Figure 5.
SAD CSF sampling study in healthy volunteers. Single doses of 30 or 90 mg of BACE inhibitor LY2811376 administered to healthy human subjects resulted in significant biomarker changes in plasma and CSF. A, Plasma concentrations of Aβ1–40 decreased in a dose-dependent manner, with the 90 mg dose producing an observed mean nadir of −80.0%. B, C, CSF concentrations of Aβ1–40 and Aβ1–42 significantly decreased relative to placebo, with a 90 mg dose producing observed mean nadirs of −58.0 and −58.1%, respectively. In placebo-treated subjects, CSF concentrations of Aβ1–40 and Aβ1–42 increased over time without a return to baseline, suggesting a procedural phenomenon rather than diurnal effect. The average predose baseline CSF concentrations of Aβ1–40 and Aβ1–42 were ∼5300 and 650 pg/ml, respectively. D, E, Administration of LY2811376 resulted in decreases in CSF concentration of sAPPβ and increases in CSF concentration of sAPPα, providing direct evidence of the mechanism of action of LY2811376 in the CNS of man. Data are presented as mean ± SD and n = 10 for all graphs.