The European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has announced it will recommend the approval of lecanemab (Leqembi; Eisai) for treating symptoms associated with early Alzheimer's disease (AD) within the European Union. This decision marks a reversal from the EMA's previous stance in July, which cited safety risks, particularly amyloid-related imaging abnormalities (ARIA), as outweighing the potential benefits. The recommendation is contingent upon restricting its use to a specific patient population.
Re-evaluation Based on Subgroup Analysis
The reversal came after Eisai submitted a subgroup analysis from the phase 3 CLARITY AD clinical trial. This analysis focused on participants who were either heterozygous or noncarriers of the apolipoprotein E ε4 (ApoE ε4) gene variant. The ApoE ε4 gene has been implicated in the development of AD, and the initial EMA concerns centered on the higher prevalence of ARIA among individuals homozygous for this variant.
Restricted Approval and Risk Mitigation
The EMA's revised opinion states that, within the restricted population assessed, the benefits of Leqembi in slowing the progression of Alzheimer's symptoms outweigh the risks. The recommendation limits the use of lecanemab to individuals with Alzheimer's disease who do not carry the ApoE ε4 gene variant or carry only one copy, and who also demonstrate confirmed amyloid pathology. The agency will also require risk mitigation measures, including a controlled access program to ensure the medication is used solely within the approved population.
Alzheimer's Association's Response
Joanne Pike, DrPH, President and CEO of the Alzheimer's Association, acknowledged the EMA's decision as "an important step toward Europeans having access to a proven treatment." However, the Alzheimer's Association has expressed disagreement with the decision to exclude ApoE ε4 homozygous carriers from the eligible treatment pool, urging the EMA to continue reviewing clinical trials and real-world evidence to potentially expand the recommendation.
Clinical Trial Data and Global Regulatory Status
The CHMP's positive opinion was primarily based on phase 3 data from Eisai's global CLARITY AD clinical trial. In this trial, lecanemab met its primary endpoint and all key secondary endpoints with statistically significant results. The CLARITY AD trial was a global, placebo-controlled, double-blind, parallel-group, randomized study involving 1795 participants with early AD, with 1521 participants being ApoE ε4 non-carriers or heterozygotes. Participants were randomly assigned to receive either lecanemab 10 mg/kg bi-weekly or placebo for 18 months.
Lecanemab has already been approved in the U.S., 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 also submitted a supplemental Biologics License Application (BLA) for intravenous maintenance dosing and is developing a subcutaneous injection formulation for enhanced convenience and adherence.
