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After re-examining its initial opinion, the European Medicines Agency (EMA) human medicines committee (CHMP) has recommended granting a marketing authorisation to Leqembi (lecanemab) for treating mild cognitive impairment (memory and thinking problems) or mild dementia due to Alzheimer’s disease (early Alzheimer’s disease) in patients who have only one or no copy of ApoE4, a certain form of the gene for the protein apolipoprotein E.
Patients with only one or no copy of ApoE4 are less likely to experience amyloid-related imaging abnormalities (ARIA) than people with two ApoE4 copies. ARIA is a recognised serious side effect with Leqembi that involves swelling and potential bleeding in the brain.
The CHMP concluded that, in the restricted population assessed in the re-examination, the benefits of Leqembi in slowing down progression of symptoms of the disease are greater than its risks. In July 2024, the Committee had issued a negative opinion on the use of Leqembi in a broader population of all patients with early Alzheimer’s disease.
Data show lower risk of ARIA in some patients
ARIA manifests in two forms: ARIA-E (oedema) involving the accumulation of fluid in the brain and ARIA-H (haemorrhage) involving small bleeds in the brain. It can occur naturally in all patients with Alzheimer’s disease, but it is exacerbated by taking medicines such as Leqembi, i.e., antibodies targeting amyloid beta. In the re-examination requested by the company, the CHMP considered subgroup analyses which excluded data from patients who carried 2 copies of the ApoE4 gene and were therefore at highest risk of ARIA.
The results of these analyses showed that among patients treated with Leqembi, 8.9% of those with only one or no copy of ApoE4 experienced ARIA-E, compared with 12.6% of all patients; similarly, 12.9% of patients in the restricted population experienced ARIA-H compared with 16.9% of the broader population.
Among patients treated with placebo (a dummy treatment), the figures were 1.3% and 6.8% for ARIA-E and ARIA-H, respectively, in the restricted population.
Alzheimer Europe welcomes the positive decision by the CHMP, which addresses many of the concerns highlighted in Alzheimer Europe’s official response to the initial CHMP decision, enabling patients to engage in discussions with their physicians and make informed decisions based on their individual circumstances, preferences and values, including the acceptability of risk and anticipated benefits.
Alzheimer Europe appreciates and supports the considered approach that the EMA has taken to identify patients likely to benefit from treatment and exclude those at greatest risk of harmful side-effects. During the re-examination, the CHMP focused on participants with only one or no copies of the ApoE4 gene, assessing data from a subgroup of 1,521 individuals out of the 1,795 participants in the Clarity-AD trial of lecanemab. In this group, the risk of amyloid-related imaging abnormalities (ARIA) was generally lower than in the full trial population, which included people with two copies of the ApoE4 gene.
Data on benefits in the restricted population
In terms of effectiveness, the benefits of Leqembi in the restricted population are in line with those seen in the broader population. For the re-examination, the company provided a subgroup analysis of data from the main study which included 1,521 patients who have one or no ApoE4 copy out of total of 1,795 patients. The main measure of effectiveness was a change in cognitive and functional symptoms after 18 months, as measured using a dementia rating scale known as CDR-SB. The scale ranges from 0 to 18, with higher scores indicating greater impairment.
After 18 months of treatment, patients treated with Leqembi had a smaller increase in CDR-SB score than those who received placebo (1.22 versus 1.75), indicating slower cognitive decline. The results of other key measures were similar to those seen with the CDR-SB scale.
Additional safety measures
The CHMP concluded that the benefits of Leqembi outweigh the risks in patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease with one or no copy of ApoE4, provided that risk minimisation measures are in place to reduce the risk of severe and symptomatic ARIA and monitor its consequences in the long term.
Leqembi will be available through a controlled access programme to ensure that the medicine is only used in the recommended patient population.
Patients will need to have MRI scans to monitor for ARIA before initiation of treatment and before the 5th, 7th and 14th dose of Leqembi. Additional MRI scans may be needed at any time during treatment if patients develop symptoms of ARIA (such as headache, confusion, visual changes, dizziness, nausea, and difficulty walking).
To increase awareness of ARIA and ensure early detection and treatment, the company will provide a guide and checklist for healthcare professionals, an alert card for patients and training programmes on ARIA for healthcare professionals. In addition, it must carry out a post-authorisation safety study to further characterise ARIA-E and ARIA-H and assess the effectiveness of the risk minimisation measures. The company will set up an EU-wide registry study with patients treated with Leqembi that can be used to estimate the incidence of side effects, including ARIA, and to determine how severe they are. The registry study can also be used to collect information about patients’ progression to the next stages of Alzheimer’s disease and the possible long-term consequences of ARIA.
As for all assessments, during the re-examination the CHMP also considered submissions from patients, carers, clinicians and organisations, who shared their perspectives on the unmet needs of patients with Alzheimer’s disease and the data on cognitive decline and risks.
The CHMP’s opinion is an intermediary step on Leqembi’s path to patient access. The opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation. Once a marketing authorisation has been granted, decisions about pricing and reimbursement will take place at the level of each Member State, taking into account the potential role and use of this medicine in the context of its national health system.
More about Leqembi and Alzheimer’s disease
Alzheimer’s disease is an irreversible and progressive brain disorder that affects memory, thinking and behaviour.
Leqembi contains the active substance lecanemab and is to be given as an infusion (drip) into a vein once every two weeks. The active substance in Leqembi, lecanemab, is a monoclonal antibody (a type of protein) that attaches to a substance called amyloid beta, which forms plaques in the brains of patients with Alzheimer’s disease. By attaching to amyloid beta, Leqembi reduces the amyloid plaques in the brain.
The most common side effects with Leqembi include infusion-related reactions, ARIA-H, ARIA-E, and headache. Leqembi must not be used by people receiving anticoagulant treatment as this could increase the risk of developing ARIA-H and bleedings in the brain.
