In its July 2024 meeting, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended not granting marketing authorization for Leqembi (lecanemab; Eisai GmbH), a medicine for the treatment of Alzheimer's disease.
The committee considered that the observed effect of Leqembi on delaying cognitive decline did not counterbalance the risk for serious adverse events associated with the medicine, particularly the frequent occurrence of amyloid-related imaging abnormalities (ARIAs) that involve swelling and potential bleeding in the brain.
The CHMP pointed out that the company that applied for authorization could ask for reexamination within 15 days of receiving the opinion.
Trial Data
Leqembi was developed with the aim of treating adults with mild cognitive impairment due to Alzheimer's disease and early-stage Alzheimer's disease. The active substance, lecanemab, is a monoclonal antibody that attaches to amyloid beta and, in doing so, aims to delay disease worsening. The drug is administered as an infusion once every 2 weeks.
In its assessment, the CHMP reviewed the findings of a study involving 1795 people with early Alzheimer's disease who had amyloid beta plaques in the brain and received either Leqembi (n = 898) or placebo (n = 897).
The main measure of effectiveness was a change in symptoms after 18 months, measured using the Clinical Dementia Rating–Sum of Boxes (CDR-SB) scale for assessing the severity of Alzheimer's disease. The rating scale includes questions that help determine how much the patient's daily life has been affected by cognitive impairment and ranges from 0 to 18, with higher scores indicating greater impairment.
The mean CDR-SB score at baseline was approximately 3.2 in both groups. The study found that after 18 months of treatment, the CDR-SB score in patients treated with Leqembi increased by 1.21 compared with 1.66 in those who received placebo. Although patients given Leqembi had lower CDR-SB scores than those given placebo, the difference between the two groups was small.
The study authors concluded that lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events.
Amyloid-Related Imaging Abnormalities
The CHMP highlighted that the most important safety concern with Leqembi was the frequent occurrence of ARIAs, a side effect seen on brain imaging that involves swelling and potential bleeding in the brain.
Although most cases of ARIA in the reviewed study were not serious and did not involve symptoms, some patients had serious events, including large bleeds in the brain that required hospitalization , the CHMP said.
In addition, the EMA committee was concerned by the fact that the risk for ARIA is more pronounced in people who have a certain form of the gene for the protein apolipoprotein E (APOE4). The risk is highest in people with two copies of the APOE4 gene, who are known to be at risk of developing Alzheimer's disease and would therefore be likely to become eligible for treatment with Leqembi.
The drug was approved by the US Food and Drug Administration in 2023.