A Phase II Trial of Tideglusib in Alzheimer's Disease

Article type: Research Article

Authors: Lovestone, Simon^a | Boada, Mercè^b | Dubois, Bruno^c | Hüll, Michael^d | Rinne, Juha O.^e | Huppertz, Hans-Jürgen^f | Calero, Miguel^g | Andrés, María V.^h | Gómez-Carrillo, Belén^h | León, Teresaⁱ | del Ser, Teodoro^{i; *} | for the ARGO investigators

Affiliations: [a] University of Oxford, Department of Psychiatry, Oxford, UK | [b] Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain | [c] Institut de la Mémoire, INSERM U1127, ICM, Université Pierre et Marie Curie-Paris 6, Hôpital de la Salpêtrière, Paris, France | [d] Centre for Geriatric Medicine Freiburg and Emmendingen Centre for Psychiatry, Freiburg, Germany | [e] Turku PET Centre and Division of Clinical Neurosciences, University of Turku and Turku University Hospital, Turku, Finland | [f] Swiss Epilepsy Centre, Zürich, Switzerland | [g] Chronic Disease Program, CIBERNED, and CIEN Foundation, Carlos III Institute of Health, Madrid, Spain | [h] Clinical Department, Noscira SA, Madrid, Spain | [i] Medical Department, Noscira SA, Madrid, Spain

Correspondence: [*] Correspondence to: Teodoro del Ser, MD, PhD, former Medical Director, Noscira SA, Plaza del Descubridor Diego de Ordás, 3, 28003 Madrid, Spain. Tel.: +34 690091942; E-mail: teodorodelser@gmail.com.

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.

Keywords: Alzheimer's disease, GSK-3, pharmacological treatment, randomized controlled clinical trial, tideglusib

DOI: 10.3233/JAD-141959

Journal: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 75-88, 2015