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European Medicines Agency Reverses Opinion on Lecanemab for Alzheimer Disease But Limits Eligible Population
The EMA recommendation excludes from treatment adults who are homozygous for the ApoE ε4 gene, a decision that the US Alzheimer's Association does not support, said the president/CEO.
In an usual regulatory shift, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) announced on Thursday that it will recommend approval of lecanemab (Leqembi; Eisai) as a treatment for symptoms associated with Alzheimer disease (AD) for marketing across the European Union, according to the manufacturer.1
The affirmative recommendation follows the EMA consensus in July that the safety risks reported with the amyloid-beta (Aβ) monoclonal antibody outweighed the potential benefits of the drug for treatment of adults with a clinical diagnosis of mild cognitive impairment and mild dementia due to AD.2 Chief among the concerns, according to an EMA statement,2 was the “frequent occurrence” of amyloid-related imaging abnormalities (ARIA), which often present in the form of brain swelling as well as small scale cerebral hemorrhage. In the clinical data reviewed by EMA, the regulators called attention to the greater prevalence of ARIA among individuals who are homozygous for the apolipoprotein E ε4 (ApoE ε4) gene variant than those who are heterozygous carriers or noncarriers.2 The ApoE protein is implicated in the development of AD.1
Eisai requested that the agency re-examine its initial negative opinion and provided a subgroup analysis of data from the phase 3 CLARITY AD clinical trial of participants who were either ApoE ε4 heterozygous or noncarriers, according to the company.1
Satisfied with the safety outcomes of the subanalysis, the European agency revised its stance on lecanemab approval, stating 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.”2 The recommendation is not universal, however, and calls for limiting use of the semimonthly infusion to that “restricted population,” ie, individuals with Alzheimer disease who do not carry the ApoE ε4 gene variant or carry 1 copy and who demonstrate “confirmed amyloid pathology.”1,2 There will be risk mitigation measures required as well, the EMA noted, including the only availability of the medication through a “controlled access program” that ensures lecanemab is used solely in the approved population.2
The EMA regulatory process requires the European Commission to make a final decision on the marketing authorization application of lecanemab based on the CHMP recommendation within 67 days of receipt of CHMP opinion.1,2
Alzheimer's Association Dissents
“This is an important step toward Europeans having access to a proven treatment that changes the underlying course of Alzheimer’s. While not a cure, this treatment can slow progression of the disease when taken in the early [disease] stages, allowing people more time to participate in daily life and live independently,” Joanne Pike, DrPH, Alzheimer’s Association president and CEO, said in an association statement. “We appreciate the EMA’s fast review and reversal of its earlier decision.”3
The US Alzheimer’s Association, however, does not fully support the current European proposal to limit access to lecanemab. “The Alzheimer’s Association disagrees with the decision to exclude this patient population [ApoE ε4 homozygous carriers] from the eligible treatment pool and encourages the EMA to continue to review clinical trials and real-world evidence and expand their recommendation.”3
The positive opinion on lecanemab from the CHMP in the European Union was primarily based on phase 3 data from Eisai’s global CLARITY AD clinical trial, in which the drug met its primary endpoint and all key secondary endpoints with statistically significant results. CLARITY AD was a global, placebo-controlled, double-blind, parallel-group, randomized study in 1795 participants with early AD of which 1521 were in the population of interest to the EMA CHMP, ie, ApoE ε4 non-carriers or heterozygotes. Participants were randomly assigned to receive either lecanemab 10 mg/kg bi-weekly or placebo for 18 months.1
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. In March 2024, Eisai submitted a supplemental Biologics License Application (BLA) for intravenous maintenance dosing that was accepted in June 2024. In May 2024, the rolling submission of a BLA for maintenance dosing of a subcutaneous injection formulation, developed to enhance convenience and adherence, was initiated in the US under Fast Track status, with the rolling submission completed in October 2024.
