Lecanemab (CLARITY AD): anti-amyloid antibody for Alzheimer disease

The approval of aducanumab in June 2021 under FDA accelerated approval had fractured the Alzheimer field. The agency overrode its own advisory committee, which had voted against approval, accepting amyloid clearance as a surrogate endpoint without direct evidence of clinical benefit. Three of the committee members resigned in protest. The episode focused intense scrutiny on what evidentiary standard the next anti-amyloid antibody would need to meet. Lecanemab, a humanized IgG1 antibody with preferential binding to protofibrils, entered its phase 3 CLARITY AD trial with that context in full view.

CLARITY AD randomized 1,795 patients with early Alzheimer disease, confirmed by amyloid PET or CSF biomarker, to lecanemab 10 mg/kg intravenously every two weeks or placebo for 18 months. Christopher van Dyck at Yale led the trial as principal investigator. The primary endpoint was change on the Clinical Dementia Rating Sum of Boxes (CDR-SB), a clinician-rated measure of functional and cognitive status. Lecanemab slowed decline by 0.45 points relative to placebo, a 27% reduction. Amyloid burden on PET fell substantially in treated patients. The trial was published in the New England Journal of Medicine in January 2023.

The FDA granted traditional approval in July 2023, the first Alzheimer drug to clear that regulatory bar on a demonstrated clinical outcome rather than a surrogate. That distinction separated lecanemab from aducanumab and largely defused the advisory-committee controversy that had surrounded the earlier approval. ARIA-E, the swelling or effusion form of amyloid-related imaging abnormalities, occurred in 12.6% of lecanemab-treated patients, and the hemorrhage form was also more frequent than with placebo. Risk was highest in APOE4 homozygotes, a finding that introduced a genotyping question into the treatment decision for a disease that had not previously required it.

Ivan Cheung, chairman and chief executive of Eisai Inc., and Lynn Kramer, Eisai's chief clinical officer for neurology, had overseen the commercial development. Centers for Medicare and Medicaid Services coverage followed in July 2023 for patients enrolled in a qualifying registry, a condition that continued to gather real-world outcomes data as a condition of broad access. Lecanemab, sold as Leqembi, requires ongoing biweekly IV infusions indefinitely, which created logistical and cost burdens that limited uptake in the first year after approval. The question of what constitutes a clinically meaningful CDR-SB difference, and whether 0.45 points is perceptible to patients and families, was debated in the neurology literature through 2024.