Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study.

Autor: Novak G; Janssen Research and Development LLC, 1125 Trenton-Harbourton Rd, Titusville, NJ, 08560, USA. gnovak1@its.jnj.com., Streffer JR; Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.; Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.; Present address: UCB Biopharma SPRL, Chemin du Foriest, B-1420, Braine-l'Alleud, Belgium., Timmers M; Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.; Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium., Henley D; Janssen Research and Development LLC, 1125 Trenton-Harbourton Rd, Titusville, NJ, 08560, USA., Brashear HR; Janssen Research and Development LLC, 1125 Trenton-Harbourton Rd, Titusville, NJ, 08560, USA., Bogert J; Janssen Research and Development LLC, Raritan, NJ, USA., Russu A; Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium., Janssens L; Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium., Tesseur I; Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.; Present address: UCB Biopharma SPRL, Chemin du Foriest, B-1420, Braine-l'Alleud, Belgium., Tritsmans L; Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium., Van Nueten L; Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium., Engelborghs S; Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.; Department of Neurology and Center for Neurosciences, UZ Brussel and Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Jazyk: angličtina
Zdroj: Alzheimer's research & therapy [Alzheimers Res Ther] 2020 May 14; Vol. 12 (1), pp. 58. Date of Electronic Publication: 2020 May 14.
DOI: 10.1186/s13195-020-00614-5
Abstrakt: Background: Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aβ), was developed for oral treatment for Alzheimer's disease (AD). The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed.
Methods: In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85 years were randomized (1:1:1) to placebo or atabecestat 10 or 50 mg once daily (later reduced to 5 and 25 mg) for 6 months. Participants entered ALZ2004, a 12-month treatment extension with placebo or atabecestat 10 or 25 mg, followed by an open-label phase. Safety, changes in CSF biomarker levels, brain volume, and effects on cognitive performance were assessed.
Results: Of 114 participants randomized in ALZ2002, 99 (87%) completed, 90 entered the ALZ2004 double-blind phase, and 77 progressed to the open-label phase. CSF Aβ fragments and sAPPβ were reduced dose-proportionately. Decreases in whole brain and hippocampal volumes were greater in participants with mild cognitive impairment (MCI) due to AD than in preclinical AD, but were not affected by treatment. In ALZ2004, change from baseline in RBANS trended toward worse scores for atabecestat versus placebo. Elevated liver enzyme adverse events reported in 12 participants on atabecestat resulted in dosage modification and increased frequency of safety monitoring. Treatment discontinuation normalized ALT or AST in all except one with pretreatment elevation, which remained mildly elevated. No case met ALT/AST > 3× ULN and total bilirubin > 2× ULN (Hy's law).
Conclusion: Atabecestat was associated with trend toward declines in cognition, and elevation of liver enzymes.
Trial Registration: ALZ2002: ClinicalTrials.gov, NCT02260674, registered October 9, 2014; ALZ2004: ClinicalTrials.gov, NCT02406027, registered April 1, 2015.
Databáze: MEDLINE
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