Preliminary Update on Lecanemab Safety in Clarity AD Open-Label Extension, Including Subcutaneous Formulation

Background: Lecanemab is an anti‐amyloid antibody that has been approved by the United States FDA for treatment of early Alzheimer's disease (AD). Lecanemab 10 mg/kg every 2 weeks (Q2W) intravenously (IV) was shown in the Clarity AD trial to slow the progression of AD. Pharmacokinetic/ pharmacodynamic (PK/PD) modeling demonstrated that lecanemab average steady‐state concentrations (Cav, ss) are associated with amyloid plaque lowering and efficacy, while maximum steady‐state concentrations (Cmax, ss) tended to be more strongly correlated with the incidence of amyloid‐related imaging abnormalities‐edema (ARIA‐E). Lecanemab SC is being tested in the Clarity AD open‐label extension (OLE) to test the hypothesis that a subcutaneous lecanemab formulation with similar Cav, ss but lower Cmax, ss will have similar or better safety profile by lowering the rates of ARIA‐E and infusionrelated reactions. Objective: To provide an update on the safety profile of lecanemab, including and immunogenicity (neutralizing antibodies (Nab) and anti‐drug antibodies [ADA]) assessments from the intravenous lecanemab clinical trials. In addition, a preliminary safety data update on the subcutaneous lecanemab formulation that is currently in development. Methods: Clarity AD is a phase 3 multicenter, double‐blind, placebo‐controlled, parallel‐group study of 18‐month treatment duration with OLE in patients with early AD with confirmed amyloid pathology. Eligible patients are randomized to placebo or 10 mg/kg biweekly initiated with full therapeutic dosing. Clinical assessments in both studies included Clinical Dementia Rating‐Sum‐of‐Boxes (CDR‐SB) and AD Assessment Scale‐Cognitive Subscale 14 (ADAS‐Cog14). A subcutaneous dose is under development based on PK/PD modeling and bioavailability data and is currently being assessed in a substudy of the OLE. ADA and NAb assays were developed and validated in accordance with FDA guidance and industry best practice and were performed using a tiered approach. Results: In the intravenous lecanemab Clarity AD phase 3 study, the incidence of treatment emergent positive ADA in lecanemab was 5.5%, respectively, with low titers. The incidence of ADA in phase 3 OLE study was 5.7%. The incidence of treatment emergent NAb positive was 4.1% in the phase 3 study, respectively, and characterized by low titers. ADA and NAb status did not meaningfully affect lecanemab serum concentration. The slowing of cognitive decline (CDR‐SB and ADAS‐Cog14) with lecanemab relative to placebo is not affected by the presence of ADA and NAb. The preliminary safety data on a subcutaneous formulation of lecanemab from the Clarity AD open‐label extension study will be presented, including data on ARIA‐E, ARIA‐H, and other adverse effects. The potential for a subcutaneous formulation to have an improved safety profile and more patient friendly route of administration will be discussed. Conclusions: Based on the ADA profile and minimal impact of ADA on PK, PD, efficacy, and safety, lecanemab is a low‐risk molecule for immunogenicity. The differential administration and PK profile of SC relative to IV is a potential basis for further improving the safety profile of lecanemab. Ongoing studies will confirm the safety and efficacy profiles of SC lecanemab.