The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending the approval of lecanemab, an amyloid-beta (Aβ) monoclonal antibody, for the treatment of adult patients with 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. This decision follows a re-examination of a prior negative opinion from July 2024.
Mechanism of Action
Lecanemab selectively binds to soluble Aβ aggregates (protofibrils) and insoluble Aβ aggregates (fibrils), which are major components of Aβ plaques in Alzheimer's disease. By reducing both Aβ protofibrils and Aβ plaques in the brain, lecanemab aims to slow the progression of the disease. Protofibrils are considered the most toxic form of Aβ, contributing significantly to the cognitive decline associated with Alzheimer's.
Clinical Trial Data
The CHMP's positive opinion is primarily based on data from the Phase 3 Clarity AD clinical trial. This global, placebo-controlled, double-blind, parallel-group, randomized study involved 1,795 patients with early Alzheimer’s disease. Participants were administered lecanemab 10 mg/kg bi-weekly or placebo for 18 months.
The primary endpoint was the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a global cognitive and functional scale. In the Clarity AD trial, treatment with lecanemab in the recommended indicated population (ApoE ε4 noncarriers or heterozygotes) reduced clinical decline on CDR-SB by 31% at 18 months compared to placebo (difference, -0.535; 95% CI, -0.778 to -0.293; P=0.00001).
Secondary endpoints also showed significant benefits. The Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL) noted 33% less decline compared to placebo at 18 months (difference, 1.936; 95% CI, 1.029 to 2.844; P=0.00002).
Adverse Reactions
The most common adverse reactions observed in the ApoE ε4 heterozygotes or non-carriers population were infusion-related reactions (26%), ARIA-H (13%), headache (11%), and ARIA-E (9%).
Alzheimer's Disease Burden
Alzheimer's disease currently affects an estimated 6.9 million people in Europe, with projections indicating a near doubling of this figure by 2050 due to aging populations. The progressive nature of the disease presents significant challenges for patients and their caregivers, highlighting the urgent need for new treatment options that can slow disease progression.
Regulatory Status and Future Development
Lecanemab has already been approved in the US, Japan, China, South Korea, Hong Kong, Israel, the United Arab Emirates, and Great Britain. It is currently under regulatory review in 17 other countries. Eisai has submitted a supplemental Biologics License Application (sBLA) to the US FDA for intravenous maintenance dosing and initiated a rolling submission for a subcutaneous injection formulation to enhance patient convenience.
Ongoing clinical studies, such as the Phase 3 AHEAD 3-45 trial for individuals with preclinical Alzheimer's, and the Tau NexGen clinical study for Dominantly Inherited Alzheimer's Disease (DIAD), continue to explore the potential of lecanemab in various stages of the disease.
