Exposure-Response Modeling to Describe Change in Brain Amyloid Following Lecanemab Administration in Patients with Early Alzheimer’s Disease
Brian Willis1, Ziad Hussein2, Seiichi Hayato3, Osamu Takenaka3, Natasha Penner1, Sanae Yasuda1, Larisa Reyderman1
1Eisai Inc., 2Eisai Co., Ltd, 3Eisai Ltd
Objective:
To describe change in brain amyloid following lecanemab administration in patients with early Alzheimer’s disease using exposure-response modeling.
Background:
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.
Design/Methods:
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.
Results:
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.
Conclusions:
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.