A positive opinion has been received from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending approval of the amyloid-beta (Aβ) monoclonal antibody lecanemab (brand name Leqembi®) as a treatment of adult patients with a clinical diagnosis of mild cognitive impairment and mild dementia due to Alzheimer’s disease (Early Alzheimer’s disease) who are apolipoprotein E ε4 (ApoE ε4)* non-carriers or heterozygotes with confirmed amyloid pathology.1 Eisai had requested a re-examination of the prior negative opinion adopted by the CHMP in July 2024. In accordance with European Medicines Agency regulatory process, the European Commission is expected to make a final decision on the marketing authorization application (MAA) of lecanemab based on the CHMP recommendation within 67 days of receipt of CHMP opinion.2
How It Works
- Leqembi contains the active substance lecanemab.
- It is 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.
Lecanemab selectively binds to soluble Aβ aggregates (protofibrils**), as well as insoluble Aβ aggregates (fibrils) which are a major component of Aβ plaques in AD, thereby reducing both Aβ protofibrils and Aβ plaques in the brain.3,4,5
Eisai serves as the lead for lecanemab’s development and regulatory submissions globally with both Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority.
Clarity AD Clinical Trial Sways EMA
Lecanemab’s Positive Opinion from EMA’s CHMP in the European Union was primarily based on Phase 3 data from Eisai’s global Clarity AD clinical trial, in which it met its primary endpoint and all key secondary endpoints with statistically significant results.1,3 Clarity AD was a Phase 3 global, placebo-controlled, double-blind, parallel-group, randomized study in 1,795 patients with early AD (MCI or mild dementia due to AD, with confirmed presence of amyloid pathology), of which 1,521 were in the recommended indicated population (ApoE ε4 non-carriers or heterozygotes ). The treatment group was administered lecanemab 10 mg/kg bi-weekly, with participants allocated in a 1:1 ratio to receive either placebo or lecanemab for 18 months.1
Clinical Trial Results
The primary endpoint was the global cognitive and functional scale, CDR-SB.1 In the Clarity AD clinical trial, treatment with lecanemab, in the recommended indicated population (ApoE ε4 non-carriers or heterozygotes), reduced clinical decline on CDR-SB by 31% at 18 months compared to placebo based on conservative control based imputation.1 The mean CDR-SB score at baseline was approximately 3.2 in both groups.1 The adjusted least-squares mean change from baseline at 18 months was 1.217 with lecanemab and 1.752 with placebo (difference, −0.535; 95% confidence interval [CI], −0.778 to −0.293; P=0.00001).1 CDR-SB is a global cognitive and functional scale that measures six domains of functioning, including memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.10
In addition, the secondary endpoint from the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), which measures information provided by people caring for patients with AD, noted 33% less decline compared to placebo at 18 months.1 The adjusted mean change from baseline at 18 months in the ADCS-MCI-ADL score was −3.873 in the lecanemab group and −5.809 in the placebo group (difference, 1.936; 95% CI, 1.029 to 2.844; P=0.00002).1 The ADCS-MCI-ADL assesses the ability of patients to function independently, including being able to dress, feed themselves and participate in community activities.
In the ApoE ε4 heterozygotes or non-carriers population, the most common adverse reactions were infusion-related reaction (26%), ARIA-H (13%), headache (11%) and ARIA-E (9%).1
8 Countries Approve, 17 Countries Reviewing
Lecanemab has been approved in the U.S., Japan, China, South Korea, Hong Kong, Israel, the United Arab Emirates and Great Britain and is under regulatory review in 17 countries. A supplemental Biologics License Application (sBLA) for intravenous maintenance dosing was submitted to the U.S. Food and Drug Administration (FDA) in March 2024, which was accepted in June 2024. In May 2024, the rolling submission of a Biologics License Application (BLA) for maintenance dosing of a subcutaneous injection formulation, which is being developed to enhance convenience for patients, was initiated in the U.S. under Fast Track status, with the rolling submission and completed in October 2024.
Preventing Alzheimer’s with Leqembi
Since July 2020 the Phase 3 clinical study (AHEAD 3-45) for individuals with preclinical AD, meaning they are clinically normal and have intermediate or elevated levels of amyloid in their brains, is ongoing. AHEAD 3-45 is conducted as a public-private partnership between the Alzheimer’s Clinical Trial Consortium that provides the infrastructure for academic clinical trials in AD and related dementias in the U.S, funded by the National Institute on Aging, part of the National Institutes of Health, Eisai and Biogen.
Since January 2022, the Tau NexGen clinical study for Dominantly Inherited AD (DIAD), that is conducted by Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), led by Washington University School of Medicine in St. Louis, is ongoing and includes lecanemab (Leqembi) as the backbone anti-amyloid therapy.
What EMA Said:
After re-examining its initial opinion, EMA’s 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.
Side Effects: ARIA
The most common side effects with Leqembi include infusion-related reactions, ARIA-H, ARIA-E, and headache.
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.
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.
Benefits in This Specific Population
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 CHMP concluded that the benefits of Leqembi outweigh the risks in these patients.
