Subcutaneous Dose Selection of Lecanemab for Treatment of Subjects with Early Alzheimer’s Disease (EAD)

Abstract

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils. Lecanemab 10 mg/kg IV biweekly dose (10BW) is being evaluated in the Clarity AD Phase 3 study in Early AD. A Phase 1 study was conducted to assess the absolute bioavailability (BA) of subcutaneous (SC) administration relative to IV infusion. Modeling and simulation analysis was conducted to demonstrate equivalence of a fixed weekly SC dose to body weight‐based IV 10BW dose with regard to lecanemab exposure, safety and efficacy.MethodBased on estimates of BA and absorption rate constant from Phase 1 and the population PK model describing lecanemab PK after IV infusion, estimates of the area under the concentration‐time curve (AUC) and maximum concentration (Cmax) at steady‐state were generated for the proposed fixed SC dose and IV 10BW. Exposure‐response simulations were conducted to compare positron emission tomography (PET) standard uptake ratio (SUVr)as a measure of pharmacodynamic effect, and incidence of amyloid related imaging abnormality‐E (ARIA‐E) as a measure of safety between SC and IV doses. The impact of body weight on the lecanemab exposure, reduction in amyloid PET SUVr and ARIA‐E risk when administered as a fixed SC dose and body weight‐based IV dose were explored.ResultPhase 1 data support a proposed fixed lecanemab SC dose of 720 mg administered weekly (720W). PK simulations demonstrate that the AUC of SC 720W were similar to IV 10BW. Exposure‐response simulations demonstrate comparable reduction in amyloid PET SUVr following SC 720W and IV 10BW, and lower incidence of ARIA‐E in SC 720W due to lower Cmax following SC administration. Lecanemab exposure differences between a fixed SC dose and body weight‐based IV dose were observed at the extremes of body weight; however, this did not have a meaningful effect on the reduction in PET SUVr and ARIA‐E risk.ConclusionThis analysis demonstrates that the proposed SC 720W results in equivalent AUC predicted to attain a comparable reduction in amyloid PET SUVr and a lower Cmax predicted to produce a lower incidence of ARIA‐E compared to IV 10BW.