Population pharmacokinetic-pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease

Abstract

Lecanemab is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregate species, while demonstrating low affinity for Aβ monomer. This article describes the population pharmacokinetic (PK) and PK/pharmacodynamic (PD) analyses for amyloid plaques, as measured using positron emission tomography (PET), and biomarkers of amyloid pathology as evidenced by Aβ42/40 ratio and plasma p-tau181 following i.v. administration of lecanemab in subjects with early Alzheimer's disease. Lecanemab PKs were well-characterized with a two-compartment model with first-order elimination. Final PK model contained 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 with lecanemab exposure as a maximum effect function stimulating the reduction of SUVr, and as a linear function increasing Aβ42/40 ratio and decreasing p-tau181 formation rates. PK/PD simulations show that 10 mg/kg biweekly dosing results in larger and faster decrease in SUVr and p-tau181 and increase in Aβ42/40 ratio as compared to 10 mg/kg monthly dose. Furthermore, the PK/PD simulations showed that after treatment discontinuation the brain amyloid re-accumulation to baseline levels is slow with a recovery half-life of ~4 years, whereas plasma Aβ42/40 ratio and p-tau181 return to baseline levels faster than amyloid. Given the relationship between changes in amyloid PET SUVr and soluble biomarkers, the developed PK/PD models can be used to inform lecanemab dose regimens in future clinical studies.

FIGURE 1

Schematic of the population PK and PK/PD models for lecanemab. CL, clearance; K _in, zero‐order rate constant for production of biomarker; K _out, first‐order rate constant of degradation of biomarker; PD, pharmacodynamic; PK, pharmacokinetic; Q, intercompartmental clearance; V ₁, central volume of distribution; V ₂, peripheral volume of distribution. The equation for standard uptake ratio (SUVr) PK/PD model is presented below: $\frac{\text{dSUVr}}{\mathrm{dt}}={\mathrm{K}}_{\text{in}}-\text{SUVr}\left(t\right)\bullet {\mathrm{K}}_{\text{out}}\bullet \left[1+\frac{{\mathrm{E}}_{\max }\bullet \text{Conc}}{{\mathrm{EC}}_{50}+\text{Conc}}\right]$ Estimated parameters included baseline SUVr, the zero‐order production rate constant of amyloid plaque (K _in), maximum exposure effect (E _max), and lecanemab concentration resulting in half of the maximum drug effect (EC₅₀), where K _out = K _in/baseline. The equations for Aβ42/40 ratio and p‐tau181 models are presented below: $\begin{array}{c}\mathbf{A\beta }\mathbf{42}/\mathbf{40}\mathbf{\text{ratio:}}\frac{\mathrm{dR}}{\mathrm{dt}}={\mathrm{K}}_{\text{in}}\bullet \left[1+\text{Slope}\bullet \text{Conc}\right]-\mathrm{R}\left(t\right)\bullet {\mathrm{K}}_{\text{out}}\hfill \end{array}$ $\begin{array}{c}\mathbf{p}\mathbf{-}\mathbf{tau}\mathbf{181:}\frac{\mathrm{dR}}{\mathrm{dt}}={\mathrm{K}}_{\text{in}}\bullet \left[1-\text{Slope}\bullet \text{Conc}\right]-\mathrm{R}\left(t\right)\bullet {\mathrm{K}}_{\text{out}}\hfill \end{array}$ For both Aβ42/40 ratio and p‐tau181 estimated parameters included baseline, first order degradation rate constant of biomarker (K _out) and slope for exposure effect, where K _in = K _out * baseline.

FIGURE 2

Effect of covariates on lecanemab AUC and C _max at steady‐state after 10 mg/kg biweekly. Covariate effects are expressed as lecanemab exposures at steady‐state relative to a reference subject. Body weight and albumin test categories (51 and 99 kg for body weight, 38 and 48 g/L for albumin) represent the 5% and 95% percentiles of PK analysis set, respectively. Plot displays relative change in a parameter with uncertainty as 90% CIs for each covariate relative to the reference 73.4 kg male, non‐Japanese subject who was administered process A formulation and is ADA negative. Filled circle and triangle: median of AUC and C _max, horizontal line: 90% CI, gray area: acceptance interval (0.80–1.25), vertical dashed line: reference. ADA, anti‐drug antibody; AUC, area under the curve; CI, confidence interval; C_max, maximum concentration; PK, pharmacokinetic.

FIGURE 3

Prediction‐corrected visual predictive check plots for PK/PD models for PET SUVr and plasma Aβ42/40 ratio and p‐tau181 (left: core placebo, right: core 10 mg/kg biweekly). Black solid line: predicted median, black dashed line: predicted 5th and 95th percentiles, red solid line: observed median, red dashed line: observed 5th and 95th percentiles, green area: 95% CI for predicted 95th percentile, red area: 95% CI for predicted median, blue area: 95% CI for predicted 5th percentile. CI, confidence interval; OLE, open‐label extension; PD, pharmacodynamic; PET, positron emission tomography; PK, pharmacokinetic; SUVr, standard uptake ratio.

FIGURE 4

Model‐predicted SUVr and plasma Aβ42/40 ratio and p‐tau181 following 18 months treatment with lecanemab at 10 mg/kg biweekly or 10 mg/kg monthly. Black dashed line in SUVr plot represents SUVr = 1.17, indicating amyloid negative line. For SUVr, baseline SUVr = 1.38 (median of Study 201) was assumed. Pink solid line and shaded area: predicted median and 95% CI for 10 mg/kg biweekly, blue solid line and shaded area: predicted median and 95% CI for 10 mg/kg monthly. CI, confidence interval; PET, positron emission tomography; SUVr, standard uptake ratio.

FIGURE 5

Model‐predicted SUVr and plasma Aβ42/40 ratio and p‐tau181 following continuous 10 mg/kg biweekly with or without treatment discontinuation. Black horizontal dashed line in SUVr plot represents SUVr = 1.17, indicating amyloid negative line. Black vertical dotted lines represent time = 1.5 years (18 months). Pink solid line: continuous 10 mg/kg biweekly for 15 years, black solid line: 10 mg/kg biweekly for 18 months followed by treatment discontinuation. PET, positron emission tomography; SUVr, standard uptake ratio.