Open AccessProfiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ‐54861911, a potent oral BACE inhibitor
Author(s) -
Timmers Maarten,
Van Broeck Bianca,
Ramael Steven,
Slemmon John,
De Waepenaert Katja,
Russu Alberto,
Bogert Jennifer,
Stieltjes Hans,
Shaw Leslie M.,
Engelborghs Sebastiaan,
Moechars Dieder,
Mercken Marc,
Liu Enchi,
Sinha Vikash,
Kemp John,
Van Nueten Luc,
Tritsmans Luc,
Streffer Johannes Rolf
Publication year - 2016
Publication title -
alzheimer's and dementia: translational research and clinical interventions
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.49
H-Index - 30
ISSN - 2352-8737
DOI - 10.1016/j.trci.2016.08.001
Subject(s) - pharmacokinetics , tolerability , pharmacodynamics , dosing , medicine , pharmacology , placebo , adverse effect , pathology , alternative medicine
Objectives Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, JNJ‐54861911, were assessed after single and multiple dosing in healthy participants. Methods Two randomized, placebo‐controlled, double‐blind studies were performed using single and multiple ascending JNJ‐54861911 doses (up to 14 days) in young and elderly healthy participants. Regular blood samples and frequent CSF samples, up to 36 hours after last dose, were collected to assess the pharmacokinetic and pharmacodynamic (Aβ, sAPPα,β,total levels) profiles of JNJ‐54861911. Results JNJ‐54861911 was well‐tolerated, adverse events were uncommon and unrelated to JNJ‐54861911. JNJ‐54861911 showed dose‐proportional CSF and plasma pharmacokinetic profiles. Plasma‐ and CSF‐Aβ and CSF‐sAPPβ were reduced in a dose‐dependent manner. Aβ reductions (up to 95%) outlasted exposure to JNJ‐54861911. APOE ε4 carrier status and baseline Aβ levels did not influence Aβ/sAPPβ reductions. Conclusion JNJ‐54861911, a potent brain‐penetrant BACE1 inhibitor, achieved high and stable Aβ reductions after single and multiple dosing in healthy participants.