1. Inicio
  2. Publicaciones
  3. Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study

Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Timmers, M
  • Streffer, JR
  • Russu, A
  • Tominaga, Y
  • Shimizu, H
  • Shiraishi, A
  • Tatikola, K
  • Smekens, P
  • Borjesson-Hanson, A
  • Andreasen, N
  • Matias-Guiu, J
  • Boada, M
  • Tesseur, I
  • Tritsmans, L
  • Van Nueten, L
  • Engelborghs, S

Abstract

Background: beta-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. Methods: In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6-8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1-40 [A beta(1-40)] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated. Results: In both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF A beta(1-40) levels from baseline at day 28 in both the 10-mg (67-68%) and 50-mg (87-90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were - 69.37 (- 72.25; - 61.50) and - 92.74 (- 100.08; - 85.39), and for Japanese with preclinical AD, they were - 62.48 (- 78.32; - 46.64) and - 80.81 (- 96.13; - 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60-70% and 90% A beta(1-40) reductions, respectively. The trend of the reduction was similar across the A beta(1-37), A beta(1-38), and A beta(1-42) fragments in both atabecestat dose groups, consistent with A beta(1-40). CSF amyloid precursor protein fragment (sAPP beta) levels declined from baseline, regardless of patient population, whereas CSF sAPPa levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period. Conclusions: JNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF A beta(1-40) reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults.

Datos de la publicación

ISSN/ISSNe:
1758-9193, 1758-9193

Alzheimers Research & Therapy  BMC

Tipo:
Article
Páginas:
85-85
PubMed:
30134967
Factor de Impacto:
2,404 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 82

Documentos

  • No hay documentos

Métricas

Filiaciones mostrar / ocultar

Keywords

  • Atabecestat; JNJ-54861911; BACE1 inhibitor; Alzheimer's disease; Amyloid; A beta processing; PK/PD relationship

Campos de Estudio

Compartir