Lecanemab is a promising experimental drug to treat Alzheimer’s that decreases the amyloid plaques that characterize this neurodegenerative disease. On September 27, the pharmaceutical companies that have developed this medicine –Biogen and Eisai– assured that it was capable of slowing up to 27% cognitive deterioration due to mild Alzheimer’s disease (early Alzheimer’s) in the initial phases of this type of dementia, in what many began to call “the beginning of the end” of this disease. The results of the phase III clinical trial confirming its efficacy have now been published in the scientific journal The New England Journal of Medicine (NEJM), and will also be presented at the Clinical Trials on Alzheimer’s Disease (CTAD) congress that is being held these days in San Francisco.
The Clarity AD was a randomized, double-blind, parallel-group, placebo-controlled, Phase 3 study in 1,795 people with early Alzheimer’s disease (one group received lecanemab and another group of 898 people received placebo) at 235 sites in the Americas. North, Europe and Asia.
Results of the trial being published in NEJM indicate that the anti-amyloid monoclonal antibody lecanemab “reduced amyloid markers in early Alzheimer’s disease and resulted in a modestly smaller decline in measures of cognition and function than placebo at 18 months, but was associated with adverse events. Longer trials are warranted to determine efficacy and safety.”
Less cognitive and functional impairment in patients treated with lecanemab
The neurologist Marc Suárez-Calvet, researcher of the Physiology of Cognition and Alzheimer’s Prevention Research Group at IMIM-Hospital del Mar and head of the Fluid Biomarkers and Translational Neurology Group at the BarcelonaBeta Brain Research Center at the Pasqual Maragall Foundation, has explained in statements to SMC Spain that: “The clinical trial demonstrates its main objective: there is less cognitive and functional deterioration in the treatment arm compared to the placebo arm. Using the CDR-SB scale (with a range of 0 to 18; a higher value means greater cognitive and functional impairment), patients in the placebo arm have an average increase of 1.66 points during the 18-month follow-up, while those treated with lecanemab only have an increase of 1.21 points”.
The anti-amyloid monoclonal antibody lecanemab “reduced amyloid markers in early Alzheimer’s disease and resulted in a modestly smaller decline in measures of cognition.”
“The study also shows that treatment with lecanemab significantly reduces the accumulation of amyloid in the brain. Finally, lecanemab treatment is also better than placebo in all secondary endpoints studied, including other cognitive scales and biological biomarkers. In conclusion, this is a well-designed, rigorous study that points to a beneficial effect of lecanemab in the early stages of Alzheimer’s disease.”
The expert adds that “although it is true that the study shows less cognitive decline in patients treated with lecanemab, the clinical relevance will have to be determined. A difference of 0.45 on the CDR-SB scale, which has a range of 0 to 18, may seem minor. However, small changes in cognition can have a large impact not only on the autonomy of patients, but also on their caregivers. On the other hand, we must bear in mind that the trial investigates the effect of the drug after administering it for 18 months. Studies of longer duration will have to be carried out to determine the long-term effect.”
Side effects of new Alzheimer’s treatment
The new drug has some side effects, as noted in the NEJM article. In this regard, Suárez Calvet points out that “there are no differences in the number of deaths or the total number of adverse effects between the arm treated with lecanemab and the placebo. However, there is a higher proportion of amyloid-related imaging abnormalities (ARIA). Although these alterations are not serious in most cases, they must be studied in detail”.
Also speaking to SMC Spain, Raquel Sánchez-Valle, head of the Neurology Service at Hospital Clínic de Barcelona and secretary of the Behavior and Dementia Study Group of the Spanish Society of Neurology, explained that “21.5% of those treated with lecanemab presented some of the magnetic resonance abnormalities that have been associated with amyloid (ARIA), compared to 9.5% in the placebo group. These alterations were more frequent in carriers of the ε4 genotype of the APOE gene, indicating that, although these alterations may appear spontaneously in patients with Alzheimer’s disease, this anti-amyloid treatment increases their frequency, especially in genetically more susceptible patients. Although most of these abnormalities were not accompanied by symptoms, 3.5% of patients who received lecanemab had symptoms related to these MRI abnormalities. Of those who received lecanemab 5 subjects (0.6%) had a cerebral hemorrhage and 1 (0.1%) of those who received placebo. There were also more drug infusion-related reactions reported in the active arm (26.4% vs. 7.4%). There were six deaths in the treatment arm and seven in the placebo arm, although none of the deaths were attributed to the drug. These effects are in my opinion relevant and require close monitoring of the drug, especially the first months, and knowledge on the part of the patients who receive the drug, but I believe that per se they are a reason, at this time, to avoid its use”.
Suarez Calvet concludes that “since Alzheimer’s is a heterogeneous disease, it will be important to determine which patients can potentially benefit most from this treatment and which of them are at higher risk of side effects. The same study shows that it is patients with allele 4 of the APOE gene who have a higher risk of adverse effects in the form of ARIA. It will probably be necessary to individualize the treatment and the doses administered for these patients”.
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