PK/PD analyses of ARIA‐E and isolated ARIA‐H in Lecanemab Clarity AD study

Abstract

AbstractBackgroundClinical efficacy of lecanemab was confirmed in a Phase 3 trial (Clarity AD, NCT03887455), reducing markers of amyloid in early Alzheimer’s disease and slowing cognitive and functional decline as compared to placebo. However, some subjects experienced amyloid‐related imaging abnormalities (ARIA) associated with edema/effusion (ARIA‐E) or hemorrhage (ARIA‐H). PK/PD analyses were performed to explore the potential relationship between ARIA‐E and isolated ARIA‐H incidences with lecanemab exposure and key covariates.MethodThe Clarity AD trial randomized 1795 participants to receive lecanemab (N = 898, 10 mg/kg bi‐weekly) or placebo (N = 897). A total of 177 ARIA‐E incidences were observed from pooled Phase 2 (NCT01767311) and Phase 3 (Clarity AD) data. Additionally, a total of 150 participants from Clarity AD trial experienced treatment‐emergent isolated ARIA‐H (an ARIA‐H event without concurrent ARIA‐E). The ARIA‐E incidence rate was modeled as a function of lecanemab steady state exposures, and effects of potential covariates were explored. Graphical PK/PD analysis was performed to examine the relationship between isolated ARIA‐H and lecanemab steady‐state exposures.ResultThe observed ARIA‐E incidence was best modeled using lecanemab maximum concentration at steady‐state (Css,max) with ApoE4 genotype identified as a significant covariate. The model indicates a higher ARIA‐E incidence in homozygous carriers compared to non‐homozygous carriers or noncarriers (p<0.0001). At mean lecanemab Css,max = 305 µg/ml in subjects receiving 10 mg/kg bi‐weekly in Clarity AD, the model predicted a 5.45% (95% CI: 3.75% ‐ 7.84%) incidence of ARIA‐E in noncarriers, 9.85% (95% CI: 7.96% ‐ 12.1%) in heterozygous, and 28.0% (95% CI: 22.6% ‐ 34.1%) in homozygous carriers. No other covariate explored (age, sex, race, baseline MMSE, or occurrence of anti‐drug antibodies) had a statistically significant effect on ARIA‐E incidence. For isolated ARIA‐H, the graphical analysis identified no apparent relationship between isolated ARIA‐H incidence with lecanemab exposure. Isolated ARIA‐H incidence was associated with ApoE4 genotype, with homozygous having the highest isolated ARIA‐H incidence.ConclusionThe incidence of ARIA‐E increased with lecanemab Css,max. The incidence rate of isolated ARIA‐H was demonstrated independent of lecanemab exposure. The ApoE4 genotype impacts both ARIA‐E and isolated ARIA‐H, with increased incidences in homozygous carriers compared to heterozygous carriers or non‐carriers.