Lecanemab in Alzheimer’s disease

Abstract

The amyloid hypothesis, which proposes the accumulation of ?-amyloid (?A) peptide at the synapse, is the key factor in the pathogenesis of Alzheimer's disease (AD) and this has been the dominant idea in the field of AD research for almost 30 years. Numerous anti-?A drugs that inhibit the production or aggregation of ?A or stimulate its clearance have failed to demonstrate clinical benefit in large-scale AD trials; for its part, aducanumab, a monoclonal antibody for the treatment of early AD, has shown its ability to substantially reduce brain plaque burden. In addition, two other potent monoclonal antibodies, lecanemab and donanemab, have shown their ability to rapidly and substantially clear brain plaques and have recently produced encouraging cognitive and clinical results in people with early AD.

Specifically, lecanemab is an antibody that binds to large aggregates of soluble ?A (protofibrils) and in the phase III clinical trial in people with early AD (CLARITY AD; NCT03887455), lecanemab slowed cognitive decline by 27% after administration for 18 months. The study enrolled 1795 participants, of whom 898 were assigned to receive lecanemab and 897 to placebo. On the Clinical Dementia Rating Scale: sum of boxes (CDR-SB), it had a mean score at baseline of approximately 3.2 in both groups. The mean change was reported and adjusted for least squares from baseline to 18 months, resulting in a decrease to 1.21 with lecanemab and 1.66 with placebo. In addition, 698 participants in a substudy had greater reductions in ?A burden with lecanemab than with placebo (difference -59.1 centiloids). The study showed that lecanemab significantly ameliorated ?A accumulation in the brain and was also better than placebo on the secondary endpoints studied (cognitive scales and biological biomarkers).