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Lecanemab may slow decline of cognition and function in Alzheimer’s Disease

Presented by
Prof. Christopher van Dyck, Yale School of Medicine, CT, USA
AAN 2023

In the placebo-controlled CLARITY AD study, lecanemab slowed the decline in measures of cognition and function in early Alzheimer’s Disease (AD) at 18 months. Lecanemab reduced markers of amyloid and tau indicating disease modification.

The study results were presented by Prof. Christopher van Dyck (Yale School of Medicine, CT, USA) [1]. He said accumulating soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate AD pathology. Lecanemab is a humanised immunoglobulin G1 (IgG1) monoclonal antibody that highly selectively binds to Aβ aggregate species and initiates microglial-mediated clearance of protofibrils and plaques.

The global, double-blind, parallel-group, phase 3 CLARITY AD trial (NCT03887455) aimed to confirm the safety and efficacy of lecanemab compared with a placebo in participants with early AD [2]. At randomisation, the 1,795 participants were 50–90 years of age with mild cognitive impairment or mild dementia due to AD, with confirmed amyloid pathology. In the 18-month randomisation phase, they were assigned 1:1 to receive intravenous lecanemab 10 mg/kg biweekly (n=898) or a matching placebo (n=897). In the open-label extension phase, all participants received lecanemab. The primary endpoint was the change in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range 0 to 18) after 18 months.

The mean CDR-SB score at baseline was approximately 3.2 in both groups. Lecanemab significantly slowed disease progression on CDR-SB by 27% at 18 months and at all time points, beginning at 6 months (see Figure). The adjusted least-squares mean change from baseline was 1.21 in the lecanemab group versus 1.66 in the placebo group (difference -0.45; 95% CI -0.67 to -0.23; P<0.001). A slope analysis using CDR-SB showed a 32% annual slowing of the slope (18–46%; P=0.00001) compared with the placebo. This means that the lecanemab group took 25.5 months to reach the same level of CDR-SB scores as the placebo at 18 months.

Figure: Lecanemab significantly slowed disease progression on CDR-SB at all time points, beginning at 6 months. Adapted from [1,2]

CDR-SB, Clinical Dementia Rating–Sum of Boxes; LS, least squares; SE, standard error.

In an exploratory analysis, lecanemab also showed consistent benefits in health-related quality of life measures and caregiver burden across different scales, Prof. Van Dyck added. The safety profile of lecanemab was acceptable: lecanemab resulted in infusion-related reactions in 26.4% and amyloid-related imaging abnormalities with oedema or effusions (ARIA-E) in 12.6% of participants.

Biomarker studies using PET and cerebrospinal fluid and plasma analyses revealed that lecanemab improved both essential biological features of AD: amyloid and tau. “This indicates disease modification, which is unprecedented in AD”, highlighted Prof. van Dyck. The recruiting AHEAD 3-45 Study (NCT04468659) will evaluate whether earlier (presymptomatic) and longer intervention may be associated with an even greater effect size. Presymptomatic patients are defined by age (55–80 years old), Clinical Dementia Rating of 0, Mini Mental State Examination score ≥27, Wechsler Memory Scale-Revised Logical Memory subscale II score of ≥6, and elevated brain amyloid pathology. For patients ≤64 years of age, 1 of the following additional risk factors is required: first-degree relative diagnosed with dementia onset before age 75, known to possess at least 1 apolipoprotein E4 variant allele, or known before screening to have elevated brain amyloid according to previous PET of CSF testing.

  1. Van Dyck CH. A study to confirm safety and efficacy of lecanemab in participants with early Alzheimer’s disease (CLARITY AD). PL5.005, AAN 2023 Annual Meeting, 22–27 April, Boston, USA.
  2. Van Dyck CH, et al. N Engl J Med 2023; 388:9–21.

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