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Abstract Details

Exposure-Response Modeling to Describe Change in Brain Amyloid Following Lecanemab Administration in Patients with Early Alzheimer’s Disease
Aging, Dementia, Cognitive, and Behavioral Neurology
P9 - Poster Session 9 (8:00 AM-9:00 AM)
Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. Lecanemab has been tested as a disease-modifying treatment for early Alzheimer’s disease in two clinical studies. As part of these studies, amyloid PET scans were collected in a subset of patients, demonstrating that lecanemab leads to pronounced reduction in brain amyloid.
To describe change in brain amyloid following lecanemab administration in patients with early Alzheimer’s disease using exposure-response modeling.
A model describing the relationship between serum lecanemab exposure and brain amyloid reduction from baseline was developed using data pooled from phase 2 and 3 studies. Individual serum lecanemab exposure was estimated using a population pharmacokinetic model and correlated with amyloid PET using an indirect response model, with a lecanemab-dependent increase in the degradation rate of amyloid introduced as linear function. The model was parametrized in terms of baseline amyloid load, elimination rate constant for amyloid removal (Kout) and exposure effect (DESLP). Inter-subject variability was estimated for each of the model parameters. Covariates were included using a forward-inclusion (p<0.01)/backwards-elimination (p<0.001) approach.
A total of 4129 observations from 1088 subjects were included. The model estimate of Kout was 0.0496 yr-1 (95% confidence interval:0.0206-0.0827), suggesting a re- accumulation half-life of brain amyloid of ~14 years. APOE4 carrier status was a statistically significant predictor of baseline amyloid (APOE4 noncarriers:65 CL; APOE4 carriers:83 CL). Age was a significant covariate on DESLP, with older patients removing amyloid at a faster rate than younger patients. None of the other covariates had a statistically significant effect on any model parameter.
An exposure-response model has been developed that describes the change in brain amyloid over time following lecanemab administration. This model provides additional insights into factors that may drive differences in the rate of brain amyloid removal between patients.
Brian A. Willis, PhD (Eli Lilly and Co.)
Dr. Willis has received personal compensation for serving as an employee of Eisai, Inc. Dr. Willis has stock in Eli Lilly and Co.
Ziad Hussein No disclosure on file
Sami Omerhoca No disclosure on file
Osamu Takenaka (Eisai) No disclosure on file
Natasha Penner No disclosure on file
Sanae Yasuda No disclosure on file
Larisa Reyderman Larisa Reyderman has nothing to disclose.