The European Medicines Agency (EMA) human medicines committee (CHMP), after re-examining its initial opinion, has recommended granting a marketing authorisation to Leqembi (lecanemab) for treating mild cognitive impairment or mild dementia due to Alzheimer’s disease in patients who have only one or no copy of ApoE4.
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.
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, but is exacerbated by medicines like 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 two 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, the figures were 1.3% and 6.8% for ARIA-E and ARIA-H, respectively, in the restricted population.
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 a 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 zero 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 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 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 (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.
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.
EMA article – Leqembi recommended for treatment of early Alzheimer’s disease (Open access)
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