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Lecanemab Efficacy, Safety in Early Alzheimer’s Disease

In results released yesterday from the highly anticipated CLARITY SF phase 3 study, the monoclonal antibody lecanemab “reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events,” researchers report. Lecanemab “binds with high affinity to soluble amyloid-beta protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils.”

The 18-month, double-blind trial included 1,795 participants aged 50 to 90 years who had early Alzheimer’s disease, defined as mild cognitive impairment or mild dementia caused by Alzheimer’s disease. The patients received intravenous lecanemab 10 mg/kg or placebo every 2 weeks. In addition to a primary endpoint of the change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment), several secondary endpoints were also tracked: change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).

“The mean CDR-SB score at baseline was approximately 3.2 in both groups,” the authors write. “The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P <0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, −59.1 centiloids; 95% CI, −62.6 to −55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, −1.44 (95% CI, −2.27 to −0.61; P <0.001); for the ADCOMS, −0.050 (95% CI, −0.074 to −0.027; P <0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P <0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.”

Reflecting on these data and other study results presented yesterday at the Clinical Trials on Alzheimer’s Disease conference in San Francisco, Sharon Cohen of the Toronto Memory Center said, “The convergence of evidence across multiple measures — cognition, function, disease progression, health-related quality of life, caregiver burden, and biomarkers — demonstrates that lecanemab treatment may offer meaningful benefits to patients, care partners, and society.… The results of CLARITY AD support the role for treatment and therapy in early Alzheimer’s disease stages of an amyloid protofibril–targeted therapy.… These results also ask us to focus on a paradigm shift of diagnosing earlier in order to achieve disease slowing and extend milder stages of disease.”

Source: New England Journal of Medicine