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

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.

Fig. 1

Dose-dependent plasma (A) and CSF (B) Aβ_1–40 reduction with mean dose normalized plasma and CSF JNJ-54861911 concentrations in the SAD study. Aβ data are represented as mean percent change from baseline over time. 1-mg cohort was only analyzed till 24 hours after treatment. CSF analysis of 3-mg cohort was performed till 28 hours after dose (data 36 hours were rejected). Plasma and CSF JNJ-54861911 concentrations presented as mean dose normalized profiles, obtained by dose-normalizing all individual PK profiles and averaging them at each time point.

Fig. 2

Stable and dose-dependent plasma (A) and CSF (B) Aβ_1–40 reduction in the MAD study as measured 14–15 days after repeated dosing with JNJ-54861911. Data of day 14 are represented as mean percent change from baseline (day 1) over time (including 95% CI bars [CI, confidence interval]). Plasma samples were taken during a longer period (up to 72 hours) as compared to CSF (up to 36 hours).

Fig. 3

Stable reduction in Aβ species (Aβ_1–42, Aβ_1–40, Aβ_1–38, Aβ_1–37) in CSF compared to baseline as measured 14–15 days after repeated dosing with 90-mg JNJ-54861911. Data of day 14 are represented as mean percent change from baseline (day 1) over time (including 95% CI bars). Data of the 90-mg dose level presented are representative for all other cohorts. Number of participants for whom samples could be analyzed and for which levels were above LOQ is indicated below figure.

Fig. 4

CSF sAPPα increase and sAPPβ decrease in the MAD study as measured 14–15 days after repeated dosing with JNJ-54861911. Data are represented as mean of the average percent change from baseline (day 1) over 24 hours, 14–15 days after repeated dosing (± standard deviation). Total sAPP levels remained rather constant over the observation period. CSF Aβ_1–40 reduction is included to allow comparison with measured changes in sAPP species.

Fig. 5

APOE ε4 carrier status has no impact on Aβ or sAPPβ reduction. Data are represented as mean of maximum percent change from day 1 baseline on day 14 (24 hours).