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.
Alzheimers Res Ther
; 12(1): 58, 2020 05 14.
Article
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| MEDLINE
| ID: mdl-32410694
ABSTRACT
BACKGROUND:
Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aß), 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 (111) 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 Aß fragments and sAPPß 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.Palabras clave
Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Secretasas de la Proteína Precursora del Amiloide
/
Enfermedad de Alzheimer
Límite:
Humans
Idioma:
En
Revista:
Alzheimers Res Ther
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos