It could be a “revolution” against Alzheimer’s, but concern is mounting over its effects on the brain. Three months after its marketing in the United States, doubts are accumulating around Lecanemab, the first drug to slow down cognitive decline in patients with this neurodegenerative disease, which affects around one million French people.
At the origin of this less favorable wind: a study published in Neurology on March 27, alerting to a “reduction in brain volume” in treated patients. Its authors have reviewed about thirty clinical trials conducted on the drugs of this family, which act by eliminating “senile plaques”, these aggregates of amyloid proteins suspected of being at the origin of the pathology. They show an average decrease in brain volume 22% greater than with a placebo. For patients included in the two main clinical trials on Lecanemab, this proportion reached 28%.
These figures shed new light on the exceptional results of Lecanemab, presented in September 2022. The American and Japanese laboratories Biogen and Eisai, partners on this project, then announced that they would slow down cognitive decline “by around 27%”, on 18 months of clinical trials, thanks to this monoclonal antibody. A first, after years of research. But already, the enthusiasm of the medical profession had been tempered by potentially serious side effects, in particular bleeding or even cerebral hemorrhages observed in patients taking anticoagulants in parallel.
Loss of neurons or reduction of toxins?
Could the atrophies pointed out by this new study undermine the effectiveness of the drug in the longer term? Scientists, for the moment, do not know anything about it. “Do we observe the elimination of toxins, as the laboratories claim, or a loss of neuron? We must check that the patients do not deteriorate more quickly after a few years of treatment. We cannot leave anything under the carpet “, enjoins Professor Philippe Amouyel, Director General of the Alzheimer Foundation, a funding organization hosted by Inserm.
Alzheimer’s remains asymptomatic for years before beginning to cause disorders in patients and make them dependent. It is at an early stage that Lecanemab could be beneficial, according to the American drug authority (FDA), which authorized it on January 6. However, this effect must be maintained over time, despite the reactions of the brain. In his report, the FDA mentions these questions, without going into depth.
“Something is going on, but we don’t understand what. We will learn from American hindsight”, summarizes Frédéric Blanc, neurologist at the Memory Center of Strasbourg University Hospitals. And to wonder: “If the drug accelerates the destruction of neurons, why would the patients be better for the duration of the treatment?”
The risk of long-term problems
The data published by the manufacturers does not specify whether these losses of brain mass have harmed the patients concerned, and if so, how. Faced with criticism, Eisai told the American magazine Science that these reductions may be due to “the removal of amyloid-beta protein from the brain by the antibody and the reduction of inflammation”. “But even if no effect has actually been identified, it is possible that a disorder will manifest itself later, or on other aspects of the patients’ lives”, for his part warned Scott Ayton, neurologist and lead author of the study, on Twitter.
Especially since the molecule is not trivial. By attacking “amyloid plaques and “neurofibrillary degeneration”, clusters and lesions around neurons, designated responsible for memory loss, it can generate “abnormalities” that are mostly benign, but potentially serious, as they are responsible for edema or hemorrhage.
During the trials, about 17% of patients had to interrupt their treatment. “Many patients will not be eligible, because they are too affected, or too at risk. And the beneficiaries will have to pass numerous surveillance examinations”, warns Frédéric Blanc, while some of his patients told him that they would go to the States. United to get it.
Atrophies, side effects, and also exorbitant price – 2,000 euros per injection – and despite everything, the dawn of “a new era”? “We must remain cautious, but after twenty years of research, 300 clinical trials, we finally have a way to act on the disease, and not only on its symptoms. This work opens the way to other discoveries, new investments, and real relief for the sick and caregivers”, maintains Frédéric Blanc. The European Medicines Agency must decide in June. Possible arrival in France? Not before 2024.