Lecanemab, a humanized immunoglobulin G1 monoclonal antibody, selectively binds to soluble Aβ aggregate species and demonstrates low affinity for Aβ monomer. Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) analyses reveal its impact on amyloid plaques and biomarkers in early Alzheimer's disease (AD). The study, involving subjects with early AD, assessed amyloid plaques using positron emission tomography (PET) and biomarkers like the Aβ42/40 ratio and plasma p-tau181 following intravenous administration of lecanemab. Lecanemab's PK was well-characterized using a two-compartment model with first-order elimination.
Key Findings
The final PK model incorporated covariate effects of anti-drug antibody positive status, sex, body weight, and albumin on clearance. The time course of amyloid PET standard uptake ratio (SUVr), plasma Aβ42/40 ratio, and p-tau181 were described using indirect response models. Lecanemab exposure stimulated the reduction of SUVr and increased the Aβ42/40 ratio while decreasing p-tau181 formation rates. PK/PD simulations indicated that a 10 mg/kg biweekly dosing regimen results in a larger and faster decrease in SUVr and p-tau181, as well as a more significant increase in the Aβ42/40 ratio, compared to a 10 mg/kg monthly dose.
Implications of Treatment Discontinuation
PK/PD simulations further demonstrated that after treatment discontinuation, the re-accumulation of brain amyloid to baseline levels is slow, with an estimated recovery half-life of approximately four years. In contrast, plasma Aβ42/40 ratio and p-tau181 return to baseline levels more rapidly than amyloid. These findings suggest that lecanemab's effect on brain amyloid is sustained longer than its impact on plasma biomarkers.
Study Design and Methods
The phase II study involved a double-blind, parallel-group, placebo-controlled, multicenter design. It randomized 856 subjects across six treatment groups, including placebo, and various lecanemab doses (2.5 mg/kg biweekly, 5.0 mg/kg monthly, 5.0 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly) for 18 months. An open-label extension (OLE) phase followed, allowing subjects to receive open-label lecanemab 10 mg/kg biweekly for up to 60 months. The PK analysis utilized pooled data from subjects in phase 1 and phase 2 studies. PK/PD analyses for SUVr, plasma Aβ42/40 ratio, and p-tau181 were performed on data from subjects with early AD receiving either lecanemab or placebo.
Population PK Analysis
Lecanemab PK was described by a two-compartment linear model. The final PK model included the covariate effects of sex, body weight, and albumin on CL, sex, and body weight on V1, and Japanese race on V2. The effect of ADA status on CL was identified as a significant covariate and included in the final PK model. Additionally, the relative F of the formulation (process B vs. process A) as an additional PK parameter was identified to be significant.
PK/PD Analysis for Amyloid PET SUVr
The relationship between serum lecanemab concentration and the amyloid PET SUVr reduction time course was well-described by an indirect response model with lecanemab concentration in the central compartment at the time of SUVr measurement, as a maximum effect (Emax) function, acting to increase the rate of plaque removal. Covariates identified in the final SUVr model indicate that APOE4 carrier subjects have higher baseline SUVr, and older subjects have higher maximum plaque removal (Emax) by lecanemab.
PK/PD Analysis for Plasma Biomarkers
For plasma Aβ42/40 ratio and p-tau181, absolute measurements over time were correlated with PK model-predicted lecanemab concentration in the central compartment at the time of the assessment by an indirect response model with exposure as a linear function increasing Aβ42/40 ratio or decreasing p-tau181. No covariate effects were retained in the final model for Aβ42/40 ratio. Only the effect of body weight on baseline remained significant and retained in the final PK/PD model for p-tau181.
Model-Based Simulations
Model-based simulations explored the effect of lecanemab dosing regimens of 10 mg/kg biweekly or 10 mg/kg monthly for a treatment duration of 18 months on SUVr and Aβ42/40 ratio and plasma p-tau181. Simulations also explored the potential impact of the treatment discontinuation on SUVr and plasma biomarkers after 18 months of continuous treatment at 10 mg/kg biweekly. The percentage of subjects achieving amyloid negativity for SUVr less than 1.17 at 18 months following continuous treatment with lecanemab at 10 mg/kg biweekly or monthly were derived.
Clinical Implications
The PK/PD models developed in this study provide valuable insights into the effect of lecanemab dosing on brain amyloid removal and plasma biomarkers of amyloid and tau pathology. The simulations support the use of a 10 mg/kg biweekly dosing regimen for optimal amyloid reduction in patients with early Alzheimer's disease. The models also offer a framework for predicting the long-term effects of lecanemab treatment and the potential for amyloid re-accumulation following treatment discontinuation.
