Tideglusib (NP031112, Nypta, Zentylor, NP12) was a novel small molecule specifically designed as a GSK3β inhibitor, [53] and in a double transgenic mouse model overexpressing human amyloid and tau proteins (APPswe-tauvlw), tideglusib reduced tau hyperphosphorylation and aggregation, protected against neuronal loss, and prevented memory deficits. [54] Tideglusib was well-tolerated in an early trial in 30 patients with mild to moderate AD [55], but in ARGO, a larger Phase 2 trial enrolling 306 CE patients, treatment with tideglusib for 26 weeks did not show clinical efficacy despite apparent pharmacodynamic effect as measured by changes in BACE1 levels in the CSF [56]. Similar results were seen in TAUROS, a Phase 2 trial in 146 patients with progressive supranuclear palsy, where 52 weeks of treatment with tideglusib was well-tolerated but lacked efficacy in the primary outcome of disease progression (PSP Rating Scale) [57,58]. Due to the results of the ARGO and TAUROS trials, tideglusib is no longer in development for neurodegenerative disease, though ongoing trials are evaluating efficacy in myotonic dystrophy (NCT02858908) and autism spectrum disorder (NCT02586935).
