P4‐366: GSI‐953, a potent and selective gamma‐secretase inhibitor: Modulation of beta‐amyloid peptides and plasma and cerebrospinal fluid pharmacokinetic/pharmacodynamic relationships in humans

Abstract

A promising Alzheimer's Disease (AD) therapeutic strategy is the reduction of pathogenic beta amyloid peptide (Aβ) through inhibition of the enzyme gamma secretase (GS). Aβ peptides can serve as biomarkers of pharmacodynamic activity of GS inhibitors (GSI). Here, we report the pharmacokinetics of our Notch-selective GSI-953, and the pharmacodynamic effects on Aβ biomarkers in plasma and cerebrospinal fluid (CSF) in healthy human subjects and subjects with AD. Plasma was obtained following single oral administration of GSI-953 in healthy young, healthy elderly and AD subjects. CSF was sampled via an indwelling lumbar catheter over a 24hr (healthy young subjects) or 12hr period (AD subjects). Aβ40 and Aβ42 were measured using immunoassays and GSI-953 levels were determined using a validated LC/MS/MS assay. Following single dose oral administration, GSI-953 concentration-time profile was characterized by rapid absorption (tmax 1–2 hrs). Mean GSI-953 Cmax and AUC increased in an approximately linear dose proportional manner. GSI-953 clearance was approximately 40% lower in the elderly in comparison to young subjects. Consequently, GSI-953 AUC was 1.6- to 2.0-fold higher in elderly at identical doses and elimination t1/2 was slightly prolonged from 5–6 hrs in young to 8–9 hrs in elderly subjects. In comparison to plasma, GSI-953 absorption into the CSF and mean elimination t1/2 in CSF was also slightly prolonged in AD patients compared to young subjects (10.6 vs. 8.5 hours). CSF concentrations (AUC) of GSI-953 were 10-fold lower than plasma. Plasma:CSF AUC ratios of GSI-953 were similar between young and AD subjects. GSI-953 was well-tolerated and no dose-limiting AEs were observed, including those expected for Notch inhibition. Plasma Aβ but not CSF Aβ levels were dose-dependently reduced following single oral doses of GSI-953 in healthy young, healthy elderly and AD subjects. A mean maximum reduction in Plasma Aβ40 and Aβ42 of 40% and 14%, respectively was observed at the highest doses tested. These data demonstrate that single doses of GSI-953 are safe and produce dose-dependent reductions of plasma but not CSF Aβ peptides in humans. GSI-953 PK demonstrates linear dose proportionality and the plasma:CSF AUC ratio is identical between young and AD subjects.