Leniolisib pharmacodynamics: time- and dose-dependent PI3K/AKT pathway activity in B cells. (A) Whole blood from leniolisib-treated patients was stimulated ex vivo at the indicated dose and day with anti-IgM and IL-4 for 20 minutes. Then intracellular levels of pAKT(S473) were quantified by flow cytometry. The dotted line and asterisk indicate that the 12-hour values are mean from pooled data at day 8 and day 15. Data are shown as mean values of the indicated number of patients with SD. (B) Individual observed leniolisib blood exposure and pAKT inhibition in ex vivo–stimulated blood from APDS patients (circles) and results of Emax concentration-response model (line). Data points represent cumulated measurements of all 6 patients at multiple doses and time points. pAKT inhibition is defined as (−1) × percentage change from baseline pAKT value. Vertical lines represent from left to right: half maximal effective concentration (EC₅₀), 70% effective concentration (EC₇₀), and 90% effective concentration (EC₉₀) values.