In CLARITY AD, lecanemab slowed decline in measures of cognition and function and reduced markers of amyloid in early Alzheimer’s disease at 18 months.
Study results were presented by Christopher van Dyck, MD. He said that the accumulation of soluble and insoluble aggregated beta amyloid (Aβ) may initiate or potentiate AD pathology. Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that highly selectively binds to Aβ aggregate species and initiates microglial-mediated clearance of protofibrils and plaques.
CLARITY AD is a global, double-blind, parallel group phase 3 trial in which lecanemab is tested against placebo in participants with early AD. The 1,795 participants were aged 50-90 with mild cognitive impairment or mild dementia due to AD, with confirmed amyloid pathology. In the 18-month randomization phase, they were assigned 1:1 to receive IV lecanemab 10 mg/kg biweekly (N=898) or matching placebo (N=897). In the open-label extension phase, all participants receive lecanemab. The primary endpoint was the change after 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range, 0-18).
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. 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 (95% CI, 18% to 46%; P=0.00001) compared with placebo. This means that the lecanemab group took 25.5 months to reach the same level as placebo reached at 18 months.
In an exploratory analysis, lecanemab also showed consistent benefits in HRQOL measures and caregiver burden across different scales, Dr. Van Dyck added. The safety profile of lecanemab was acceptable. Lecanemab resulted in infusion-related reactions in 26.4% of patients and amyloid-related imaging abnormalities with edema or effusions (ARIA-E) in 12.6%.
Biomarker studies using PET, cerebrospinal fluid, and plasma analyses revealed that lecanemab improved both essential biological features of AD, amyloid and tau. This indicated disease modification, which Dr. Van Dyck said was “unprecedented” in AD. The AHEAD study is now evaluating whether earlier (presymptomatic) and longer intervention may be associated with greater effect size.
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