Population pharmacokinetics and exposure-response analyses of amyloid PET SUVr and plasma biomarkers Aβ42/40 ratio and p-tau181 for lecanemab in subjects with early Alzheimerís disease
Seiichi Hayato (1), Osamu Takenaka (1), Sree Harsha Sreerama Reddy (2), Larisa Reyderman (2), Akihiko Koyama (2), Chad Swanson (2), Sanae Yasuda (2), Ziad Hussein (3)
(1) Eisai Co., Ltd., Tokyo, Japan, (2) Eisai Inc., Nutley, NJ, USA, (3) Eisai Ltd., Hatfield, UK
Introduction/Objectives: Lecanemab (BAN2401) is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregate species, while demonstrating low affinity for Aβ monomers. The objective of this analysis was to describe the population pharmacokinetics (PK) and exposure-response (E-R) analyses for amyloid plaques, as measured using positron emission tomography (PET), and biomarkers of amyloid pathology as evidenced by plasma Ab42/40 ratio and p-tau181 following IV administration of lecanemab in subjects with early Alzheimer’s disease (EAD).
Methods: Phase 2 Study 201 core was an 18-month multicenter, double-blind, placebo-controlled study evaluating 5 lecanemab dosing regimens and placebo in patients with EAD. Study 201 open-label extension (OLE) was initiated to allow patients to receive open-label lecanemab 10 mg/kg-biweekly for up to 24 months. There was a gap period of at least 9 months without treatment between the last dose in the Core Study and the first dose in the OLE Phase. PK analysis was performed on pooled data from two Phase 1 studies and Study 201 core and OLE. The final population PK model was used to derive the post hoc estimates of individual PK parameters that were used in the subsequent E-R analyses. The E-R analyses for amyloid PET standard uptake ratio (SUVr) and plasma Ab42/40 ratio and p-tau181 were performed on data from subjects with EAD receiving either lecanemab or placebo who participated in Study 201 core and OLE. Covariates were selected based on clinical relevance and biological plausibility and tested using a stepwise approach. Final PK and E-R models were evaluated for performance using goodness-of-fit plots, simulated prediction-corrected visual predictive checks and non-parametric bootstrapping.
Results: The PK dataset included 9027 serum lecanemab observations, from 725 subjects. The amyloid PET SUVr E-R dataset included 1213 observations from 374 subjects from Study 201 core and OLE. There was a total of 2021 observations from 562 subjects in the plasma p-tau181 dataset and a total of 1254 observations from 284 subjects in the plasma Aβ42/40 ratio dataset, both from Study 201 core and OLE. Lecanemab PK was best characterized with a two-compartment model with first-order elimination. Final PK model contained covariate effects of anti-drug antibody (ADA) positive status, sex, body weight and albumin on clearance and sex and body weight on central volume of distribution. The time course of amyloid PET SUVr and plasma Ab42/40 ratio and p-tau181 were described using indirect response models with lecanemab exposure as an Emax function stimulating the reduction of amyloid PET SUVr, and as a linear function increasing Ab42/40 ratio and decreasing p-tau181 formation rates. Based on E-R analysis for amyloid PET SUVr the time for amyloid re-accumulation to reach 50% recovery of baseline level (recovery half-life) is estimated to be approximately 4 years. The recovery half-life of plasma Aβ42/40 ratio level to baseline level prior to initiating lecanemab treatment is estimated to be approximately 1.9 years which is comparable to that for plasma p-tau181 (approximately 1.5 years) but shorter than that for amyloid PET SUVr. E-R simulations show that 10 mg/kg biweekly dosing results in larger and faster decrease in amyloid PET SUVr and p-tau181 and larger and faster increase in Ab42/40 ratio as compared to 10 mg/kg monthly dose. Simulations also suggest that beyond the recommended dosing regimen of 10 mg/kg biweekly for 18 months amyloid negativity (PET SUVr: <1.17) is predicted to be maintained with less frequent monthly or every 3 months dosing whereas plasma p-tau181 and Ab42/40 ratio are predicted to be maintained with monthly dosing pending future study results.
Conclusions: The developed PK and E-R models provide insights in the effect of lecanemab dosing on the extent of brain amyloid removal and plasma biomarkers of amyloid and tau pathology. These models can be used to inform lecanemab dose regimens in future clinical studies.
 Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alz Res Therapy. 2021; 13, 80.