title: 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.
authors.affiliation: Medical Director, Medical Department, Noscira SA, Madrid, Tres Cantos, Spain. tdeserq@meditex.es
authors.forename: Teodoro
authors.initials: T
authors.lastname: del Ser
authors.forename: Klaus C
authors.initials: KC
authors.lastname: Steinwachs
authors.forename: Hermann J
authors.initials: HJ
authors.lastname: Gertz
authors.forename: María V
authors.initials: MV
authors.lastname: Andrés
authors.forename: Belén
authors.initials: B
authors.lastname: Gómez-Carrillo
authors.forename: Miguel
authors.initials: M
authors.lastname: Medina
authors.forename: Joan A
authors.initials: JA
authors.lastname: Vericat
authors.forename: Pilar
authors.initials: P
authors.lastname: Redondo
authors.forename: David
authors.initials: D
authors.lastname: Fleet
authors.forename: Teresa
authors.initials: T
authors.lastname: León
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D013830:Thiadiazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D002800:Cholinesterase Inhibitors; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; D038362:Glycogen Synthase Kinase 3; C520571:tideglusib