Treatment of Alzheimer's Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study

Article type: Research Article

Authors: del Ser, Teodoro^{a; *} | Steinwachs, Klaus C.^b | Gertz, Hermann J.^c | Andrés, María V.^a | Gómez-Carrillo, Belén^a | Medina, Miguel^{a; 1} | Vericat, Joan A.^{a; 2} | Redondo, Pilar^a | Fleet, David^d | León, Teresa^a

Affiliations: [a] Medical Director, Medical Department, Noscira SA, Madrid, Tres Cantos, Spain | [b] Institute of Psychogerontology, University Erlangen-Nuremberg, Nüemberg, Germany | [c] Memory Clinic, Department of Psychiatry, University of Leipzig, Leipzig, Germany | [d] Statistical Consultant, Data Magik Ltd., London, UK

Correspondence: [*] Correspondence to: Teodoro del Ser, Medical Director, Noscira SA, Avda. de la Industria 52, 28760 Tres Cantos, Madrid, Spain. Tel.: +34 918061130; Fax: +34 91803 46 60; E-mail: [email protected].

Note: [1] Current affiliation: Biomedical Research Networking Center on Neurodegenerative Diseases, Madrid, Spain.

Note: [2] Dr. Joan A. Vericat passed away on 4 July 2012. We are indebted to his warm and continuous collaboration and would like to dedicate this paper to his memory.

Abstract: This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 × ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD.

Keywords: Alzheimer's disease, clinical trial, glycogen synthase kinase-3, pharmacological treatment, tideglusib

DOI: 10.3233/JAD-2012-120805

Journal: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 205-215, 2013