Subcutaneous (SC) lecanemab is predicted to achieve comparable efficacy and improved safety compared to lecanemab IV in early Alzheimer’s disease (AD)

Abstract Background Lecanemab is an anti‐amyloid antibody that has been approved by the United States FDA for treatment of early AD under the accelerated approval pathway. 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) are correlated with the incidence of amyloid‐related imaging abnormalities‐edema (ARIA‐E). SC lecanemab is being developed to improve patient convenience and safety profile by lowering the rate of ARIA‐E. Method Two single‐dose studies (NCT05045716 and NCT05533801) were conducted in healthy subjects to establish absolute bioavailability of a drug‐in‐vial (SC vial) formulation and to compare PK of SC vial and autoinjector (AI). In the first study, subjects were administered 10 mg/kg IV Q2W or 700 mg SC vial once‐weekly (QW) lecanemab (n = 30/arm). In the second study, subjects were administered 720 mg SC vial or 720 mg AI lecanemab (n = 80/arm). Serum lecanemab concentrations were measured for 50 days, and noncompartmental PK parameters were calculated. Result The absolute bioavailability of SC vial was 49.7% (90%CI:43.5‐56.8). Cmax following SC vial was 22.8% of IV (59.8 vs 262 µg/mL). AI had 20% higher AUC than SC vial (20900 vs 17400 µg.h/mL). PK modeling demonstrated that Cav,ss following 720 mg QW, administered by SC vial or AI, is similar to 10 mg/kg IV lecanemab. Cmax,ss following SC vial or AI will be approximately half that of IV. Based on these results, exposure‐response models predict similar amyloid plaque lowering and efficacy for IV, SC vial and AI. ARIA‐E rates are expected to be reduced with SC formulations (APOE4 carriers, IV:14.0%, SC Vial:4.8%, AI:5.6%; APOE4 noncarriers, IV:5.4%, SC Vial:1.7%, AI:2.0%). Conclusion 720mg QW using SC vial or AI results in comparable Cav,ss to 10 mg/kg Q2W IV lecanemab and is expected to have similar amyloid plaque lowering and efficacy. SC lecanemab has the potential to substantially lower incidence of ARIA‐E compared to IV. Ongoing studies will confirm the safety and efficacy profiles of SC lecanemab.