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 for the treatment of adult patients with mild cognitive impairment and mild dementia due to Alzheimer’s disease, specifically those 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 and marks a significant step forward in addressing the unmet needs of individuals in the early stages of Alzheimer's. The European Commission is expected to make a final decision on the marketing authorization application within 67 days.
Mechanism of Action
Lecanemab, a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody, selectively binds to soluble amyloid-beta (Aβ) aggregates (protofibrils) and insoluble Aβ aggregates (fibrils). By targeting both forms of amyloid, lecanemab aims to reduce Aβ protofibrils and plaques in the brain, which are implicated in the pathogenesis of Alzheimer's disease. Protofibrils are considered the most toxic form of Aβ, contributing significantly to cognitive decline by injuring neurons and disrupting cell communication.
Clinical Trial Data
The CHMP's positive opinion was primarily based on data from the Phase 3 Clarity AD clinical trial. This global, placebo-controlled, double-blind study involved 1,795 patients with early Alzheimer's disease. Participants were randomized 1:1 to receive either 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, lecanemab demonstrated a statistically significant reduction in 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). The mean CDR-SB score at baseline was approximately 3.2 in both groups. Additionally, the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL) showed 33% less decline in the lecanemab group 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 (amyloid-related imaging abnormalities with hemorrhage, 13%), headache (11%), and ARIA-E (amyloid-related imaging abnormalities with edema, 9%).
Global Regulatory Status and Ongoing Studies
Lecanemab has already 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. Eisai and Biogen are co-commercializing and co-promoting the product, with Eisai having final decision-making authority. Further studies are ongoing, including the Phase 3 AHEAD 3-45 study for individuals with preclinical Alzheimer's and the Tau NexGen clinical study for Dominantly Inherited Alzheimer's Disease (DIAD).
Alzheimer's Disease Burden
Alzheimer's disease affects an estimated 6.9 million people in Europe, with projections indicating a near doubling of this figure by 2050. The availability of new treatment options like lecanemab is crucial to address the significant unmet need for therapies that can slow the progression of early Alzheimer's disease and reduce the overall burden on affected individuals and society.
