The Effects of Lecanemab Treatment on Soluble CSF Aβ Protofibrils (PF) in Clarity AD
Kanta Horie1, Akihiko Koyama1, Pallavi Sachdev1, Kazuyoshi Shuta2, Kazuhiro Tahara2, Michio Kanekiyo1, Shobha Dhadda1, Larisa Reyderman1, Steven Hersch1, Michael Irizarry1, Lynn Kramer1
1Eisai Inc., 2Eisai Co. Ltd.
Objective:
To further characterize CSF amyloid-β protofibrils (Aβ-PF) in the Clarity AD trial: (1) at baseline, (2) as the target engagement biomarker (in-vivo protofibril binding) of lecanemab, (3) longitudinally in the placebo arm (natural history), and (4) by investigating the associations between the change from baseline levels of CSF Aβ-PF and neurodegenerative biomarkers in placebo and lecanemab-treated subjects.
Background:
Lecanemab is a monoclonal antibody that binds with high affinity to soluble Aβ-PF, which are highly toxic and are in equilibrium with amyloid plaques.
Design/Methods:
Aβ-PF levels were quantified in the CSF samples collected in the Clarity AD trial in 410 subjects. Other biomarker assessments including amyloid PET, and CSF biomarkers including t-tau, p-tau181, neurogranin, MTBR-tau243.
Results:
Baseline CSF Aβ-PF positively correlated with neurogranin (r=0.153, p=0.0127) and negatively correlated with amyloid PET centiloid (r=-0.202, p=0.0005). In the lecanemab-treatment arm, the CSF total Aβ-PF levels (free and bound) increased relative to placebo at each post-baseline assessment (p=0.0126 at 12 months and numerically higher at 18 months). In amyloid-negative subjects (Centiloid<30), lecanemab-treatment group demonstrated a larger change from baseline in CSF Aβ-PF compared with amyloid-positive subjects at 18 months. Increases in baseline CSF Aβ-PF correlated positively with the increases in the CSF t-tau (r=0.286, p=0.0069), neurogranin (r=0.262, p=0.0138), p-tau181 (r=0.304, p=0.0040), and MTBR-tau243 (r=0.252, p=0.0155). In the lecanemab-treatment arm, even though we observed an increase in total CSF Aβ-PF levels, there were no significant associations between the changes from baseline (%) in CSF Aβ-PF and the neurodegenerative or tau-related biomarkers.
Conclusions:
The observed increase in total CSF Aβ-PF levels with lecanemab-treatment demonstrates target engagement, and mobilization of Aβ-PF from amyloid plaques (pharmacodynamic effect), confirming the unique dual mechanism of lecanemab targeting Aβ-PF and plaques. Lecanemab treatment disrupts the association between CSF Aβ-PF and AD biomarkers changes observed in the placebo arm, suggesting neutralization of Aβ-PF toxicity.
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