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

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

  • Alzheimers Dement (N Y). 2016 Aug 24;2(3):202-212. doi: 10.1016/j.trci.2016.08.001.
Maarten Timmers 1 2,  Bianca Van Broeck 1,  Steven Ramael 3,  John Slemmon 4,  Katja De Waepenaert 1,  Alberto Russu 1,  Jennifer Bogert 5,  Hans Stieltjes 1,  Leslie M Shaw 6,  Sebastiaan Engelborghs 2 7,  Dieder Moechars 1,  Marc Mercken 1,  Enchi Liu 4,  Vikash Sinha 8,  John Kemp 1,  Luc Van Nueten 1,  Luc Tritsmans 1,  Johannes Rolf Streffer 1 2
Affiliations

Affiliations

  • 1 Janssen Research and Development, Janssen Pharmaceutica N.V., Beerse, Belgium.
  • 2 Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 3 SGS Life Science Services, Antwerp, Belgium.
  • 4 Janssen Research and Development LLC, La Jolla, CA, USA.
  • 5 Janssen Research and Development LLC, Raritan, NJ, USA.
  • 6 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 7 Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
  • 8 Janssen Research and Development LLC, Titusville, NJ, USA.
PMID: 29067308 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.

Keywords

Alzheimer's disease; Amyloid β; BACE inhibitors; BACE1; JNJ-54861911; β-secretase enzyme.

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