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Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study
BACKGROUND: β-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 o...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106931/ https://www.ncbi.nlm.nih.gov/pubmed/30134967 http://dx.doi.org/10.1186/s13195-018-0415-6 |
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author | Timmers, Maarten Streffer, Johannes Rolf Russu, Alberto Tominaga, Yushin Shimizu, Hiroko Shiraishi, Ayako Tatikola, Kanaka Smekens, Pascale Börjesson-Hanson, Anne Andreasen, Niels Matias-Guiu, Jorge Baquero, Miquel Boada, Mercè Tesseur, Ina Tritsmans, Luc Van Nueten, Luc Engelborghs, Sebastiaan |
author_facet | Timmers, Maarten Streffer, Johannes Rolf Russu, Alberto Tominaga, Yushin Shimizu, Hiroko Shiraishi, Ayako Tatikola, Kanaka Smekens, Pascale Börjesson-Hanson, Anne Andreasen, Niels Matias-Guiu, Jorge Baquero, Miquel Boada, Mercè Tesseur, Ina Tritsmans, Luc Van Nueten, Luc Engelborghs, Sebastiaan |
author_sort | Timmers, Maarten |
collection | PubMed |
description | BACKGROUND: β-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 [Aβ(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 Aβ(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% Aβ(1–40) reductions, respectively. The trend of the reduction was similar across the Aβ(1–37), Aβ(1–38), and Aβ(1–42) fragments in both atabecestat dose groups, consistent with Aβ(1–40). CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα 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 Aβ(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. TRIAL REGISTRATION: ALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13195-018-0415-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6106931 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-61069312018-08-29 Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study Timmers, Maarten Streffer, Johannes Rolf Russu, Alberto Tominaga, Yushin Shimizu, Hiroko Shiraishi, Ayako Tatikola, Kanaka Smekens, Pascale Börjesson-Hanson, Anne Andreasen, Niels Matias-Guiu, Jorge Baquero, Miquel Boada, Mercè Tesseur, Ina Tritsmans, Luc Van Nueten, Luc Engelborghs, Sebastiaan Alzheimers Res Ther Research BACKGROUND: β-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 [Aβ(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 Aβ(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% Aβ(1–40) reductions, respectively. The trend of the reduction was similar across the Aβ(1–37), Aβ(1–38), and Aβ(1–42) fragments in both atabecestat dose groups, consistent with Aβ(1–40). CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα 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 Aβ(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. TRIAL REGISTRATION: ALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13195-018-0415-6) contains supplementary material, which is available to authorized users. BioMed Central 2018-08-23 /pmc/articles/PMC6106931/ /pubmed/30134967 http://dx.doi.org/10.1186/s13195-018-0415-6 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Timmers, Maarten Streffer, Johannes Rolf Russu, Alberto Tominaga, Yushin Shimizu, Hiroko Shiraishi, Ayako Tatikola, Kanaka Smekens, Pascale Börjesson-Hanson, Anne Andreasen, Niels Matias-Guiu, Jorge Baquero, Miquel Boada, Mercè Tesseur, Ina Tritsmans, Luc Van Nueten, Luc Engelborghs, Sebastiaan Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study |
title | Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study |
title_full | Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study |
title_fullStr | Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study |
title_full_unstemmed | Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study |
title_short | Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study |
title_sort | pharmacodynamics of atabecestat (jnj-54861911), an oral bace1 inhibitor in patients with early alzheimer’s disease: randomized, double-blind, placebo-controlled study |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106931/ https://www.ncbi.nlm.nih.gov/pubmed/30134967 http://dx.doi.org/10.1186/s13195-018-0415-6 |
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