P1‐363: MONITORING THE SOLUBLE AMYLOID PRECURSOR PROTEIN ALPHA (SAPPA) AND BETA (SAPPB) FRAGMENTS IN PLASMA AND CSF FROM HEALTHY INDIVIDUALS TREATED WITH BACE INHIBITOR AZD3293 IN A MULTIPLE ASCENDING DOSE STUDY: PHARMACOKINETIC AND PHARMACODYNAMIC CORRELATE

Abstract

BACE1 catalyzes sAPP cleavage during β -amyloid (A β) peptide production and is a key therapeutic opportunity in AD. Biomarkers of target engagement and mechanism of action can yield early indications of efficacy, help set clinical doses and characterize PK/PD of candidate drugs. Clinical data for soluble fragments alpha (sAPPα) and beta (sAPPβ) were collected during a Multiple Ascending Dose study in elderly Healthy Volunteers, with the BACE inhibitor AZD3293. Based upon known sAPP metabolism, we hypothesized that a dose dependent decrease of sAPP β, and increase of sAPPα, would result from BACE1 inhibition in this study. Methods to quantitate alpha (sAPPα) and beta (sAPPβ) fragments in human matrices were developed. CSF and plasma in healthy volunteers were sampled pre-treatment and during 24h continuous CSF sampling after 14 days of 15 and 50 mg dosing. Plasma and CSF sAPP α and β data were compared to corresponding AZD3293 concentration data to assess PK/PD correlations. A dose-dependent sustained decrease in CSF of sAPPβ, and broadly dose-dependent increase of sAPPα, were observed. While sAPPα levels generally increased, data were variable with no apparent dose dependency. Within the linear range of the sAPPβ assay, a direct correlation between AZD3293 concentration (Cmax) and sAPPβ inhibition was observed on a similar timeline to effects seen for A β4 0/42 (data not shown). The observations are consistent with the hypothesized mechanism of action of AZD3293 and indicate that sustained inhibition of BACE1 leads to reduced sAPP β levels and increased flux through the non-pathogenic α- secretase-mediated pathway. Therefore, measures of amyloid metabolism other than Aβ42/40 have significant utility in determining PK/PD relationships in BACE1 inhibition.