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

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.

Further understanding of tau phosphorylation: implications for therapy

“…A placebo-controlled, escalating-dose Phase IIa clinical trial in 30 patients with mild-to-moderate AD treated for 20 weeks showed positive trends on the MMSE and ADAS-Cog tests [50]. The compound, with orphan drug status designation by both US FDA and EMA, was also tested in a 1-year study (TAUROS) in 146 patients with PSP, but despite a signal toward reduced brain atrophy in a subgroup analysis [51], the study primary end points were not met [52].…”

Chemical Modulators of Protein Misfolding, Neurodegeneration and Tau

“…It increases the levels of neurotrophic peptide insulin growth factor 1 (IGF-1), and promotes endogenous hippocampal neurogenesis in vitro and in vivo through GSK-3b inhibition [11]. Clinical trials with tideglusib show good tolerability (Phase I study, healthy volunteers, oral daily dosages between 50 and 1200 mg, up to 14 days) [12]. A Phase IIa study on 30 AD patients (400 to 1000 mg daily, p.o., 15 weeks) confirms the good tolerability of tideglusib and provides signs of efficacy in mild to moderate AD patients [11].…”

Inibidores Da GSK-3: Uma Nova Estratégia Para a Regeneração Dental

“…Um dos compostos da classe das TDZDs, conhecido como tideglusibe (Figura 2), foi planejado para o tratamento da doença de Alzheimer e da paralisia supranuclear progressiva, atuando como um inibidor reversível da GSK-3α α β (TOLOSA et al, 2014;HOGLINGER et al, 2014;DEL SER et al, 2013). A proposta da ligação de tiazolidinedionas como o tideglusibe à isoforma α , envolve a interação com o sítio de ligação do substrato por ligações de hidrogênio por meio dos aminoácidos arginina 96 e lisina 205 e interações de elétrons com a tirosina 216 da estrutura da enzima (SILVA et al, 2014).…”