Pharmacokinetic and Pharmacodynamic Effects of a γ-Secretase Modulator, PF-06648671, on CSF Amyloid-β Peptides in Randomized Phase I Studies

gamma-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-beta (A beta) 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 A beta 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 A beta 42 and A beta 40 concentrations in CSF, with greater effects on A beta 42, and increased A beta 37 and A beta 38 levels, particularly A beta 37. No significant change in total A beta was observed. The PK/PD model well described the tendency of observed CSF A beta data and the steady-state effects of PF-06648671, supporting its use for predicting central A beta effects and optimal dose selection for GSMs in future trials.