Pharmacokinetic and pharmacodynamic effects of a γ‐secretase modulator, PF‐06648671, on CSF amyloid‐β peptides in randomized Phase 1 studies

gamma-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-beta (Abeta) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-06648671 on multiple Abeta species in cerebrospinal fluid (CSF). Healthy subjects (n = 120) received single doses or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse eventswere deemed not drug related. PF-06648671 decreased Abeta42 and Abeta40 concentrations in CSF, with greater effects on Abeta42, and increased Abeta37 and Abeta38 levels, particularly Abeta37. No significant change in total Abeta was observed. The PK/PD model well described the tendency of observed CSF Abeta data and the steady-state effects of PF-06648671, supporting its use for predicting central Abeta effects and optimal dose selection for GSMs in future trials.