RESUMEN
γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-ß (Aß) 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 Aß 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 Aß42 and Aß40 concentrations in CSF, with greater effects on Aß42, and increased Aß37 and Aß38 levels, particularly Aß37. No significant change in total Aß was observed. The PK/PD model well described the tendency of observed CSF Aß data and the steady-state effects of PF-06648671, supporting its use for predicting central Aß effects and optimal dose selection for GSMs in future trials.
