Abstract Details

Title The Effects of Lecanemab Treatment on Soluble CSF Aß Protofibrils (PF) in Clarity AD

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S1 - New Perspectives on Alzheimer's Therapeutics (1:24 PM-1:36 PM)

Poster/Presentation
Number 003

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.

Authors/Disclosures
Kanta Horie, PhD PRESENTER	Dr. Horie has received personal compensation for serving as an employee of Eisai Inc.
Akihiko Koyama (Eisai Inc.)	No disclosure on file
Pallavi Sachdev (Eisai Inc.)	No disclosure on file
Kazuyoshi Shuta, MSc	Mr. Shuta has received personal compensation for serving as an employee of Eisai Co., Ltd..
Kazuhiro Tahara	Mr. Tahara has nothing to disclose.
Michio Kanekiyo, MS	Mr. Kanekiyo has received personal compensation for serving as an employee of Eisai Inc. Mr. Kanekiyo has stock in Eisai Co Ltd..
Shobha Dhadda	Shobha Dhadda has received personal compensation for serving as an employee of Eisai Inc.
Larisa Reyderman	Larisa Reyderman has nothing to disclose.
Steven M. Hersch, MD, PhD (Eisai Inc.)	Dr. Hersch has received personal compensation for serving as an employee of Eisai Inc.. Dr. Hersch has stock in Voyager Therapeutics. The institution of an immediate family member of Dr. Hersch has received research support from NIH. Dr. Hersch has received intellectual property interests from a discovery or technology relating to health care.
Michael C. Irizarry, MD (Eisai, Inc)	Dr. Irizarry has received personal compensation for serving as an employee of Eisai, Inc..
Lynn D. Kramer, MD, FAAN (Eisai Inc.)	Dr. Kramer has received personal compensation for serving as an employee of Eisai Inc. Dr. Kramer has received personal compensation in the range of $1,000,000+ for serving as an officer or member of the Board of Directors for Eisai Co., Ltd..

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