 2021. They include Lecanemab, which is available in the United States and other countries and is produced by Eisai and Biogen, and Eli Lilly’s Donanemab.
“The Cochrane review is built on an inherently flawed methodology,” a spokesperson for Lilly told The Epoch Times in an email. “It pools data from across multiple amyloid-targeting therapies as a class, including molecules that did not achieve their clinical trial endpoints and were never granted regulatory approval.
“Combining data on unsuccessful molecules with approved medicines artificially dilutes the observed benefit and produces class-level conclusions that do not reflect the evidence for any individual approved therapy. Regulatory authorities around the world have evaluated donanemab’s clinical data on its own merits, and that review, not pooled analyses that blend successful and unsuccessful molecules, is the appropriate standard for determining benefit and risk for patients.”
Eisai and Biogen did not respond to requests for comment by publication time.
Nonino and the other authors of the new review, published on April 16 by global nonprofit organization Cochrane, reported funding from government authorities in Italy. Their conflicts of interest included four authors being practicing neurologists.
A meta-analysis in 2022 concluded that the anti-amyloid drugs had a “statistically significant clinical effect of these drugs on cognitive decline after 18 months,” but that the effect “remains below the previously established minimal clinically relevant values” and that there was also an increase in adverse events such as hemorrhage. The authors, based in France, said that the risk-benefit ratio was questionable.
A group of Chinese researchers said in a review the following year that the drugs had significant but small effects on cognitive decline and an acceptable safety profile.
Reacting to the new review, Robert Howard, professor of old-age psychiatry at the University College London, said in a statement that it was well-conducted.
“While disappointing, the results and conclusions should not come as a surprise to those who have appreciated the very small benefits of treatment (generally around 2% of the range of changes measured by validated tests of cognitive functioning or functional ability) seen in the individual clinical trials of these drugs,” Howard said. “While these benefits may have achieved statistical significance within clinical trials where very large numbers of participants allowed the detection of tiny differences, they did not achieve accepted levels of clinical efficacy or what would be appreciable in an individual patient.”
While it is possible that longer periods of time beyond the 18-month limit of the review would reveal more pronounced benefits, emerging trial data from beyond 18 months indicate that is not true, Howard said.
Dr. Susan Kohlhaas, executive director of research at Alzheimer’s Research UK, said that the review had major limitations, such as including drugs such as aducanumab that have been discontinued due to failed trials.
“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,” she said.
