Promising results for lecanemab's efficacy in patients with mild cognitive impairment or mild dementia associated with Alzheimer disease were accompanied by reports of adverse effects associated with treatment.
Lecanemab (Leqembi) is a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody that reduces forms insoluble amyloid beta (Aβ) proteins responsible for cognitive impairment and the development of Alzheimer disease (AD). The drug works to reduce Aβ plaques and prevent Aβ deposition in the brain, which is implicated in the pathophysiology of AD.
It was recently approved by the FDA under the accelerated approval pathway for the treatment of AD.1
Lecanemab consists of monoclonal antibodies that target extracellular Aβ plaques. Those Aβ plagues are linked to synaptic impairment, neuronal death, and progressive neurodegeneration.
The consequence of the presence Aβ plagues is dementia and cognitive impairment associated with AD. Aβ peptides exist in various conformational states but the antibody targets mostly soluble aggregated Aβ, which are the most neurotoxic; moreover, it works on Aβ oligomers, protofibrils, and insoluble fibrils.2
The phase 3 CLARITY study of lecanemab was successfully completed and its primary endpoint and all key secondary endpoints demonstrated statistically significant reductions in cognitive and functional decline in patients with early-stage AD. The study involved 1795 patients with early-onset AD from Japan, the United States, Europe, and China.
In the randomized control trial, 898 participants were assigned to receive lecanemab and 897 were assigned to the placebo cohort. The therapy lasted 18 months and patients received the drug by intravenous (IV) infusions 10 mg per kilogram of body weight every 2 weeks.3
The result of the clinical trial for lecanemab was promising. After 18 months of therapy, the rate of cognitive decline in patients at 18 months compared with placebo was -0.45 (95% Confidence Interval (CI): -0.67, -0.23; P=0.00005), representing a 27% slowing of decline.
Cognitive decline was measured using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). The therapy lasted 18 months, but most people noticed clear effects after 6 months of treatment.3
Such results have not yet been obtained in any studies of potential drugs for AD. The drug may help to slow down AD development, allowing patients to stay in the stage of mild cognitive impairment for as long as possible.
The promising results of the drug's efficacy were overshadowed by the numerous adverse effects (AEs) that were noted in the control group. Approximately 6.9% of study participants administered lecanemab IV infusion discontinued treatment due to AEs compared to 2.9% of participants receiving placebo.
Overall, serious AEs occurred in 14% of patients in the lecanemab group and 11.3% patients in the placebo group. The most common AEs of taking lecanemab were cerebral edema ARIA-E and bleeding into the brain, which are life-threatening.
Importantly, the incidence of these AEs was higher in people who had the APOE4 gene, which may increase the risk of AD or other types of dementia.3 A total of 13 deaths have occurred in the CLARITY trial, 7 in the placebo group and 6 in the lecanemab group.
The age and medical condition of any trial participants should be considered when evaluating a death. Neuroscientists who reviewed the records of a patient who died after extensive brain swelling and bleeding linked the death to lecanemab use.4
There is still significant uncertainty and controversy regarding lecanemab treatment. A previously approved drug for AD, aducanumab (Aduhelm), also gained controversy because of its accelerated approval. The FDA issued the approval even though its advisory body did not recommend it.
The experts noted that there will be limited access to the therapy because only patients with mild dementia can receive lecanemab, which significantly narrows the group of patients who can start the new treatment. In addition, patients with an increased risk for cerebral edema and cerebral hemorrhagic stroke, as well as those taking blood thinners, should be excluded.
However, if the treatment is fully approved, the Centers for Medicare & Medicaid Services released a statement noting that patients will receive coverage.5