A Phase II Trial of Tideglusib in Alzheimer's Disease
Abstract
BACKGROUND: The ARGO study was a phase II, double-blind, placebo controlled, four parallel arm trial of tideglusib in Alzheimer's disease (AD). OBJECTIVE: To prove the clinical efficacy of an inhibitor of glycogen synthase kinase-3 (GSK-3), in AD. METHODS: Mild to moderate (Mini-Mental State Examination (MMSE) score, 14-26) AD patients on cholinesterase inhibitor and/or memantine treatment were administered tideglusib or placebo for 26 weeks. The ADAS-cog15 was the primary efficacy measure; function, cognition, behavior, and quality of life were assessed as secondary measures; cerebral atrophy in MRI and the levels of tau, amyloid-β, and BACE1 in cerebrospinal fluid (CSF) were exploratory endpoints. RESULTS: 306 AD patients were randomized to active (1000 mg QD: n = 86, 1000 mg QOD: n = 90, and 500 mg QD: n = 50) or placebo (n = 85) in 55 sites in four European countries. There were no statistically significant differences between either active and placebo arms in the efficacy variables. However, BACE1 in CSF significantly decreased with treatment in a small subgroup of patients. Participants with mild AD in the 500 mg QD group showed significant responses on ADAS-cog15, MMSE, and word fluency. Diarrhea (14-18% in active, 11% placebo) and dose-dependent, mild to moderate, and fully reversible transaminase increase (9-16% in active, 3.5% placebo) were the most frequent adverse events. CONCLUSIONS: Short term (26 weeks) tideglusib was acceptably safe but produced no clinical benefit in this trial. However, given the non-linear dose response, especially in mildly affected patients, further dose finding studies in early disease stages and for longer duration are warranted to examine GSK-3 inhibition in AD patients.
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This lack of efficacy may be due to critical role of GSK-3 in multifunctional signaling pathways.
“Moreover, use of tau kinase inhibitors such as the GSK-3 inhibitor Tideglusib to attenuate pathological tau hyperphosphorylation also showed little or no efficacy in Phase 2 trials, probably due to the critical role of GSK-3 in multifunctional signaling pathways [650, 651].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [650]
Use of tau kinase inhibitors such as GSK-3 inhibitor Tideglusib to attenuate pathological tau hyperphosphorylation showed little or no efficacy in Phase 2 trials.
“Moreover, use of tau kinase inhibitors such as the GSK-3 inhibitor Tideglusib to attenuate pathological tau hyperphosphorylation also showed little or no efficacy in Phase 2 trials, probably due to the critical role of GSK-3 in multifunctional signaling pathways [650, 651].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [650]
Clinical studies in patients with mild-to-moderate AD or PSP treated with tideglusib were negative on clinical outcomes.
“The clinical studies in patients with mild-to-moderate AD (NCT01350362, NCT00948259) or PSP (NCT01049399) patients treated with tideglusib were negative on the clinical outcomes [218]; however, a subgroup analysis of PSP patients showed reduced brain atrophy [219].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [218]
A phase 2 trial of tideglusib in mild to moderate Alzheimer disease did not reduce rate of cognitive or functional decline compared to placebo.
“However, a phase 2 trial in mild to moderate AD did not demonstrate any reduction in rate of cognitive or functional decline as compared to placebo (Lovestone et al., 2015)”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Lovestone et al., 2015
Tideglusib failed to improve cognition in a phase 2 clinical study, and CSF levels of Aβ42, total tau, and pTau181 were not altered.
“Tideglusib, a small-molecule GSK3β inhibitor, failed to improve cognition in a phase 2 clinical study, and CSF levels of Aβ42, total tau, and pTau181 were not altered, resulting in failure of the trial [175,176].”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [176]
In a larger phase II study, tideglusib treatment was associated with significant cognitive improvement and a reduction in CSF levels of β-secretase in a subgroup of patients with mild AD, but when the entire study cohort was analysed, tideglusib produced no significant improvements.
“In a larger phase II study, tideglusib treatment was associated with significant cognitive improvement and a reduction in CSF levels of β-secretase in a subgroup of patients with mild AD122. However, when the entire study cohort was analysed, tideglusib was found to be well tolerated but produced no significant improvements122.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [122]
Tideglusib did not meet phase 2 clinical endpoints in patients with mild and moderate AD.
“Another GSK-3 inhibitor, tideglusib, did not meet phase 2 clinical endpoints in patients with mild and moderate AD.80”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [80]
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- Authors
- Lovestone, S., for the ARGO investigators, Boada, M., Dubois, B., Hüll, M., Rinne, J. O., Huppertz, H.-J., Calero, M., Andrés, M. V., Gómez-Carrillo, B., León, T., & del Ser, T.
- Affiliations
- University of Oxford (GB)
- Fundació ACE (ES)
- Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
- Inserm (FR)
- University of Turku (FI)
- Instituto de Salud Carlos III (ES)
- Clinical Department, Noscira SA, Madrid, Spain
- Medical Department, Noscira SA, Madrid, Spain
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2015-03-03
- Volume
- 45
- Issue
- 1
- Pages
- 75-88
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1522284801
- Cited by
- 536
- References
- 47
- Citations by year
- 2026: 44 · 2025: 67 · 2024: 59 · 2023: 46 · 2022: 38 · 2021: 59 · 2020: 61 · 2019: 31 · 2018: 46 · 2017: 39 · 2016: 31 · 2015: 14
- FWCI
- 32.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10053)
- 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
- tideglusib, Alzheimer's disease
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Dose-Response Relationship, Drug, Double-Blind Method, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Thiadiazoles, Amyloid beta-Peptides, Neuroprotective Agents
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