Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: Randomized, double-blind, placebo-controlled study
Open accessAbstract
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. 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. 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. 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. ALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015.
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β-secretase inhibitors such as lanabecestat, verubecestat, and atabecestat target Bace-1 to decrease synthesis of amyloid beta.
“In order to decrease the synthesis of amyloid beta, β-secretase inhibitors (BACE inhibitors) such lanabecestat (labeled as 8, Figure 5) [157,161,162], verubecestat (labeled as 9, Figure 5) [157,163,164], and atabecestat (labeled as 10, Figure 5) target the enzyme Bace-1 [157,165].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [165]
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- Authors
- Timmers, M., Streffer, J. R., Russu, A., Tominaga, Y., Shimizu, H., Shiraishi, A., Tatikola, K., Smekens, P., Börjesson-Hanson, A., Andreasen, N., Matias-Guiu, J., Baquero, M., Boada, M., Tesseur, I., Tritsmans, L., Van Nueten, L., & Engelborghs, S.
- Affiliations
- Janssen (Belgium) (BE)
- Janssen Pharmaceutical K.K. (Japan) (JP)
- Janssen Research & Development (United States) (US)
- Karolinska Institutet (SE)
- Hospital Universitari i Politècnic La Fe (ES)
- University of Antwerp (BE)
- Corresponding author
- Timmers, Maarten
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2018-08-23
- Volume
- 10
- Issue
- 1
- Pages
- 85-85
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC6106931
- OpenAlex
- W2888033839
- Cited by
- 112
- References
- 22
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 18 · 2023: 10 · 2022: 12 · 2021: 22 · 2020: 18 · 2019: 13 · 2018: 2
- FWCI
- 9.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Janssen Research & Development, a division of Janssen Pharmaceutica N.V., Beerse, Belgium
- Janssen Pharmaceutical K.K. Japan
- Flanders Innovation & Entrepreneurship (VLAIO), Belgium (IWT 120834)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- BACE1 inhibitors, Alzheimer's disease, preclinical Alzheimer's disease, pharmacodynamics, pharmacokinetics, Japanese patients, Caucasian patients, pharmacokinetic-pharmacodynamic modeling, CNS penetration, mild cognitive impairment, drug safety
- MeSH terms
- Administration, Oral, Aged, Alzheimer Disease, Double-Blind Method, Female, Humans, Male, Peptide Fragments, Pyridines, Thiazines, Biomarkers, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, tau Proteins, Treatment Outcome, White People, Asian People, Amyloid Precursor Protein Secretases
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