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

Abstract

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).

Lanabecestat: Neuroimaging results in early symptomatic Alzheimer's disease

“…21 MRI analyses of brain volumes after atabecestat exposure in people with preclinical AD and MCI due to AD did not show a clear treatment-related difference. 22 Significantly greater decrease in whole brain volume was observed for lanabecestat 20 mg and 50 mg groups in (A) AMARANTH and for lanabecestat 50 mg group in (B) DAYBREAK-ALZ compared to placebo. Significantly greater decrease in hippocampal volume was observed for lanabecestat 20 mg and 50 mg groups compared to placebo in (C) AMARANTH, but not in (D) DAYBREAK-ALZ.…”

Physiological Roles of Monomeric Amyloid-β and Implications for Alzheimer’s Disease Therapeutics

“…Given the potential clinical significance and market effects of AD therapeutics, there have been many attempts to target Aβ using various approaches focusing on different stages of the amyloid cascade ( Table 1 ) [ 185 - 228 ]. For example, inhibitors of Aβ-related secretases aim to decrease the production of Aβ itself as a preventative measure, while anti-Aβ immunotherapies induce partial or complete clearance of Aβ at the end of the amyloid cascade.…”

Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease

“…It inhibits APP cleavage by the enzyme BACE and thus reduces Aβ level in cerebrospinal fluid (CSF). Results of long-term safety and tolerability of atabecestat in the early AD patients evaluated through a randomized, double-blind, placebo-controlled study and a two-period extension study showed it to be associated with a trend toward declines in cognition, and elevation of liver enzymes [ 54 ].…”