Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor

• Published in: Alzheimer's & dementia : translational research & clinical interventions Vol. 2; no. 3; pp. 202 - 212
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016; Elsevier
• Subjects: Alzheimer's disease; Amyloid β; BACE inhibitors; BACE1; JNJ-54861911; Neurology; Other; β-secretase enzyme; JNJ-54861911; BACE1; BACE inhibitors; Alzheimer's disease; Amyloid β; β-secretase enzyme
• ISSN: 2352-8737; 2352-8737
• DOI: 10.1016/j.trci.2016.08.001

Abstract 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.